Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes 1 – 5 . Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75 , which are associated with reduced incidence of CHIP. We also identify novel rare variant associations with clonal haematopoiesis and telomere length. Analysis of 5,041 health traits from the UK Biobank (UKB) found relationships between CHIP and severe COVID-19 outcomes, cardiovascular disease, haematologic traits, malignancy, smoking, obesity, infection and all-cause mortality. Longitudinal and Mendelian randomization analyses revealed that CHIP is associated with solid cancers, including non-melanoma skin cancer and lung cancer, and that CHIP linked to DNMT3A is associated with the subsequent development of myeloid but not lymphoid leukaemias. Additionally, contrary to previous findings from the initial 50,000 UKB exomes 6 , our results in the full sample do not support a role for IL-6 inhibition in reducing the risk of cardiovascular disease among CHIP carriers. Our findings demonstrate that CHIP represents a complex set of heterogeneous phenotypes with shared and unique germline genetic causes and varied clinical implications.

Remodeling of cytoskeleton structures, such as microtubule assembly, is believed to be crucial for growth cone initiation and regrowth of injured axons. Autophagy plays important roles in maintaining cellular homoeostasis, and its dysfunction causes neuronal degeneration. The role of autophagy in axon regeneration after injury remains speculative. Here we demonstrate a role of autophagy in regulating microtubule dynamics and axon regeneration. We found that autophagy induction promoted neurite outgrowth, attenuated the inhibitory effects of nonpermissive substrate myelin, and decreased the formation of retraction bulbs following axonal injury in cultured cortical neurons. Interestingly, autophagy induction stabilized microtubules by degrading SCG10, a microtubule disassembly protein in neurons. In mice with spinal cord injury, local administration of a specific autophagy-inducing peptide, Tat-beclin1, to lesion sites markedly attenuated axonal retraction of spinal dorsal column axons and cortical spinal tract and promoted regeneration of descending axons following long-term observation. Finally, administration of Tat-beclin1 improved the recovery of motor behaviors of injured mice. These results show a promising effect of an autophagyinducing reagent on injured axons, providing direct evidence supporting a beneficial role of autophagy in axon regeneration.autophagy | microtubule stabilization | axon regeneration I t is generally believed that the inability of adult central nervous system (CNS) neurons to regenerate their axons following injury is due to the presence of abundant inhibitory factors in extrinsic milieu and the lack of intrinsic growth ability (1-5). A number of extrinsic growth-inhibitory factors have been identified, including oligodendrocyte-derived myelin-associated glycoprotein (MAG), Nogo, OMgp, or astrocyte-derived chondroitin sulfate proteoglycans (CSPGs), which act through their respective receptors to suppress axon growth and regeneration (6-11). However, genetic ablation or elimination of these inhibitory receptors does not promote axon regeneration (12, 13) or shows marginal effects (14, 15).Many inhibitory factors act through signaling cascades to modulate cytoskeletal dynamics (16,17). Indeed, it has been observed that CNS axons form numerous retraction bulbs (RBs) with a disorganized array of microtubules (MTs), whereas peripheral nervous system (PNS) axons rapidly form a growth cone with stable, well-organized bundling of MTs following injury (18). In line with this notion, pharmacological stabilization of MTs promotes axon regeneration after spinal cord injury (SCI) (19,20). In addition, analyses of gene-targeted mice have led to identification of several intrinsic inhibitors of axon regeneration in the adult CNS, including phosphatase and tensin homolog (PTEN) and the suppressor of cytokine signaling 3 (SOCS3) (21,22). However, manipulating individual proteins or in combinations allows limited axonal regeneration or sprouting, which is usually associated with temporary improvement ...

ScopeMetabolic flexibility is the ability to switch metabolism between carbohydrate oxidation (CHO) and fatty acid oxidation (FAO) and is a biomarker for metabolic health. The effect on metabolic health of nicotinamide riboside (NR) as an exclusive source of vitamin B3 is unknown and is examined here for a wide range of NR.Design and methodsNine‐week‐old male C57BL/6JRcc mice received a semi‐purified mildly obesogenic (40 en% fat) diet containing 0.14% L‐tryptophan and either 5, 15, 30, 180, or 900 mg NR per kg diet for 15 weeks. Body composition and metabolic parameters were analyzed. Metabolic flexibility was measured using indirect calorimetry. Gene expression in epididymal white adipose tissue (eWAT) was measured using qRT‐PCR .ResultsThe maximum delta respiratory exchange ratio when switching from CHO to FAO (maxΔRERCHO1→FAO) and when switching from FAO to CHO (maxΔRERFAO→CHO2) were largest in 30 mg NR per kg diet (30NR). In eWAT, the gene expression of Pparγ, a master regulator of adipogenesis, and of Sod2 and Prdx3, two antioxidant genes, were significantly upregulated in 30NR compared to 5NR.Conclusion30NR is most beneficial for metabolic health, in terms of metabolic flexibility and eWAT gene expression, of mice on an obesogenic diet.

Rheumatoid arthritis (RA) affects millions world-wide. While anti-TNF treatment is widely used to reduce disease progression, treatment fails in ∼one-third of patients. No biomarker currently exists that identifies non-responders before treatment. A rigorous community-based assessment of the utility of SNP data for predicting anti-TNF treatment efficacy in RA patients was performed in the context of a DREAM Challenge (http://www.synapse.org/RA_Challenge). An open challenge framework enabled the comparative evaluation of predictions developed by 73 research groups using the most comprehensive available data and covering a wide range of state-of-the-art modelling methodologies. Despite a significant genetic heritability estimate of treatment non-response trait (h2=0.18, P value=0.02), no significant genetic contribution to prediction accuracy is observed. Results formally confirm the expectations of the rheumatology community that SNP information does not significantly improve predictive performance relative to standard clinical traits, thereby justifying a refocusing of future efforts on collection of other data.

Two experiments were conducted to study the effects of stocking density on growth performance, carcass yield, and foot pad lesions of White Pekin ducks from hatch to 14 d of age (experiment 1) and from 14 to 42 d of age (experiment 2), respectively. All ducks were reared in raised plastic wire-floor pens with a pen size of 30 m(2), and males and females were mixed at a ratio of 1:1 in each pen of both experiments. In experiment 1, a total of 10,200 ducks that were 1 d old were allotted to 20 pens according to the stocking densities of 13, 15, 17, 19, and 21 birds/m(2) (or 8.4, 9.7, 10.9, 11.9, and 13.0 kg of actually achieved BW/m(2)), respectively, with 4 replicates per treatment. In experiment 2, a total of 3,150 ducks that were 14 d old were allotted to 15 pens according to the stocking densities of 5, 6, 7, 8, and 9 birds/m(2) (or 17.0, 20.3, 23.6, 26.9, and 29.9 kg of actually achieved BW/m(2)), respectively, with 3 replicates per treatment. The stocking density had significant effects on final BW and weight gain of starter and growing ducks (P < 0.05), but not on feed/gain and mortality in both periods (P > 0.05). The final BW and weight gain of starter and growing ducks all decreased with increasing density (P < 0.05). Final BW and weight gain of starter ducks were reduced significantly as stocking density increased from 17 to 21 birds/m(2) (P < 0.05). In addition, final BW and weight gain of growing ducks decreased significantly when stocking density was 9 birds/m(2) (P < 0.05). On the other hand, increasing stocking density did not markedly influence the carcass, breast meat, leg meat, abdominal fat, and foot pad lesions of growing ducks (P > 0.05).

Background Myopia is a good model for understanding the interaction between genetics and environmental stimuli. Here we dissect the biological processes affecting myopia progression. Methods Human Genetic Analyses: (1) gene set analysis (GSA) of new genome wide association study (GWAS) data for 593 individuals with high myopia (refraction ≤ -6 diopters [D]); (2) over-representation analysis (ORA) of 196 genes with de novo mutations, identified by whole genome sequencing of 45 high-myopia trio families, and (3) ORA of 284 previously reported myopia risk genes. Contributions of the enriched signaling pathways in mediating the genetic and environmental interactions during myopia development were investigated in vivo and in vitro . Results All three genetic analyses showed significant enrichment of four KEGG signaling pathways, including amphetamine addiction, extracellular matrix (ECM) receptor interaction, neuroactive ligand-receptor interaction, and regulation of actin cytoskeleton pathways. In individuals with extremely high myopia (refraction ≤ -10 D), the GSA of GWAS data revealed significant enrichment of the HIF-1α signaling pathway. Using human scleral fibroblasts, silencing the key nodal genes within protein-protein interaction networks for the enriched pathways antagonized the hypoxia-induced increase in myofibroblast transdifferentiation. In mice, scleral HIF-1α downregulation led to hyperopia, whereas upregulation resulted in myopia. In human subjects, near work, a risk factor for myopia, significantly decreased choroidal blood perfusion, which might cause scleral hypoxia. Interpretation Our study implicated the HIF-1α signaling pathway in promoting human myopia through mediating interactions between genetic and environmental factors. Funding National Natural Science Foundation of China grants; Natural Science Foundation of Zhejiang Province.

The oxygen isotope signature (d 18 O) of stalagmite SI3 collected from Shizi Cave in north-east Sichuan Province provides an Asian Summer Monsoon (ASM) record in Central China for the period 54-46 ka. The SI3 d 18 O record clearly shows a negative d 18 O excursion centred around 49.4 ka, which was reported in Hulu Cave in East China but not identified in the speleothem records from South-west China. As a whole, this record displays a higher coherence with the two Hulu records from East China than with the speleothem d 18 O records from South-west China, suggesting that at 54-46 ka, Central China was influenced more by the East Asian Summer Monsoon than by the Indian Summer Monsoon. It also displays a significant negative d 18 O excursion at 47.5-46.6 ka, which is not clearly documented in two other speleothem d 18 O records previously reported from South-west China. This suggests that details of the Greenland interstadial 12 warrant further investigations in future in monsoonal China. The SI3 d 18 O record displays more significant centennial-scale variations than the other four speleothem d 18 O records from East and South-west China, which may be due to the fact that the study site is closer to the north-west boundary of the ASM and more sensitive to variations of the ASM than East and South-west China.

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