임상 논문

Despite therapeutic advances, multiple myeloma (MM) remains incurable due to the development of drug resistance by malignant plasma cells (PCs) and a severe immunosuppressive bone marrow (BM) microenvironment. Oncolytic virotherapy offers the dual benefit of tumor cell lysis and immune activation, but the efficacy of human viruses is often hampered by pre-existing antiviral immunity. Here, we demonstrated that bovine herpesvirus type 1 (BoHV-1), a virus that is nonpathogenic to humans, efficiently infected MM cells, inducing mitochondrial apoptosis and suppressing pro-survival programs, including MYC targets, oxidative phosphorylation, and the unfolded protein response. Infected tumor cells upregulated NK-activating ligands and downregulated MHC class I, enhancing susceptibility to NK-mediated cytotoxicity. In patientderived BM mononuclear cells (BMMCs), BoHV-1 selectively reduced malignant PCs and immunosuppressive myeloid subsets, while sparing lymphoid populations and hematopoietic progenitors. The infection promoted activation of CD8⁺ T cells, NK cells, and monocytes, driving a shift toward a pro-inflammatory M1-like polarization. Monocyte depletion in BMMCs attenuated the BoHV-1 anti-MM effect, confirming their functional contribution. This pronounced immune remodeling was accompanied by an inflammatory cytokine storm dominated by type I/II interferons and key innate immune mediators. Co-treatment of BoHV-1 with either bortezomib or lenalidomide increased anti-MM cytotoxicity. Finally, BoHV-1 upregulated CD38 on both MM cells and immune effectors, thereby increasing sensitivity to the anti-CD38 daratumumab. These findings establish BoHV-1 as a promising immunovirotherapy agent, effective as a single agent and in combination strategies, by coupling direct oncolysis with broad immune remodeling of the BM microenvironment. Risk of fractures may be increased in individuals with iron deficiency, iron overload, and/or HFE hemochromatosis. To test this hypothesis, we followed 142,146 Danish general population individuals for a median of 11 years (range:0-41) after study enrolment for hospital and emergency room admissions with fractures. All individuals had blood samples drawn at study enrolment. We measured iron, transferrin saturation, and ferritin in 136,611, 136,555, and 37,990 individuals, respectively, while 132,499 individuals were genotyped for the HFE C282Y and H63D variants. We found a U-shaped relationship between fracture risk and concentrations of plasma iron and transferrin saturation when studying all individuals irrespective of genotype. When studied according to plasma ferritin, fracture risk was increased in individuals with low ferritin concentrations, while risk was not increased in individuals with high concentrations. When compared to non-carriers, HFE C282Y homozygotes had increased risk of any fracture (hazard ratio[HR]:1.38;95%CI:1.09-1.75;p=0.008), and risk was increased even in C282Y homozygotes with normal ferritin concentrations (HR:2.89;95%CI:1.50-5.56), which is important as these individuals would not usually be recommended for HFE genotyping according to clinical guidelines. When compared to non-carriers, risk of fracture of the hip and femur was increased in C282Y homozygotes (HR:1.78;95%CI:1.17-2.70;p=0.007) but surprisingly also in H63D homozygotes (HR:1.21;95%CI:1.00-1.47;p=0.04), C282Y heterozygotes (HR:1.10;95%CI:1.00-1.21;p=0.04), and C282Y/H63D compound heterozygotes (HR:1.23;95%CI:1.00-1.51;p=0.05). The markedly increased fracture risk in C282Y homozygotes with normal ferritin may challenge the presumption that systemic iron accumulation is the primary mechanism causing their increased fracture risk. Further studies are needed to examine whether phlebotomy reduces fracture risk. Fertilization ensures the transmission of genetic material across generations through a series of precisely coordinated physiological and molecular events. To fertilize an oocyte, a spermatozoon must pass through the cumulus cell layer, penetrate the zona pellucida (ZP), and ultimately adhere to and fuse with the oolemma (the oocyte plasma membrane). Upon fusion, the oocyte initiates mechanisms to block additional sperm entry at both the ZP and oolemma. These processes are highly dynamic in space and time, posing substantial technical barriers to their mechanistic dissection. Nonetheless, recent in silico, in vitro, and in vivo studies have begun to elucidate how intricate networks of intracellular signaling cascades and extracellular protein-protein interactions orchestrate successful fertilization in vertebrates. However, the extent to which these findings accurately reflect the biology of human sperm-oocyte interactions remains obscure, owing to ethical constraints on human gamete experimentation and the limited availability of patients harboring pathogenic variants in fertilization-related genes. This narrative review synthesizes current knowledge of the molecular determinants governing mammalian sperm-oocyte interactions, summarizes relevant genetic anomalies identified in infertile patients, and discusses emerging experimental approaches for the direct investigation of human fertilization. We also explore how recent mechanistic insights and technological innovations may inform the diagnosis and treatment of fertilization disorders and guide the development of novel contraceptive strategies. We searched PubMed, Google Scholar, and Scopus to identify research and review articles published in English. Studies limited to non-mammalian species and non-peer-reviewed preprints were excluded. Searches used terms related to fertilization, sperm-oocyte interactions, ZP, cumulus cells, polyspermy block, and human infertility, alone or in combination. Additional searches targeted key proteins and emerging technologies relevant to mammalian fertilization, clinical diagnostics, and contraceptive development. Our mechanistic understanding of mammalian gamete interactions has predominantly stemmed from in vitro and in vivo animal studies, which have revealed key molecular processes, such as sperm hyaluronidase-mediated cumulus matrix dispersal, translocation of sperm acrosomal membrane proteins to enable oolemma interaction, and ZP glycoprotein cleavage underlying the polyspermy block. While studies in model species remain indispensable, translating this knowledge to human biology requires meticulous validation. The integration of interdisciplinary approaches, such as humanized mouse models, artificial human oocytes, xenospecies fertilization assays, antibody inhibition studies, and high-throughput interactome screening, offers promising avenues to clarify interspecies discrepancies and generate insights more directly relevant to human gamete interactions. Advances in the mechanistic dissection of sperm-oocyte interactions are anticipated to support the development of diagnostic tools and therapeutic interventions for infertility caused by defective fertilization. In parallel, these discoveries may enable the rational design of safe, reversible contraceptives that selectively block gamete interactions without compromising other physiological processes. N/A. The compositional and structural heterogeneity of plasma HDL (high-density lipoprotein) underlies its multiple proposed cardioprotective functions. This review explores current ideas for how the structural diversity of HDL particles arises during their biogenesis through ABCA1 (ATP-binding cassette transporter A1)-mediated efflux of membrane phospholipids and cholesterol to APOA1 (apolipoprotein A1), HDL's major protein. The proposed mechanisms driving the formation of nascent HDL particles, varying in size and in the number of APOA1 and lipid molecules they contain, are described. Subsequent remodeling in the plasma compartment produces HDL subspecies with distinct sets of associated proteins. The role of differently sized HDL particles in promoting reverse cholesterol transport by t

Despite therapeutic advances, multiple myeloma (MM) remains incurable due to the development of drug resistance by malignant plasma cells (PCs) and a severe immunosuppressive bone marrow (BM) microenvironment. Oncolytic virotherapy offers the dual benefit of tumor cell lysis and immune activation, but the efficacy of human viruses is often hampered by pre-existing antiviral immunity. Here, we demonstrated that bovine herpesvirus type 1 (BoHV-1), a virus that is nonpathogenic to humans, efficiently infected MM cells, inducing mitochondrial apoptosis and suppressing pro-survival programs, including MYC targets, oxidative phosphorylation, and the unfolded protein response. Infected tumor cells upregulated NK-activating ligands and downregulated MHC class I, enhancing susceptibility to NK-mediated cytotoxicity. In patientderived BM mononuclear cells (BMMCs), BoHV-1 selectively reduced malignant PCs and immunosuppressive myeloid subsets, while sparing lymphoid populations and hematopoietic progenitors. The infection promoted activation of CD8⁺ T cells, NK cells, and monocytes, driving a shift toward a pro-inflammatory M1-like polarization. Monocyte depletion in BMMCs attenuated the BoHV-1 anti-MM effect, confirming their functional contribution. This pronounced immune remodeling was accompanied by an inflammatory cytokine storm dominated by type I/II interferons and key innate immune mediators. Co-treatment of BoHV-1 with either bortezomib or lenalidomide increased anti-MM cytotoxicity. Finally, BoHV-1 upregulated CD38 on both MM cells and immune effectors, thereby increasing sensitivity to the anti-CD38 daratumumab. These findings establish BoHV-1 as a promising immunovirotherapy agent, effective as a single agent and in combination strategies, by coupling direct oncolysis with broad immune remodeling of the BM microenvironment. Risk of fractures may be increased in individuals with iron deficiency, iron overload, and/or HFE hemochromatosis. To test this hypothesis, we followed 142,146 Danish general population individuals for a median of 11 years (range:0-41) after study enrolment for hospital and emergency room admissions with fractures. All individuals had blood samples drawn at study enrolment. We measured iron, transferrin saturation, and ferritin in 136,611, 136,555, and 37,990 individuals, respectively, while 132,499 individuals were genotyped for the HFE C282Y and H63D variants. We found a U-shaped relationship between fracture risk and concentrations of plasma iron and transferrin saturation when studying all individuals irrespective of genotype. When studied according to plasma ferritin, fracture risk was increased in individuals with low ferritin concentrations, while risk was not increased in individuals with high concentrations. When compared to non-carriers, HFE C282Y homozygotes had increased risk of any fracture (hazard ratio[HR]:1.38;95%CI:1.09-1.75;p=0.008), and risk was increased even in C282Y homozygotes with normal ferritin concentrations (HR:2.89;95%CI:1.50-5.56), which is important as these individuals would not usually be recommended for HFE genotyping according to clinical guidelines. When compared to non-carriers, risk of fracture of the hip and femur was increased in C282Y homozygotes (HR:1.78;95%CI:1.17-2.70;p=0.007) but surprisingly also in H63D homozygotes (HR:1.21;95%CI:1.00-1.47;p=0.04), C282Y heterozygotes (HR:1.10;95%CI:1.00-1.21;p=0.04), and C282Y/H63D compound heterozygotes (HR:1.23;95%CI:1.00-1.51;p=0.05). The markedly increased fracture risk in C282Y homozygotes with normal ferritin may challenge the presumption that systemic iron accumulation is the primary mechanism causing their increased fracture risk. Further studies are needed to examine whether phlebotomy reduces fracture risk. Fertilization ensures the transmission of genetic material across generations through a series of precisely coordinated physiological and molecular events. To fertilize an oocyte, a spermatozoon must pass through the cumulus cell layer, penetrate the zona pellucida (ZP), and ultimately adhere to and fuse with the oolemma (the oocyte plasma membrane). Upon fusion, the oocyte initiates mechanisms to block additional sperm entry at both the ZP and oolemma. These processes are highly dynamic in space and time, posing substantial technical barriers to their mechanistic dissection. Nonetheless, recent in silico, in vitro, and in vivo studies have begun to elucidate how intricate networks of intracellular signaling cascades and extracellular protein-protein interactions orchestrate successful fertilization in vertebrates. However, the extent to which these findings accurately reflect the biology of human sperm-oocyte interactions remains obscure, owing to ethical constraints on human gamete experimentation and the limited availability of patients harboring pathogenic variants in fertilization-related genes. This narrative review synthesizes current knowledge of the molecular determinants governing mammalian sperm-oocyte interactions, summarizes relevant genetic anomalies identified in infertile patients, and discusses emerging experimental approaches for the direct investigation of human fertilization. We also explore how recent mechanistic insights and technological innovations may inform the diagnosis and treatment of fertilization disorders and guide the development of novel contraceptive strategies. We searched PubMed, Google Scholar, and Scopus to identify research and review articles published in English. Studies limited to non-mammalian species and non-peer-reviewed preprints were excluded. Searches used terms related to fertilization, sperm-oocyte interactions, ZP, cumulus cells, polyspermy block, and human infertility, alone or in combination. Additional searches targeted key proteins and emerging technologies relevant to mammalian fertilization, clinical diagnostics, and contraceptive development. Our mechanistic understanding of mammalian gamete interactions has predominantly stemmed from in vitro and in vivo animal studies, which have revealed key molecular processes, such as sperm hyaluronidase-mediated cumulus matrix dispersal, translocation of sperm acrosomal membrane proteins to enable oolemma interaction, and ZP glycoprotein cleavage underlying the polyspermy block. While studies in model species remain indispensable, translating this knowledge to human biology requires meticulous validation. The integration of interdisciplinary approaches, such as humanized mouse models, artificial human oocytes, xenospecies fertilization assays, antibody inhibition studies, and high-throughput interactome screening, offers promising avenues to clarify interspecies discrepancies and generate insights more directly relevant to human gamete interactions. Advances in the mechanistic dissection of sperm-oocyte interactions are anticipated to support the development of diagnostic tools and therapeutic interventions for infertility caused by defective fertilization. In parallel, these discoveries may enable the rational design of safe, reversible contraceptives that selectively block gamete interactions without compromising other physiological processes. N/A. The compositional and structural heterogeneity of plasma HDL (high-density lipoprotein) underlies its multiple proposed cardioprotective functions. This review explores current ideas for how the structural diversity of HDL particles arises during their biogenesis through ABCA1 (ATP-binding cassette transporter A1)-mediated efflux of membrane phospholipids and cholesterol to APOA1 (apolipoprotein A1), HDL's major protein. The proposed mechanisms driving the formation of nascent HDL particles, varying in size and in the number of APOA1 and lipid molecules they contain, are described. Subsequent remodeling in the plasma compartment produces HDL subspecies with distinct sets of associated proteins. The role of differently sized HDL particles in promoting reverse cholesterol transport by t

Despite therapeutic advances, multiple myeloma (MM) remains incurable due to the development of drug resistance by malignant plasma cells (PCs) and a severe immunosuppressive bone marrow (BM) microenvironment. Oncolytic virotherapy offers the dual benefit of tumor cell lysis and immune activation, but the efficacy of human viruses is often hampered by pre-existing antiviral immunity. Here, we demonstrated that bovine herpesvirus type 1 (BoHV-1), a virus that is nonpathogenic to humans, efficiently infected MM cells, inducing mitochondrial apoptosis and suppressing pro-survival programs, including MYC targets, oxidative phosphorylation, and the unfolded protein response. Infected tumor cells upregulated NK-activating ligands and downregulated MHC class I, enhancing susceptibility to NK-mediated cytotoxicity. In patientderived BM mononuclear cells (BMMCs), BoHV-1 selectively reduced malignant PCs and immunosuppressive myeloid subsets, while sparing lymphoid populations and hematopoietic progenitors. The infection promoted activation of CD8⁺ T cells, NK cells, and monocytes, driving a shift toward a pro-inflammatory M1-like polarization. Monocyte depletion in BMMCs attenuated the BoHV-1 anti-MM effect, confirming their functional contribution. This pronounced immune remodeling was accompanied by an inflammatory cytokine storm dominated by type I/II interferons and key innate immune mediators. Co-treatment of BoHV-1 with either bortezomib or lenalidomide increased anti-MM cytotoxicity. Finally, BoHV-1 upregulated CD38 on both MM cells and immune effectors, thereby increasing sensitivity to the anti-CD38 daratumumab. These findings establish BoHV-1 as a promising immunovirotherapy agent, effective as a single agent and in combination strategies, by coupling direct oncolysis with broad immune remodeling of the BM microenvironment. Risk of fractures may be increased in individuals with iron deficiency, iron overload, and/or HFE hemochromatosis. To test this hypothesis, we followed 142,146 Danish general population individuals for a median of 11 years (range:0-41) after study enrolment for hospital and emergency room admissions with fractures. All individuals had blood samples drawn at study enrolment. We measured iron, transferrin saturation, and ferritin in 136,611, 136,555, and 37,990 individuals, respectively, while 132,499 individuals were genotyped for the HFE C282Y and H63D variants. We found a U-shaped relationship between fracture risk and concentrations of plasma iron and transferrin saturation when studying all individuals irrespective of genotype. When studied according to plasma ferritin, fracture risk was increased in individuals with low ferritin concentrations, while risk was not increased in individuals with high concentrations. When compared to non-carriers, HFE C282Y homozygotes had increased risk of any fracture (hazard ratio[HR]:1.38;95%CI:1.09-1.75;p=0.008), and risk was increased even in C282Y homozygotes with normal ferritin concentrations (HR:2.89;95%CI:1.50-5.56), which is important as these individuals would not usually be recommended for HFE genotyping according to clinical guidelines. When compared to non-carriers, risk of fracture of the hip and femur was increased in C282Y homozygotes (HR:1.78;95%CI:1.17-2.70;p=0.007) but surprisingly also in H63D homozygotes (HR:1.21;95%CI:1.00-1.47;p=0.04), C282Y heterozygotes (HR:1.10;95%CI:1.00-1.21;p=0.04), and C282Y/H63D compound heterozygotes (HR:1.23;95%CI:1.00-1.51;p=0.05). The markedly increased fracture risk in C282Y homozygotes with normal ferritin may challenge the presumption that systemic iron accumulation is the primary mechanism causing their increased fracture risk. Further studies are needed to examine whether phlebotomy reduces fracture risk. Fertilization ensures the transmission of genetic material across generations through a series of precisely coordinated physiological and molecular events. To fertilize an oocyte, a spermatozoon must pass through the cumulus cell layer, penetrate the zona pellucida (ZP), and ultimately adhere to and fuse with the oolemma (the oocyte plasma membrane). Upon fusion, the oocyte initiates mechanisms to block additional sperm entry at both the ZP and oolemma. These processes are highly dynamic in space and time, posing substantial technical barriers to their mechanistic dissection. Nonetheless, recent in silico, in vitro, and in vivo studies have begun to elucidate how intricate networks of intracellular signaling cascades and extracellular protein-protein interactions orchestrate successful fertilization in vertebrates. However, the extent to which these findings accurately reflect the biology of human sperm-oocyte interactions remains obscure, owing to ethical constraints on human gamete experimentation and the limited availability of patients harboring pathogenic variants in fertilization-related genes. This narrative review synthesizes current knowledge of the molecular determinants governing mammalian sperm-oocyte interactions, summarizes relevant genetic anomalies identified in infertile patients, and discusses emerging experimental approaches for the direct investigation of human fertilization. We also explore how recent mechanistic insights and technological innovations may inform the diagnosis and treatment of fertilization disorders and guide the development of novel contraceptive strategies. We searched PubMed, Google Scholar, and Scopus to identify research and review articles published in English. Studies limited to non-mammalian species and non-peer-reviewed preprints were excluded. Searches used terms related to fertilization, sperm-oocyte interactions, ZP, cumulus cells, polyspermy block, and human infertility, alone or in combination. Additional searches targeted key proteins and emerging technologies relevant to mammalian fertilization, clinical diagnostics, and contraceptive development. Our mechanistic understanding of mammalian gamete interactions has predominantly stemmed from in vitro and in vivo animal studies, which have revealed key molecular processes, such as sperm hyaluronidase-mediated cumulus matrix dispersal, translocation of sperm acrosomal membrane proteins to enable oolemma interaction, and ZP glycoprotein cleavage underlying the polyspermy block. While studies in model species remain indispensable, translating this knowledge to human biology requires meticulous validation. The integration of interdisciplinary approaches, such as humanized mouse models, artificial human oocytes, xenospecies fertilization assays, antibody inhibition studies, and high-throughput interactome screening, offers promising avenues to clarify interspecies discrepancies and generate insights more directly relevant to human gamete interactions. Advances in the mechanistic dissection of sperm-oocyte interactions are anticipated to support the development of diagnostic tools and therapeutic interventions for infertility caused by defective fertilization. In parallel, these discoveries may enable the rational design of safe, reversible contraceptives that selectively block gamete interactions without compromising other physiological processes. N/A. The compositional and structural heterogeneity of plasma HDL (high-density lipoprotein) underlies its multiple proposed cardioprotective functions. This review explores current ideas for how the structural diversity of HDL particles arises during their biogenesis through ABCA1 (ATP-binding cassette transporter A1)-mediated efflux of membrane phospholipids and cholesterol to APOA1 (apolipoprotein A1), HDL's major protein. The proposed mechanisms driving the formation of nascent HDL particles, varying in size and in the number of APOA1 and lipid molecules they contain, are described. Subsequent remodeling in the plasma compartment produces HDL subspecies with distinct sets of associated proteins. The role of differently sized HDL particles in promoting reverse cholesterol transport by t

Despite therapeutic advances, multiple myeloma (MM) remains incurable due to the development of drug resistance by malignant plasma cells (PCs) and a severe immunosuppressive bone marrow (BM) microenvironment. Oncolytic virotherapy offers the dual benefit of tumor cell lysis and immune activation, but the efficacy of human viruses is often hampered by pre-existing antiviral immunity. Here, we demonstrated that bovine herpesvirus type 1 (BoHV-1), a virus that is nonpathogenic to humans, efficiently infected MM cells, inducing mitochondrial apoptosis and suppressing pro-survival programs, including MYC targets, oxidative phosphorylation, and the unfolded protein response. Infected tumor cells upregulated NK-activating ligands and downregulated MHC class I, enhancing susceptibility to NK-mediated cytotoxicity. In patientderived BM mononuclear cells (BMMCs), BoHV-1 selectively reduced malignant PCs and immunosuppressive myeloid subsets, while sparing lymphoid populations and hematopoietic progenitors. The infection promoted activation of CD8⁺ T cells, NK cells, and monocytes, driving a shift toward a pro-inflammatory M1-like polarization. Monocyte depletion in BMMCs attenuated the BoHV-1 anti-MM effect, confirming their functional contribution. This pronounced immune remodeling was accompanied by an inflammatory cytokine storm dominated by type I/II interferons and key innate immune mediators. Co-treatment of BoHV-1 with either bortezomib or lenalidomide increased anti-MM cytotoxicity. Finally, BoHV-1 upregulated CD38 on both MM cells and immune effectors, thereby increasing sensitivity to the anti-CD38 daratumumab. These findings establish BoHV-1 as a promising immunovirotherapy agent, effective as a single agent and in combination strategies, by coupling direct oncolysis with broad immune remodeling of the BM microenvironment. Risk of fractures may be increased in individuals with iron deficiency, iron overload, and/or HFE hemochromatosis. To test this hypothesis, we followed 142,146 Danish general population individuals for a median of 11 years (range:0-41) after study enrolment for hospital and emergency room admissions with fractures. All individuals had blood samples drawn at study enrolment. We measured iron, transferrin saturation, and ferritin in 136,611, 136,555, and 37,990 individuals, respectively, while 132,499 individuals were genotyped for the HFE C282Y and H63D variants. We found a U-shaped relationship between fracture risk and concentrations of plasma iron and transferrin saturation when studying all individuals irrespective of genotype. When studied according to plasma ferritin, fracture risk was increased in individuals with low ferritin concentrations, while risk was not increased in individuals with high concentrations. When compared to non-carriers, HFE C282Y homozygotes had increased risk of any fracture (hazard ratio[HR]:1.38;95%CI:1.09-1.75;p=0.008), and risk was increased even in C282Y homozygotes with normal ferritin concentrations (HR:2.89;95%CI:1.50-5.56), which is important as these individuals would not usually be recommended for HFE genotyping according to clinical guidelines. When compared to non-carriers, risk of fracture of the hip and femur was increased in C282Y homozygotes (HR:1.78;95%CI:1.17-2.70;p=0.007) but surprisingly also in H63D homozygotes (HR:1.21;95%CI:1.00-1.47;p=0.04), C282Y heterozygotes (HR:1.10;95%CI:1.00-1.21;p=0.04), and C282Y/H63D compound heterozygotes (HR:1.23;95%CI:1.00-1.51;p=0.05). The markedly increased fracture risk in C282Y homozygotes with normal ferritin may challenge the presumption that systemic iron accumulation is the primary mechanism causing their increased fracture risk. Further studies are needed to examine whether phlebotomy reduces fracture risk. Fertilization ensures the transmission of genetic material across generations through a series of precisely coordinated physiological and molecular events. To fertilize an oocyte, a spermatozoon must pass through the cumulus cell layer, penetrate the zona pellucida (ZP), and ultimately adhere to and fuse with the oolemma (the oocyte plasma membrane). Upon fusion, the oocyte initiates mechanisms to block additional sperm entry at both the ZP and oolemma. These processes are highly dynamic in space and time, posing substantial technical barriers to their mechanistic dissection. Nonetheless, recent in silico, in vitro, and in vivo studies have begun to elucidate how intricate networks of intracellular signaling cascades and extracellular protein-protein interactions orchestrate successful fertilization in vertebrates. However, the extent to which these findings accurately reflect the biology of human sperm-oocyte interactions remains obscure, owing to ethical constraints on human gamete experimentation and the limited availability of patients harboring pathogenic variants in fertilization-related genes. This narrative review synthesizes current knowledge of the molecular determinants governing mammalian sperm-oocyte interactions, summarizes relevant genetic anomalies identified in infertile patients, and discusses emerging experimental approaches for the direct investigation of human fertilization. We also explore how recent mechanistic insights and technological innovations may inform the diagnosis and treatment of fertilization disorders and guide the development of novel contraceptive strategies. We searched PubMed, Google Scholar, and Scopus to identify research and review articles published in English. Studies limited to non-mammalian species and non-peer-reviewed preprints were excluded. Searches used terms related to fertilization, sperm-oocyte interactions, ZP, cumulus cells, polyspermy block, and human infertility, alone or in combination. Additional searches targeted key proteins and emerging technologies relevant to mammalian fertilization, clinical diagnostics, and contraceptive development. Our mechanistic understanding of mammalian gamete interactions has predominantly stemmed from in vitro and in vivo animal studies, which have revealed key molecular processes, such as sperm hyaluronidase-mediated cumulus matrix dispersal, translocation of sperm acrosomal membrane proteins to enable oolemma interaction, and ZP glycoprotein cleavage underlying the polyspermy block. While studies in model species remain indispensable, translating this knowledge to human biology requires meticulous validation. The integration of interdisciplinary approaches, such as humanized mouse models, artificial human oocytes, xenospecies fertilization assays, antibody inhibition studies, and high-throughput interactome screening, offers promising avenues to clarify interspecies discrepancies and generate insights more directly relevant to human gamete interactions. Advances in the mechanistic dissection of sperm-oocyte interactions are anticipated to support the development of diagnostic tools and therapeutic interventions for infertility caused by defective fertilization. In parallel, these discoveries may enable the rational design of safe, reversible contraceptives that selectively block gamete interactions without compromising other physiological processes. N/A. The compositional and structural heterogeneity of plasma HDL (high-density lipoprotein) underlies its multiple proposed cardioprotective functions. This review explores current ideas for how the structural diversity of HDL particles arises during their biogenesis through ABCA1 (ATP-binding cassette transporter A1)-mediated efflux of membrane phospholipids and cholesterol to APOA1 (apolipoprotein A1), HDL's major protein. The proposed mechanisms driving the formation of nascent HDL particles, varying in size and in the number of APOA1 and lipid molecules they contain, are described. Subsequent remodeling in the plasma compartment produces HDL subspecies with distinct sets of associated proteins. The role of differently sized HDL particles in promoting reverse cholesterol transport by t

Despite therapeutic advances, multiple myeloma (MM) remains incurable due to the development of drug resistance by malignant plasma cells (PCs) and a severe immunosuppressive bone marrow (BM) microenvironment. Oncolytic virotherapy offers the dual benefit of tumor cell lysis and immune activation, but the efficacy of human viruses is often hampered by pre-existing antiviral immunity. Here, we demonstrated that bovine herpesvirus type 1 (BoHV-1), a virus that is nonpathogenic to humans, efficiently infected MM cells, inducing mitochondrial apoptosis and suppressing pro-survival programs, including MYC targets, oxidative phosphorylation, and the unfolded protein response. Infected tumor cells upregulated NK-activating ligands and downregulated MHC class I, enhancing susceptibility to NK-mediated cytotoxicity. In patientderived BM mononuclear cells (BMMCs), BoHV-1 selectively reduced malignant PCs and immunosuppressive myeloid subsets, while sparing lymphoid populations and hematopoietic progenitors. The infection promoted activation of CD8⁺ T cells, NK cells, and monocytes, driving a shift toward a pro-inflammatory M1-like polarization. Monocyte depletion in BMMCs attenuated the BoHV-1 anti-MM effect, confirming their functional contribution. This pronounced immune remodeling was accompanied by an inflammatory cytokine storm dominated by type I/II interferons and key innate immune mediators. Co-treatment of BoHV-1 with either bortezomib or lenalidomide increased anti-MM cytotoxicity. Finally, BoHV-1 upregulated CD38 on both MM cells and immune effectors, thereby increasing sensitivity to the anti-CD38 daratumumab. These findings establish BoHV-1 as a promising immunovirotherapy agent, effective as a single agent and in combination strategies, by coupling direct oncolysis with broad immune remodeling of the BM microenvironment. Risk of fractures may be increased in individuals with iron deficiency, iron overload, and/or HFE hemochromatosis. To test this hypothesis, we followed 142,146 Danish general population individuals for a median of 11 years (range:0-41) after study enrolment for hospital and emergency room admissions with fractures. All individuals had blood samples drawn at study enrolment. We measured iron, transferrin saturation, and ferritin in 136,611, 136,555, and 37,990 individuals, respectively, while 132,499 individuals were genotyped for the HFE C282Y and H63D variants. We found a U-shaped relationship between fracture risk and concentrations of plasma iron and transferrin saturation when studying all individuals irrespective of genotype. When studied according to plasma ferritin, fracture risk was increased in individuals with low ferritin concentrations, while risk was not increased in individuals with high concentrations. When compared to non-carriers, HFE C282Y homozygotes had increased risk of any fracture (hazard ratio[HR]:1.38;95%CI:1.09-1.75;p=0.008), and risk was increased even in C282Y homozygotes with normal ferritin concentrations (HR:2.89;95%CI:1.50-5.56), which is important as these individuals would not usually be recommended for HFE genotyping according to clinical guidelines. When compared to non-carriers, risk of fracture of the hip and femur was increased in C282Y homozygotes (HR:1.78;95%CI:1.17-2.70;p=0.007) but surprisingly also in H63D homozygotes (HR:1.21;95%CI:1.00-1.47;p=0.04), C282Y heterozygotes (HR:1.10;95%CI:1.00-1.21;p=0.04), and C282Y/H63D compound heterozygotes (HR:1.23;95%CI:1.00-1.51;p=0.05). The markedly increased fracture risk in C282Y homozygotes with normal ferritin may challenge the presumption that systemic iron accumulation is the primary mechanism causing their increased fracture risk. Further studies are needed to examine whether phlebotomy reduces fracture risk. Fertilization ensures the transmission of genetic material across generations through a series of precisely coordinated physiological and molecular events. To fertilize an oocyte, a spermatozoon must pass through the cumulus cell layer, penetrate the zona pellucida (ZP), and ultimately adhere to and fuse with the oolemma (the oocyte plasma membrane). Upon fusion, the oocyte initiates mechanisms to block additional sperm entry at both the ZP and oolemma. These processes are highly dynamic in space and time, posing substantial technical barriers to their mechanistic dissection. Nonetheless, recent in silico, in vitro, and in vivo studies have begun to elucidate how intricate networks of intracellular signaling cascades and extracellular protein-protein interactions orchestrate successful fertilization in vertebrates. However, the extent to which these findings accurately reflect the biology of human sperm-oocyte interactions remains obscure, owing to ethical constraints on human gamete experimentation and the limited availability of patients harboring pathogenic variants in fertilization-related genes. This narrative review synthesizes current knowledge of the molecular determinants governing mammalian sperm-oocyte interactions, summarizes relevant genetic anomalies identified in infertile patients, and discusses emerging experimental approaches for the direct investigation of human fertilization. We also explore how recent mechanistic insights and technological innovations may inform the diagnosis and treatment of fertilization disorders and guide the development of novel contraceptive strategies. We searched PubMed, Google Scholar, and Scopus to identify research and review articles published in English. Studies limited to non-mammalian species and non-peer-reviewed preprints were excluded. Searches used terms related to fertilization, sperm-oocyte interactions, ZP, cumulus cells, polyspermy block, and human infertility, alone or in combination. Additional searches targeted key proteins and emerging technologies relevant to mammalian fertilization, clinical diagnostics, and contraceptive development. Our mechanistic understanding of mammalian gamete interactions has predominantly stemmed from in vitro and in vivo animal studies, which have revealed key molecular processes, such as sperm hyaluronidase-mediated cumulus matrix dispersal, translocation of sperm acrosomal membrane proteins to enable oolemma interaction, and ZP glycoprotein cleavage underlying the polyspermy block. While studies in model species remain indispensable, translating this knowledge to human biology requires meticulous validation. The integration of interdisciplinary approaches, such as humanized mouse models, artificial human oocytes, xenospecies fertilization assays, antibody inhibition studies, and high-throughput interactome screening, offers promising avenues to clarify interspecies discrepancies and generate insights more directly relevant to human gamete interactions. Advances in the mechanistic dissection of sperm-oocyte interactions are anticipated to support the development of diagnostic tools and therapeutic interventions for infertility caused by defective fertilization. In parallel, these discoveries may enable the rational design of safe, reversible contraceptives that selectively block gamete interactions without compromising other physiological processes. N/A. The compositional and structural heterogeneity of plasma HDL (high-density lipoprotein) underlies its multiple proposed cardioprotective functions. This review explores current ideas for how the structural diversity of HDL particles arises during their biogenesis through ABCA1 (ATP-binding cassette transporter A1)-mediated efflux of membrane phospholipids and cholesterol to APOA1 (apolipoprotein A1), HDL's major protein. The proposed mechanisms driving the formation of nascent HDL particles, varying in size and in the number of APOA1 and lipid molecules they contain, are described. Subsequent remodeling in the plasma compartment produces HDL subspecies with distinct sets of associated proteins. The role of differently sized HDL particles in promoting reverse cholesterol transport by t

Despite therapeutic advances, multiple myeloma (MM) remains incurable due to the development of drug resistance by malignant plasma cells (PCs) and a severe immunosuppressive bone marrow (BM) microenvironment. Oncolytic virotherapy offers the dual benefit of tumor cell lysis and immune activation, but the efficacy of human viruses is often hampered by pre-existing antiviral immunity. Here, we demonstrated that bovine herpesvirus type 1 (BoHV-1), a virus that is nonpathogenic to humans, efficiently infected MM cells, inducing mitochondrial apoptosis and suppressing pro-survival programs, including MYC targets, oxidative phosphorylation, and the unfolded protein response. Infected tumor cells upregulated NK-activating ligands and downregulated MHC class I, enhancing susceptibility to NK-mediated cytotoxicity. In patientderived BM mononuclear cells (BMMCs), BoHV-1 selectively reduced malignant PCs and immunosuppressive myeloid subsets, while sparing lymphoid populations and hematopoietic progenitors. The infection promoted activation of CD8⁺ T cells, NK cells, and monocytes, driving a shift toward a pro-inflammatory M1-like polarization. Monocyte depletion in BMMCs attenuated the BoHV-1 anti-MM effect, confirming their functional contribution. This pronounced immune remodeling was accompanied by an inflammatory cytokine storm dominated by type I/II interferons and key innate immune mediators. Co-treatment of BoHV-1 with either bortezomib or lenalidomide increased anti-MM cytotoxicity. Finally, BoHV-1 upregulated CD38 on both MM cells and immune effectors, thereby increasing sensitivity to the anti-CD38 daratumumab. These findings establish BoHV-1 as a promising immunovirotherapy agent, effective as a single agent and in combination strategies, by coupling direct oncolysis with broad immune remodeling of the BM microenvironment. Risk of fractures may be increased in individuals with iron deficiency, iron overload, and/or HFE hemochromatosis. To test this hypothesis, we followed 142,146 Danish general population individuals for a median of 11 years (range:0-41) after study enrolment for hospital and emergency room admissions with fractures. All individuals had blood samples drawn at study enrolment. We measured iron, transferrin saturation, and ferritin in 136,611, 136,555, and 37,990 individuals, respectively, while 132,499 individuals were genotyped for the HFE C282Y and H63D variants. We found a U-shaped relationship between fracture risk and concentrations of plasma iron and transferrin saturation when studying all individuals irrespective of genotype. When studied according to plasma ferritin, fracture risk was increased in individuals with low ferritin concentrations, while risk was not increased in individuals with high concentrations. When compared to non-carriers, HFE C282Y homozygotes had increased risk of any fracture (hazard ratio[HR]:1.38;95%CI:1.09-1.75;p=0.008), and risk was increased even in C282Y homozygotes with normal ferritin concentrations (HR:2.89;95%CI:1.50-5.56), which is important as these individuals would not usually be recommended for HFE genotyping according to clinical guidelines. When compared to non-carriers, risk of fracture of the hip and femur was increased in C282Y homozygotes (HR:1.78;95%CI:1.17-2.70;p=0.007) but surprisingly also in H63D homozygotes (HR:1.21;95%CI:1.00-1.47;p=0.04), C282Y heterozygotes (HR:1.10;95%CI:1.00-1.21;p=0.04), and C282Y/H63D compound heterozygotes (HR:1.23;95%CI:1.00-1.51;p=0.05). The markedly increased fracture risk in C282Y homozygotes with normal ferritin may challenge the presumption that systemic iron accumulation is the primary mechanism causing their increased fracture risk. Further studies are needed to examine whether phlebotomy reduces fracture risk. Fertilization ensures the transmission of genetic material across generations through a series of precisely coordinated physiological and molecular events. To fertilize an oocyte, a spermatozoon must pass through the cumulus cell layer, penetrate the zona pellucida (ZP), and ultimately adhere to and fuse with the oolemma (the oocyte plasma membrane). Upon fusion, the oocyte initiates mechanisms to block additional sperm entry at both the ZP and oolemma. These processes are highly dynamic in space and time, posing substantial technical barriers to their mechanistic dissection. Nonetheless, recent in silico, in vitro, and in vivo studies have begun to elucidate how intricate networks of intracellular signaling cascades and extracellular protein-protein interactions orchestrate successful fertilization in vertebrates. However, the extent to which these findings accurately reflect the biology of human sperm-oocyte interactions remains obscure, owing to ethical constraints on human gamete experimentation and the limited availability of patients harboring pathogenic variants in fertilization-related genes. This narrative review synthesizes current knowledge of the molecular determinants governing mammalian sperm-oocyte interactions, summarizes relevant genetic anomalies identified in infertile patients, and discusses emerging experimental approaches for the direct investigation of human fertilization. We also explore how recent mechanistic insights and technological innovations may inform the diagnosis and treatment of fertilization disorders and guide the development of novel contraceptive strategies. We searched PubMed, Google Scholar, and Scopus to identify research and review articles published in English. Studies limited to non-mammalian species and non-peer-reviewed preprints were excluded. Searches used terms related to fertilization, sperm-oocyte interactions, ZP, cumulus cells, polyspermy block, and human infertility, alone or in combination. Additional searches targeted key proteins and emerging technologies relevant to mammalian fertilization, clinical diagnostics, and contraceptive development. Our mechanistic understanding of mammalian gamete interactions has predominantly stemmed from in vitro and in vivo animal studies, which have revealed key molecular processes, such as sperm hyaluronidase-mediated cumulus matrix dispersal, translocation of sperm acrosomal membrane proteins to enable oolemma interaction, and ZP glycoprotein cleavage underlying the polyspermy block. While studies in model species remain indispensable, translating this knowledge to human biology requires meticulous validation. The integration of interdisciplinary approaches, such as humanized mouse models, artificial human oocytes, xenospecies fertilization assays, antibody inhibition studies, and high-throughput interactome screening, offers promising avenues to clarify interspecies discrepancies and generate insights more directly relevant to human gamete interactions. Advances in the mechanistic dissection of sperm-oocyte interactions are anticipated to support the development of diagnostic tools and therapeutic interventions for infertility caused by defective fertilization. In parallel, these discoveries may enable the rational design of safe, reversible contraceptives that selectively block gamete interactions without compromising other physiological processes. N/A. The compositional and structural heterogeneity of plasma HDL (high-density lipoprotein) underlies its multiple proposed cardioprotective functions. This review explores current ideas for how the structural diversity of HDL particles arises during their biogenesis through ABCA1 (ATP-binding cassette transporter A1)-mediated efflux of membrane phospholipids and cholesterol to APOA1 (apolipoprotein A1), HDL's major protein. The proposed mechanisms driving the formation of nascent HDL particles, varying in size and in the number of APOA1 and lipid molecules they contain, are described. Subsequent remodeling in the plasma compartment produces HDL subspecies with distinct sets of associated proteins. The role of differently sized HDL particles in promoting reverse cholesterol transport by t

Despite therapeutic advances, multiple myeloma (MM) remains incurable due to the development of drug resistance by malignant plasma cells (PCs) and a severe immunosuppressive bone marrow (BM) microenvironment. Oncolytic virotherapy offers the dual benefit of tumor cell lysis and immune activation, but the efficacy of human viruses is often hampered by pre-existing antiviral immunity. Here, we demonstrated that bovine herpesvirus type 1 (BoHV-1), a virus that is nonpathogenic to humans, efficiently infected MM cells, inducing mitochondrial apoptosis and suppressing pro-survival programs, including MYC targets, oxidative phosphorylation, and the unfolded protein response. Infected tumor cells upregulated NK-activating ligands and downregulated MHC class I, enhancing susceptibility to NK-mediated cytotoxicity. In patientderived BM mononuclear cells (BMMCs), BoHV-1 selectively reduced malignant PCs and immunosuppressive myeloid subsets, while sparing lymphoid populations and hematopoietic progenitors. The infection promoted activation of CD8⁺ T cells, NK cells, and monocytes, driving a shift toward a pro-inflammatory M1-like polarization. Monocyte depletion in BMMCs attenuated the BoHV-1 anti-MM effect, confirming their functional contribution. This pronounced immune remodeling was accompanied by an inflammatory cytokine storm dominated by type I/II interferons and key innate immune mediators. Co-treatment of BoHV-1 with either bortezomib or lenalidomide increased anti-MM cytotoxicity. Finally, BoHV-1 upregulated CD38 on both MM cells and immune effectors, thereby increasing sensitivity to the anti-CD38 daratumumab. These findings establish BoHV-1 as a promising immunovirotherapy agent, effective as a single agent and in combination strategies, by coupling direct oncolysis with broad immune remodeling of the BM microenvironment. Risk of fractures may be increased in individuals with iron deficiency, iron overload, and/or HFE hemochromatosis. To test this hypothesis, we followed 142,146 Danish general population individuals for a median of 11 years (range:0-41) after study enrolment for hospital and emergency room admissions with fractures. All individuals had blood samples drawn at study enrolment. We measured iron, transferrin saturation, and ferritin in 136,611, 136,555, and 37,990 individuals, respectively, while 132,499 individuals were genotyped for the HFE C282Y and H63D variants. We found a U-shaped relationship between fracture risk and concentrations of plasma iron and transferrin saturation when studying all individuals irrespective of genotype. When studied according to plasma ferritin, fracture risk was increased in individuals with low ferritin concentrations, while risk was not increased in individuals with high concentrations. When compared to non-carriers, HFE C282Y homozygotes had increased risk of any fracture (hazard ratio[HR]:1.38;95%CI:1.09-1.75;p=0.008), and risk was increased even in C282Y homozygotes with normal ferritin concentrations (HR:2.89;95%CI:1.50-5.56), which is important as these individuals would not usually be recommended for HFE genotyping according to clinical guidelines. When compared to non-carriers, risk of fracture of the hip and femur was increased in C282Y homozygotes (HR:1.78;95%CI:1.17-2.70;p=0.007) but surprisingly also in H63D homozygotes (HR:1.21;95%CI:1.00-1.47;p=0.04), C282Y heterozygotes (HR:1.10;95%CI:1.00-1.21;p=0.04), and C282Y/H63D compound heterozygotes (HR:1.23;95%CI:1.00-1.51;p=0.05). The markedly increased fracture risk in C282Y homozygotes with normal ferritin may challenge the presumption that systemic iron accumulation is the primary mechanism causing their increased fracture risk. Further studies are needed to examine whether phlebotomy reduces fracture risk. Fertilization ensures the transmission of genetic material across generations through a series of precisely coordinated physiological and molecular events. To fertilize an oocyte, a spermatozoon must pass through the cumulus cell layer, penetrate the zona pellucida (ZP), and ultimately adhere to and fuse with the oolemma (the oocyte plasma membrane). Upon fusion, the oocyte initiates mechanisms to block additional sperm entry at both the ZP and oolemma. These processes are highly dynamic in space and time, posing substantial technical barriers to their mechanistic dissection. Nonetheless, recent in silico, in vitro, and in vivo studies have begun to elucidate how intricate networks of intracellular signaling cascades and extracellular protein-protein interactions orchestrate successful fertilization in vertebrates. However, the extent to which these findings accurately reflect the biology of human sperm-oocyte interactions remains obscure, owing to ethical constraints on human gamete experimentation and the limited availability of patients harboring pathogenic variants in fertilization-related genes. This narrative review synthesizes current knowledge of the molecular determinants governing mammalian sperm-oocyte interactions, summarizes relevant genetic anomalies identified in infertile patients, and discusses emerging experimental approaches for the direct investigation of human fertilization. We also explore how recent mechanistic insights and technological innovations may inform the diagnosis and treatment of fertilization disorders and guide the development of novel contraceptive strategies. We searched PubMed, Google Scholar, and Scopus to identify research and review articles published in English. Studies limited to non-mammalian species and non-peer-reviewed preprints were excluded. Searches used terms related to fertilization, sperm-oocyte interactions, ZP, cumulus cells, polyspermy block, and human infertility, alone or in combination. Additional searches targeted key proteins and emerging technologies relevant to mammalian fertilization, clinical diagnostics, and contraceptive development. Our mechanistic understanding of mammalian gamete interactions has predominantly stemmed from in vitro and in vivo animal studies, which have revealed key molecular processes, such as sperm hyaluronidase-mediated cumulus matrix dispersal, translocation of sperm acrosomal membrane proteins to enable oolemma interaction, and ZP glycoprotein cleavage underlying the polyspermy block. While studies in model species remain indispensable, translating this knowledge to human biology requires meticulous validation. The integration of interdisciplinary approaches, such as humanized mouse models, artificial human oocytes, xenospecies fertilization assays, antibody inhibition studies, and high-throughput interactome screening, offers promising avenues to clarify interspecies discrepancies and generate insights more directly relevant to human gamete interactions. Advances in the mechanistic dissection of sperm-oocyte interactions are anticipated to support the development of diagnostic tools and therapeutic interventions for infertility caused by defective fertilization. In parallel, these discoveries may enable the rational design of safe, reversible contraceptives that selectively block gamete interactions without compromising other physiological processes. N/A. The compositional and structural heterogeneity of plasma HDL (high-density lipoprotein) underlies its multiple proposed cardioprotective functions. This review explores current ideas for how the structural diversity of HDL particles arises during their biogenesis through ABCA1 (ATP-binding cassette transporter A1)-mediated efflux of membrane phospholipids and cholesterol to APOA1 (apolipoprotein A1), HDL's major protein. The proposed mechanisms driving the formation of nascent HDL particles, varying in size and in the number of APOA1 and lipid molecules they contain, are described. Subsequent remodeling in the plasma compartment produces HDL subspecies with distinct sets of associated proteins. The role of differently sized HDL particles in promoting reverse cholesterol transport by t