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This systematic review and meta-analysis was aimed at determining whether paternal age is a risk factor for offspring birth defects.

A total of 38 and 11 studies were included in the systematic review and meta-analysis, respectively. Compared with reference, fathers aged 25 to 29, young fathers (< 20 years) could increase the risk of urogenital abnormalities (OR 1.50, 95 % CI 1.03-2.19) and chromosome disorders (OR 1.38, 95 % CI 1.12-1.52) in their offsprings; old fathers (≥ 40 years) could increase the risk of cardiovascular abnormalities (OR 1.10, 95 % CI 1.01-1.20), facial deformities (OR 1.08, 95 % CI 1.00-1.17), urogenital abnormalities (OR 1.28, 95 % CI 1.07-1.52), and chromosome disorders (OR 1.30, 95 % CI 1.12-1.52).

Our study indicated that paternal age is associated with a moderate increase in the incidence of urogenital and cardiovascular abnormalities, facial deformities, and chromosome disorders.

PubMed, Web of Science, the Cochrane Library, and Embase were searched for relevant literatures from 1960 to February 2020. The systematic review follows PRISMA guidelines. Relevant meta-analyses were performed.
PubMed, Web of Science, the Cochrane Library, and Embase were searched for relevant literatures from 1960 to February 2020. The systematic review follows PRISMA guidelines. Relevant meta-analyses were performed.Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] less then 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls (P = 0.001); half were previously unknown (AF less then 0.000002). MYO6, MYO7A, PTPRQ, and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1 N321I/+ mice, carrying the TMC1p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy.Rare high-3He/4He signatures in ocean island basalts (OIB) erupted at volcanic hotspots derive from deep-seated domains preserved in Earth's interior. Only high-3He/4He OIB exhibit anomalous 182W-an isotopic signature inherited during the earliest history of Earth-supporting an ancient origin of high 3He/4He. However, it is not understood why some OIB host anomalous 182W while others do not. We provide geochemical data for the highest-3He/4He lavas from Iceland (up to 42.9 times atmospheric) with anomalous 182W and examine how Sr-Nd-Hf-Pb isotopic variations-useful for tracing subducted, recycled crust-relate to high 3He/4He and anomalous 182W. These data, together with data on global OIB, show that the highest-3He/4He and the largest-magnitude 182W anomalies are found only in geochemically depleted mantle domains-with high 143Nd/144Nd and low 206Pb/204Pb-lacking strong signatures of recycled materials. In contrast, OIB with the strongest signatures associated with recycled materials have low 3He/4He and lack anomalous 182W. These observations provide important clues regarding the survival of the ancient He and W signatures in Earth's mantle. We show that high-3He/4He mantle domains with anomalous 182W have low W and 4He concentrations compared to recycled materials and are therefore highly susceptible to being overprinted with low 3He/4He and normal (not anomalous) 182W characteristic of subducted crust. Thus, high 3He/4He and anomalous 182W are preserved exclusively in mantle domains least modified by recycled crust. This model places the long-term preservation of ancient high 3He/4He and anomalous 182W in the geodynamic context of crustal subduction and recycling and informs on survival of other early-formed heterogeneities in Earth's interior.The function of the nucleus depends on the integrity of the nuclear lamina, an intermediate filament network associated with the linker of nucleoskeleton and cytoskeleton (LINC) complex. The LINC complex spans the nuclear envelope and mediates nuclear mechanotransduction, the process by which mechanical signals and forces are transmitted across the nuclear envelope. In turn, the AAA+ ATPase torsinA is thought to regulate force transmission from the cytoskeleton to the nucleus. In humans, mutations affecting nuclear envelope-associated proteins cause laminopathies, including progeria, myopathy, and dystonia, though the extent to which endogenous mechanical stresses contribute to these pathologies is unclear. Here, we use the Caenorhabditis elegans germline as a model to investigate mechanisms that maintain nuclear integrity as germ cell nuclei progress through meiotic development and migrate for gametogenesis-processes that require LINC complex function. We report that decreasing the function of the C. elegans torsinA homolog, OOC-5, rescues the sterility and premature aging caused by a null mutation in the single worm lamin homolog. We show that decreasing OOC-5/torsinA activity prevents nuclear collapse in lamin mutants by disrupting the function of the LINC complex. At a mechanistic level, OOC-5/torsinA promotes the assembly or maintenance of the lamin-associated LINC complex and this activity is also important for interphase nuclear pore complex insertion into growing germline nuclei. These results demonstrate that LINC complex-transmitted forces damage nuclei with a compromised nuclear lamina. Thus, the torsinA-LINC complex nexus might comprise a therapeutic target for certain laminopathies by preventing damage from endogenous cellular forces.Tumor-associated macrophages (TAMs) can have protumor properties, including suppressing immune responses, promoting vascularization and, consequently, augmenting tumor progression. To stop TAM-mediated immunosuppression, we use a novel treatment by injecting antibodies specific for scavenger receptor MARCO, which is expressed on a specific subpopulation of TAMs in the tumor. We now report the location of this TAM as well as the pleiotropic mechanism of action of anti-MARCO antibody treatment on tumor progression and further show that this is potentially relevant to humans. Using specific targeting, we observed decreased tumor vascularization, a switch in the metabolic program of MARCO-expressing macrophages, and activation of natural killer (NK) cell killing through TNF-related apoptosis-inducing ligand (TRAIL). This latter activity reverses the effect of melanoma cell-conditioned macrophages in blocking NK activation and synergizes with T cell-directed immunotherapy, such as antibodies to PD-1 or PD-L1, to enhance tumor killing. Tetramisole in vivo Our study thus reveals an approach to targeting the immunosuppressive tumor microenvironment with monoclonal antibodies to enhance NK cell activation and NK cell-mediated killing. This can complement existing T cell-directed immunotherapy, providing a promising approach to combinatorial immunotherapy for cancer.Protein design provides a stringent test for our understanding of protein folding. We previously described principles for designing ideal protein structures stabilized by consistent local and nonlocal interactions, based on a set of rules relating local backbone structures to tertiary packing motifs. The principles have made possible the design of protein structures having various topologies with high thermal stability. Whereas nonlocal interactions such as tight hydrophobic core packing have traditionally been considered to be crucial for protein folding and stability, the rules proposed by our previous studies suggest the importance of local backbone structures to protein folding. In this study, we investigated the robustness of folding of de novo designed proteins to the reduction of the hydrophobic core, by extensive mutation of large hydrophobic residues (Leu, Ile) to smaller ones (Val) for one of the designs. Surprisingly, even after 10 Leu and Ile residues were mutated to Val, this mutant with the core mostly filled with Val was found to not be in a molten globule state and fold into the same backbone structure as the original design, with high stability. These results indicate the importance of local backbone structures to the folding ability and high thermal stability of designed proteins and suggest a method for engineering thermally stabilized natural proteins.In 1966, Henry Beecher published his foundational paper "Ethics and Clinical Research," bringing to light unethical experiments that were routinely being conducted by leading universities and government agencies. A common theme was the lack of voluntary consent. Research regulations surrounding laboratory experiments flourished after his work. More than half a century later, we seek to follow in his footsteps and identify a new domain of risk to the public certain types of field experiments. The nature of experimental research has changed greatly since the Belmont Report. Due in part to technological advances including social media, experimenters now target and affect whole societies, releasing interventions into a living public, often without sufficient review or controls. A large number of social science field experiments do not reflect compliance with current ethical and legal requirements that govern research with human participants. Real-world interventions are being conducted without consent or notice to the public they affect. Follow-ups and debriefing are routinely not being undertaken with the populations that experimenters injure. Importantly, even when ethical research guidelines are followed, researchers are following principles developed for experiments in controlled settings, with little assessment or protection for the wider societies within which individuals are embedded. We strive to improve the ethics of future work by advocating the creation of new norms, illustrating classes of field experiments where scholars do not appear to have recognized the ways such research circumvents ethical standards by putting people, including those outside the manipulated group, into harm's way.Mushroom-forming fungi in the order Agaricales represent an independent origin of bioluminescence in the tree of life; yet the diversity, evolutionary history, and timing of the origin of fungal luciferases remain elusive. We sequenced the genomes and transcriptomes of five bonnet mushroom species (Mycena spp.), a diverse lineage comprising the majority of bioluminescent fungi. Two species with haploid genome assemblies ∼150 Mb are among the largest in Agaricales, and we found that a variety of repeats between Mycena species were differentially mediated by DNA methylation. We show that bioluminescence evolved in the last common ancestor of mycenoid and the marasmioid clade of Agaricales and was maintained through at least 160 million years of evolution. Analyses of synteny across genomes of bioluminescent species resolved how the luciferase cluster was derived by duplication and translocation, frequently rearranged and lost in most Mycena species, but conserved in the Armillaria lineage. Luciferase cluster members were coexpressed across developmental stages, with the highest expression in fruiting body caps and stipes, suggesting fruiting-related adaptive functions.
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