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The history of long-term environmental exposure to heavy metals can be recorded in the genome as sporadic and specific mutations. Variable environments introduce diverse and adaptive mutations to organisms. To reveal the information hidden in genomes about environmental exposure to heavy metals, we performed long-term mutation accumulation (MA) experiments with

Several sets of Paleozoic tight reservoirs are developed in the Central Uplift of the South Yellow Sea Basin. A qualitative analysis of the microscopic pore structure of the tight reservoir rocks was carried out through cast thin slice and scanning electron microscopic image observation. Based on reservoir petrophysical properties, thirty core samples in the Central Uplift of the South Yellow Sea Basin were selected for high-pressure mercury intrusion (HPMI) analysis, which was then combined with fractal calculation to classify and evaluate the tight reservoirs. The analysis of the HPMI curves and related parameters shows that the Paleozoic tight reservoirs can be divided into three types: Type-A, Type-B and Type-C. Type-A sandstone reservoirs contain pores with size mostly ranging between 0.01 and 0.1 μm, followed by pores with size range of 0.001–0.01 μm, and relatively fewer pores larger than 0.1 μm. The Type-B reservoirs are carbonate rocks with extremely heterogeneous pore size distribution, which is closely related to the development of dissolution pores and microfractures. Type-C sandstone reservoirs are dominated by nanopores and submicron pores that distribute more heterogeneously than pores in Type-A reservoirs. The pore distribution in sandstone reservoirs shows significant fractal characteristics and is closely related to the pore size. The heterogeneity of nanopore distribution has a negative correlation with porosity and median pressure and a relatively weak correlation with permeability. Our study has important implications for petroleum exploration in the South Yellow Sea Basin.

Weihong Lu,1,2 Silan Zheng,3 Jingqi Zhou,3 Shunfa Huang,4 Ning Chen,3 Zhibin Li5 1Department of Gynecology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, People’s Republic of China; 2Xiamen Clinical Research Center for Cancer Therapy, Xiamen, People’s Republic of China; 3Department of Endocrinology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, People’s Republic of China; 4Department of Radiology, Zhongshan Hospital (Xiamen), Fudan University, Xiamen, People’s Republic of China; 5Epidemiology Research Unit, Translational Medicine Research Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, People’s Republic of ChinaCorrespondence: Ning Chen, Department of Endocrinology, Zhongshan Hospital (Xiamen), Fudan University, No. 668 Jinhu Road, Xiamen, 361000, People’s Republic of China, Tel/Fax +86-0592-3569583, Email chen.ning@zsxmhospital.com Zhibin Li, Epidemiology Research Unit, Translational Medicine Research Center, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, No. 55 Zhenhai Road, Xiamen, 361003, People’s Republic of China, Tel +86-592-2137364, Fax +86-592-2137557, Email zhibinli33@hotmail.comObjective: This study aimed to examine associations between plasma sex-related hormones with bone mineral density (BMD) and risks of osteoporosis or osteopenia in men and postmenopausal women patients with type 2 diabetes mellitus (T2DM).Methods: Baseline information on an ongoing cohort of 149 men and 102 postmenopausal women with T2DM in Xiamen, China were analyzed. Plasma estradiol (E2), total testosterone (T), follicle-stimulating hormone (FSH), luteinizing hormone (LH) and prolactin (PRL) were measured. BMD of lumbar spine (L2-4), femoral neck (FN) and total hip (TH) were determined by dual-energy X-ray absorptiometry (DXA). Osteoporosis or osteopenia was defined as the minimum T-scores of BMD of these three different sites of − 1.0 or below.Results: T2DM patients with osteoporosis/osteopenia (66.4% in men and 79.4% in postmenopausal women), compared to those without, showed significantly decreased level of E2 (75.3± 28.9 vs. 107.8± 25.9pmol/L and 18.4 (18.4– 29.5) vs. 22.8 (18.4– 40.5) pmol/L for men and postmenopausal women, respectively, both p-values < 0.05), but not other sex-related hormones (including T, FSH, LH, or PRL). For all T2DM patients together and men separately, multivariable linear regression and logistic regression analyses showed that higher E2 levels were significantly associated with higher BMD T-scores in L2-4, FN, TH and minimum of these three different sites, lower 10-year probability of major osteoporotic fractures (MOF) and hip fractures (HFs) estimated by Fracture Risk Assessment Tool score, as well as decreased risk of osteoporosis/osteopenia. As for postmenopausal women T2DM patients, E2 level was positively associated with BMD T-scores in L2-4 and minimum of three different sites but was not independently associated with risk of osteoporosis/osteopenia.Conclusion: Higher plasma E2 was significantly associated with increased BMD and lower risk of osteoporosis or osteopenia in T2DM patients, especially for men. Screening of BMD and estradiol levels as well as evaluating risks of osteoporosis/osteopenia are important for T2DM patients.Keywords: estradiol, bone mineral density, osteoporosis, osteopenia, diabetes, BMD

Atractylodes macrocephala Koidz. (AM), an herb of traditional Chinese medicine, is well-known for anti-oxidant, anti-tumor and immune regulation potential. However, it is low bioactive compound content that restricts the application of this species. Elicitation is considered as an effective method to enhance biomass and bioactive compound in plants. Our precious study found that polysaccharide of Chrysanthemun indicum L. could promote plant growth by triggering plant defense. In the present study, polysaccharide of Chrysanthemun indicum L. is used to stimulate the accumulation of biomass and bioactive compound with different concentration in Atractylodes macrocephala Koidz. during pot, plot and field experiments. The results suggested that polysaccharide of Chrysanthemun indicum L. could significantly enhance the accumulation of biomass, atractylenolides and polysacchrides. Moreover, 2 mg/mL is determined and verified to be the appropriate concentration during field experiments. In addition, RT-qPCR revealed that CIP-induced terpenoid synthesis in AM mainly depended on mevalonate (MVA) pathway. This is the first report on the discovery of polysaccharide of Chrysanthemun indicum L. for the enhanced accumulation of biaomass and bioactive compound and the use of its for agricultural production.

Vertebrate myoblast fusion allows for multinucleated muscle fibers to compound the size and strength of mononucleated cells, but the evolution of this important process is unknown. We investigated the evolutionary origins and function of membrane-coalescing agents Myomaker and Myomixer in various groups of chordates. Here, we report that Myomaker likely arose through gene duplication in the last common ancestor of tunicates and vertebrates, while Myomixer appears to have evolved de novo in early vertebrates. Functional tests revealed a complex evolutionary history of myoblast fusion. A prevertebrate phase of muscle multinucleation driven by Myomaker was followed by the later emergence of Myomixer that enables the highly efficient fusion system of vertebrates. Evolutionary comparisons between vertebrate and nonvertebrate Myomaker revealed key structural and mechanistic insights into myoblast fusion. Thus, our findings suggest an evolutionary model of chordate fusogens and illustrate how new genes shape the emergence of novel morphogenetic traits and mechanisms.

Summary Objective Osteoarthritis (OA) and rheumatoid arthritis (RA) are both debilitating diseases that cause significant morbidity and disability globally. This study aims to investigate the causal effects of varying blood levels of five minerals -- iron, zinc, copper, calcium, and magnesium, on OA and RA. Design We performed two-sample Mendelian randomization (MR) analyses to assess the associations of five circulating minerals with OA and RA. Single nucleotide polymorphisms (SNPs) serving as genetic instruments for the circulating mineral levels were selected from large genome-wide association studies of European-descent individuals. The associations of these SNPs with OA and RA were evaluated in UK Biobank participants. Multiple sensitivity analyses were applied to detect and correct for the presence of pleiotropy. Results Genetically determined copper and zinc status were associated with OA, but not with RA. Per standard deviation (SD) increment in copper increases the risk of OA (OR = 1.07, 95% CI: 1.02–1.13) and one of its subtypes, localized OA (OR = 1.08, 95% CI: 1.03–1.15). Per SD increment in zinc is positively associated with risks of OA (OR = 1.07, 95% CI: 1.01–1.13), generalized OA (OR = 1.18, 95% CI: 1.05–1.31), and unspecified OA (OR = 1.21, 95% CI: 1.11–1.31). Additionally, per SD increment in calcium decreases the risk of localized OA (OR = 0.83, 95% CI: 0.69–0.98). Conclusions Genetically high zinc and copper status were positively associated with OA, but not with RA. Given the modifiable nature of circulating mineral status, these findings warrant further investigation for OA prevention strategies.

Background The genetic locus 3p21.31 has been associated with severe coronavirus disease 2019 (COVID-19), but the underlying pathophysiological mechanism is unknown. Methods To identify intermediate traits associated with the 3p21.31 locus, we first performed a phenome-wide association study (PheWAS) with 923 phenotypes in 310 999 European individuals from the UK Biobank. For genes potentially regulated by the COVID-19 risk variant, we examined associations between their expression and the polygenic score (PGS) of 1263 complex traits in a meta-analysis of 31 684 blood samples. For the prioritized blood cell traits, we tested their associations with age and sex in the same UK Biobank sample. Results Our PheWAS highlighted multiple blood cell traits to be associated with the COVID-19 risk variant, including monocyte count and percentage (p = 1.07 × 10–8, 4.09 × 10–13), eosinophil count and percentage (p = 5.73 × 10–3, 2.20 × 10–3), and neutrophil percentage (p = 3.23 × 10–3). The PGS analysis revealed positive associations between the expression of candidate genes and genetically predicted counts of specific blood cells: CCR3 with eosinophil and basophil (p = 5.73 × 10–21, 5.08 × 10–19); CCR2 with monocytes (p = 2.40 × 10–10); and CCR1 with monocytes and neutrophil (p = 1.78 × 10–6, 7.17 × 10–5). Additionally, we found that almost all examined white blood cell traits are significantly different across age and sex groups. Conclusions Our findings suggest that altered blood cell traits, especially those of monocyte, eosinophil, and neutrophil, may represent the mechanistic links between the genetic locus 3p21.31 and severe COVID-19. They may also underlie the increased risk of severe COVID-19 in older adults and men.

Highlights • An unbiased analysis of 974 diseases revealed new risk factors of severe COVID-19. • Delirium, dementia, amnestic, and other cognitive disorders increase its risk. • Genetic variants in SARS‑CoV‑2 infection genes are associated with severe COVID-19. • There is an urgent need for special dementia care during the pandemic., Introduction Our understanding of risk factors for COVID‑19, including pre-existing medical conditions and genetic variations, is limited. To what extent the pre-existing clinical condition and genetic background have implications for COVID-19 still needs to be explored. Methods Our study included 389,620 participants of European descent from the UK Biobank, of whom 3,884 received the COVID-19 test and 1,091 were tested positive for COVID-19. We examined the association of COVID-19 status with an extensive list of 974 medical conditions and 30 blood biomarkers. Additionally, we tested the association of genetic variants in two key genes related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, angiotensin-converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), with COVID-19 or any other phenotypes. Results The most significant risk factors for COVID-19 include Alzheimer’s disease (OR = 2.29, 95% CI: 1.25–4.16), dementia (OR = 2.16, 95% CI: 1.36–3.42), and the overall category of delirium, dementia, amnestic and other cognitive disorders (OR = 1.90, 95% CI: 1.24–2.90). Evidence suggesting associations of genetic variants in SARS-CoV-2 infection-related genes with COVID-19 (rs7282236, OR = 1.33, 95% CI: 1.14–1.54, p = 2.31 × 10−4) and other phenotypes, such as an immune deficiency (p = 5.65 × 10−5) and prostate cancer (p = 1.1 × 10−5), was obtained. Conclusions Our unbiased and extensive search identified pre-existing Alzheimer’s disease and dementia as top risk factors for hospital admission due to COVID-19, highlighting the importance of providing special protective care for patients with cognitive disorders during this pandemic. We also obtained evidence suggesting a direct association of genetic variants with COVID-19.

Pressure ulcer (PU) is a type of chronic ulcer, placing a high burden not only on patients’ families but also on national healthcare systems globally. To determine the level, trends, and burden of PU worldwide and to provide an essential foundation for building targeted public policies on PUs at the national, regional, and global levels, data on PU were obtained from the Global Burden of Disease (GBD) 2019 Study. The incidence, disability-adjusted life years (DALYs), and deaths of PUs in 204 countries and regions from 1990 to 2019 were calculated and stratified by sex, age, geographical location, and sociodemographic index (SDI). The estimated annual percentage change (EAPC) of incidence, DALYs, and deaths was calculated to evaluate the temporal trends. A total of 3,170,796 new cases (95% uncertainty interval (UI), 3,499,729–2,875,433 cases) of PU were identified globally in 2019, more than 55% of which were among male individuals, and most of the new cases were concentrated in those 75–90 years of age. The burden of PU measured in DALYs was 481 423 (95% UI, 583 429-374 334) in 2019, 73% and 27% of which could be attributed to years of life lost (YLLs) and years lived with disability (YLDs), respectively. The burden increased gradually from 1990 to 2019 (from 267 846 [360 562-211 024] to 481 423 [95% UI, 583 429-374 334]). A total of 24 389 deaths were attributed to PU (95% UI, 31 260.82-17 299). The EAPC of incidence, DALYs, and deaths were negative in most regions, the age-standardized rate (ASR) of incidence, DALYs, and deaths were considered to be decreasing in most of the regions, and the EAPCs were negatively correlated with the SDI levels, universal health coverage (UHC), and gross domestic product (GDP), which shows that the ASRs of PU decreased as the economy developed and countries’ healthcare system performances improved.

The purpose of this study was to investigate the clinical efficacy of compound polymyxin B ointment for treating chronic refractory wounds. A retrospective analysis was performed on 111 patients who underwent chronic refractory wound treatment. Patients were divided into 2 groups, with 45 patients included in the experimental group (compound polymyxin B group) and 66 patients included in the control group (silver sulfadiazine group). After thorough debridement in both groups, either compound polymyxin B ointment or silver sulfadiazine cream was evenly applied to the patient’s wound and covered with sterile gauze. In both groups, dressing changes were dependent on the wound’s condition and secretions. Using the Bates-Jensen Wound Assessment Tool (BWAT), patients in both groups were scored, after which wound healing, infection, and healing time were compared. There was no significant difference in BWAT scores between the 2 groups on the 7th or 14th day; however, on the 21st day, the BWAT score in the experimental group was significantly lower than that of the control group. The difference was statistically significant ( P < .05). There was no significant difference in the BWAT-I scores between the 2 groups on the seventh day. The healing time in the experimental group was significantly shorter than that of the control group, and the difference was statistically significant ( P < .05). For the treatment of chronic refractory wounds, thorough debridement followed by compound polymyxin B ointment topical application can reduce and control wound infection effectively and accelerate the process of wound repair.

The vascular causes of lower-extremity ulcers cannot be neglected because they can directly affect treatment methods. No detailed epidemiological statistics have described vascular etiological diagnosis in China. This study aimed to explore the prevalence of clinical vascular etiological examination of lower-extremity ulcers and improve the diagnosis and treatment effectiveness of lower-extremity ulcers. Data were collected from the WoundCareLog database, which includes 2413 cases of lower-extremity ulcers from 478 hospitals nationwide. Data analysis revealed that 1698 (70.4%) lower-extremity blood flow examinations (including physical examination [PE] and assistant examinations [AE]) were performed, of which 61.7% were PE, 10.4% were AE only, and 27.9% were the combined PE and AE[PAE]. The proportion of nonexaminations was higher in the nondiabetic group than in the diabetic group (χ2 = 34.5; P < .01). The positive rates of vascular etiological examination in the diabetic and nondiabetic groups were 69.7% and 70.7%, respectively. Among the four economic regions of China, there were statistically significant differences in the use of the different examination methods. The examination of vascular diseases in lower-extremity ulcers in China has not been fully popularized and requires improvement; there was no statistically significant difference between examination rates by doctors and nurses, which is mainly based on PE. However, PE has certain rates of misdiagnosis and missed diagnosis. The false-positive and false-negative rates were 25.7% and 57.6%, respectively. The use of an AE can compensate for this deficiency by making diagnosis more precise, while the quantitative diagnostic criteria allow disease diagnosis to transcend geographical and operator differences and maximize uniformity. The vascular B-ultrasound examination is more suitable for the medical environment in China because of its mature technology, high hospital penetration rate, and low cost.

An efficient organocatalytic asymmetric Michael addition of 4-substituted-pyrazol-5-ones to β-trifluoromethyl-α,β-unsaturated ketones was developed. In the presence of a dipeptide-based urea-amide tertiary amine catalyst, an array of chiral products containing pyrazolone and trifluoromethyl moieties bearing vicinal quaternary and tertiary stereocenters were obtained in good yields with good to excellent enantioselectivity and diastereoselectivity (up to 95% yields, up to 97% ee, and >20:1 d.r.). Moreover, the reaction was compatible with 4-substituted-pyrazol-5-ones containing either aryl or alkyl group at the C3 position.

The white-blotched river stingray (Potamotrygon leopoldi) is a cartilaginous fish native to the Xingu River, a tributary of the Amazon River system. It possesses a lot of unique biological features such as disc-like body shape, bizarre color pattern and living in freshwater habitat while most stingrays and their close relatives are sea dwellers. As a member of the Potamotrygonidae family, P. leopoldi bears evolutionary signification in fish phylogeny, niche adaptation and skeleton formation. In this study, we present its draft genome of 4.11 Gb comprised of 16,227 contigs and 13,238 scaffolds, which has contig N50 of 3,937 kilobases and scaffold N50 of 5,675 kilobases in size. Our analysis shows that P. leopoldi is a slow-evolving fish, diverged from elephant shark about 96 million years ago. We find that two gene families related to immune system, immunoglobulin heavy constant delta genes, and T-cell receptor alpha/delta variable genes, stand out expanded in P. leopoldi only, suggesting robustness in response to freshwater pathogens in adapting novel environments. We also identified the Hox gene clusters in P. leopoldi and discovered that seven Hox genes shared by five representative fishes are missing in P. leopoldi. The RNA-seq data from P. leopoldi and other three fish species demonstrate that fishes have a more diversified tissue expression spectrum as compared to the corresponding mammalian data. Our functional studies suggest that the lack of genes encoding vitamin D-binding protein in cartilaginous (both P. leopoldi and Callorhinchus milii) fishes could partly explain the absence of hard bone in their endoskeleton. Overall, this genome resource provides new insights into the niche-adaptation, body plan and skeleton formation of P. leopoldi as well as the genome evolution in cartilaginous fish.

The size of an animal is determined by the size of its musculoskeletal system. Myoblast fusion is an innovative mechanism that allows for multinucleated muscle fibers to compound the size and strength of individual mononucleated cells. However, the evolutionary history of the control mechanism underlying this important process is currently unknown. The phylum Chordata hosts closely related groups that span distinct myoblast fusion states: no fusion in cephalochordates, restricted fusion and multinucleation in tunicates, and extensive, obligatory fusion in vertebrates. To elucidate how these differences may have evolved, we studied the evolutionary origins and function of membrane-coalescing agents Myomaker and Myomixer in various groups of chordates. Here we report that Myomaker likely arose through gene duplication in the last common ancestor of tunicates and vertebrates, while Myomixer appears to have evolved de novo in early vertebrates. Functional tests revealed an unexpectedly complex evolutionary history of myoblast fusion in chordates. A pre-vertebrate phase of muscle multinucleation driven by Myomaker was followed by the later emergence of Myomixer that enables the highly efficient fusion system of vertebrates. Thus, our findings reveal the evolutionary origins of chordate-specific fusogens and illustrate how new genes can shape the emergence of novel morphogenetic traits and mechanisms.

Although oncogenicity of the stem cell regulator SOX9 has been implicated in many solid tumors, its role in lymphomagenesis remains largely unknown. In this study, SOX9 was overexpressed preferentially in a subset of diffuse large B-cell lymphomas (DLBCLs) that harbor IGH-BCL2 translocations. SOX9 positivity in DLBCL correlated with an advanced stage of disease. Silencing of SOX9 decreased cell proliferation, induced G1/S arrest, and increased apoptosis of DLBCL cells, both in vitro and in vivo. Whole-transcriptome analysis and chromatin immunoprecipitation–sequencing assays identified DHCR24, a terminal enzyme in cholesterol biosynthesis, as a direct target of SOX9, which promotes cholesterol synthesis by increasing DHCR24 expression. Enforced expression of DHCR24 was capable of rescuing the phenotypes associated with SOX9 knockdown in DLBCL cells. In models of DLBCL cell line xenografts, SOX9 knockdown resulted in a lower DHCR24 level, reduced cholesterol content, and decreased tumor load. Pharmacological inhibition of cholesterol synthesis also inhibited DLBCL xenograft tumorigenesis, the reduction of which is more pronounced in DLBCL cell lines with higher SOX9 expression, suggesting that it may be addicted to cholesterol. In summary, our study demonstrated that SOX9 can drive lymphomagenesis through DHCR24 and the cholesterol biosynthesis pathway. This SOX9-DHCR24-cholesterol biosynthesis axis may serve as a novel treatment target for DLBCLs.

Background: The pandemic of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly emerged to seriously threaten public health. We aimed to investigate whether white blood cell traits have potential causal effects on severe COVID-19 using Mendelian randomization (MR). Methods: To evaluate the causal associations between various white blood cell traits and severe COVID-19, we conducted a two-sample MR analysis with summary statistics from recent large genome-wide association studies. Findings: Our MR results indicated potential causal associations of white blood cell count, myeloid white blood cell count, and granulocyte count with severe COVID-19, with odds ratios (OR) of 0.84 (95% CI: 0.72-0.98), 0.81 (95% CI: 0.70-0.94), and 0.84 (95% CI: 0.71-0.99), respectively. Increasing eosinophil percentage of white blood cells was associated with a higher risk of severe COVID-19 (OR: 1.22, 95% CI: 1.03-1.45). Interpretation: Our results suggest the potential causal effects of lower white blood cell count, lower myeloid white blood cell count, lower granulocyte count, and higher eosinophil percentage of white blood cells on an increased risk of severe COVID-19. Funding Statement: KY is supported by the University of Georgia Research Foundation Declaration of Interests: The authors declare no conflicts of interest.

The white-blotched river stingray (Potamotrygon leopoldi) is a cartilaginous fish native to the Xingu River, a tributary of the Amazon River system. As a rare freshwater dwelling cartilaginous fish in the Potamotrygonidae family that no member has the genome sequencing information, P. leopoldi provides the evolutionary details in fish phylogeny, niche adaptation, and skeleton formation. In this study, we present its draft genome of 4.11 Gb comprised of 16,227 contigs and 13,238 scaffolds, which has contig N50 of 3937 kb and scaffold N50 of 5675 kb in size. Our analysis shows that P. leopoldi is a slow-evolving fish that diverged from elephant sharks about 96 million years ago. Our analyses show that two gene families related to the immune system, immunoglobulin heavy constant delta genes and T-cell receptor alpha/delta variable genes, stand out expanded in P. leopoldi only. We also identified the Hox gene clusters in P. leopoldi and discovered that seven Hox genes shared by five representative fishes are missing in P. leopoldi. The RNA sequencing data from P. leopoldi and other three fish species demonstrate that fishes have a more diversified tissue expression spectrum as compared to the corresponding mammalian data. Our functional studies suggest that the lack of genes encoding vitamin D-binding protein in cartilaginous (both P. leopoldi and Callorhinchus milii) fishes could partly explain the absence of hard bone in their endoskeleton. Overall, this genome resource provides new insights into the niche adaptation, body plan, and skeleton formation of P. leopoldi as well as the genome evolution in cartilaginous fish.

Increasing evidence shows that white blood cells are associated with the risk of coronavirus disease 2019 (COVID-19), but the direction and causality of this association are not clear. To evaluate the causal associations between various white blood cell traits and the COVID-19 susceptibility and severity, we conducted two-sample bidirectional Mendelian Randomization (MR) analyses with summary statistics from the largest and most recent genome-wide association studies. Our MR results indicated causal protective effects of higher basophil count, basophil percentage of white blood cells, and myeloid white blood cell count on severe COVID-19, with odds ratios (OR) per standard deviation increment of 0.75 (95% CI: 0.60-0.95), 0.70 (95% CI: 0.54-0.92), and 0.85 (95% CI: 0.73-0.98), respectively. Neither COVID-19 severity nor susceptibility was associated with white blood cell traits in our reverse MR results. Genetically predicted high basophil count, basophil percentage of white blood cells, and myeloid white blood cell count are associated with a lower risk of developing severe COVID-19. Individuals with a lower genetic capacity for basophils are likely at risk, while enhancing the production of basophils may be an effective therapeutic strategy.

PurposeThe genetic locus 3p21.31 has been associated with severe coronavirus disease 2019 (COVID-19), but the underlying pathophysiological mechanism is unknown.MethodsTo identify intermediate traits of the COVID-19 risk variant, we performed a phenome-wide association study (PheWAS) with 923 phenotypes in 310,999 European individuals from UK Biobank. For candidate target genes, we examined associations between their expression and the polygenic score (PGS) of 1,263 complex traits in a meta-analysis of 31,684 blood samples.ResultsOur PheWAS identified and replicated multiple blood cell traits to be associated with the COVID-19 risk variant, including monocyte count and percentage (p = 1.07×10−8, 4.09×10−13), eosinophil count and percentage (p = 5.73×10−3, 2.20×10−3), and neutrophil percentage (p = 3.23×10−3). The PGS analysis revealed positive associations between the expression of candidate genes and genetically predicted counts of specific blood cells: CCR3 with eosinophil and basophil (p = 5.73×10−21, 5.08×10−19); CCR2 with monocytes (p = 2.40×10−10); and CCRl with monocytes and neutrophil (p = 1.78×10−6, 7.17×10−5).ConclusionsMultiple blood cell traits, especially monocyte, eosinophil, and neutrophil numbers, are associated with the COVID-19 risk variant and the expression of its candidate target genes, representing probable mechanistic links between the genetic locus 3p21.31 and severe COVID-19.

As a result of the COVID-19 pandemic, evidence revealed that SARS-CoV-2 infection caused taste loss at a rate higher than that of influenza. ACE2, the entry receptor of SARS-CoV-2, has been identified in the oral epithelium; however, it is unclear at what developmental stage ACE2 expression emerges and whether ACE2 is expressed in taste buds. To identify the specific developmental stage, we analyzed RNA-Seq data from embryonic and newborn mouse oral tissue. We found that robust ACE2 expression was observed in the newborn oral epithelium. In contrast, only extremely low levels, if any, of ACE2 transcripts in the embryonic stage oral tissue were found (E12.5 and E14.5). Analyses of three public scRNA-seq data sets of adult mouse tongue epithelial cells showed that receptors for various viruses were enriched in distinct clusters of tongue epithelial cells. ACE2 was enriched in a subpopulation of epithelial cells in the basal region of nongustatory filiform papillae but not in the taste papillae or taste buds. Expression of ACE2 was detected in a small proportion of type III taste cells. Our results indicate that when applied across species, nongustatory papilla epithelial cells are the prime targets for SARS-CoV-2 infection in the tongue; thus, taste loss in COVID-19 patients is likely not caused by a direct infection of SARS-CoV-2 to taste bud cells. Additionally, fetuses at different stages of development may have distinct susceptibility to SARS-CoV-2 infection.

Supplemental material, Supplementary_figures_v2_xyz3635604710e57 for Genomic Survey of Tyrosine Kinases Repertoire in Electrophorus electricus With an Emphasis on Evolutionary Conservation and Diversification by Ling Li, Dangyun Liu, Ake Liu, Jingquan Li, Hui Wang and Jingqi Zhou in Evolutionary Bioinformatics

Supplemental material, TableS2_xyz363560f474193 for Genomic Survey of Tyrosine Kinases Repertoire in Electrophorus electricus With an Emphasis on Evolutionary Conservation and Diversification by Ling Li, Dangyun Liu, Ake Liu, Jingquan Li, Hui Wang and Jingqi Zhou in Evolutionary Bioinformatics

Background/Aims: Nodal cilia that rotate in the ventral node play an important role in establishing left-right asymmetry during embryogenesis; however, inv mutant cilia present abnormal movement and induce laterality defects. The mechanism of their motility, which is regulated by dynein activation and microtubule arrangement, has not been fully understood. This study analyzed the dynein-triggered ciliary motion in the abnormal ultrastructure of the inv mutant, aiming to quantitatively evaluate the influence of microtubule mislocalization on the movement of the cilium. Methods: We established a realistic 3-D model of an inv mutant cilium with an ultrastructure based on tomographic datasets generated by ultra-high voltage electron microscopy. The time-variant activation of the axonemal dynein force was simulated by pairs of point loads and embedded at dynein-mounted positions between adjacent microtubule doublets in this mathematical model. Utilizing the finite element method and deformable grid, the motility of the mutant cilium that is induced by various dynein activation hypotheses was investigated and compared to experimental observation. Results: The results indicate that for the inv mutant, simulations of the ciliary movement with the engagement of dyneins based on the distance-controlled pattern in the partially activation scenario are broadly consistent with the observation; the shortening of the microtubules induces smaller movement amplitudes, while the angles of the mislocalized microtubules affect the pattern of the ciliary movement, and during the ciliary movement, the microtubules swing and twist in the mutant ciliary body. Conclusion: More generally, this study implies that dynein engagement is sensitive to subtle geometric changes in the axoneme, and thus, this geometry greatly influences the integrity of a well-formed ciliary rotation.

OBJECTIVES: To disentangle the shared and unique causal clinical effects of five circulating minerals – iron, zinc, copper, calcium, and magnesium. METHODS: Genetic instruments for circulating minerals were curated from existing genome-wide association studies. Candidate clinical outcomes were identified with a phenome-wide association study (PheWAS) between these genetic instruments and 853 phenotypes in 310,999 individuals from the UK Biobank. Two-sample Mendelian Randomization (MR) analyses were performed to evaluate the causal associations between genetically predicted circulating mineral levels and candidate clinical outcomes. Multiple sensitivity tests were applied to detect and correct for the presence of horizontal pleiotropy. RESULTS: Iron and copper were found to share the most clinical outcomes. Genetically predicted higher blood levels of iron and copper are associated with lower risks of iron deficiency anemia and lipid metabolism disorders, including hyperlipidemia and hypercholesterolemia. Consistently, they are also associated with lower blood levels of total cholesterol and low-density lipoprotein cholesterol. On the other hand, osteoarthrosis (OA) and its subcategories are associated with the most minerals, including zinc, copper, and calcium. Genetically predicted higher blood levels of zinc and copper are associated with increased risk of OA, while calcium exhibits protective effects. Another five shared clinical effects were identified. For instance, zinc and magnesium are associated with a higher risk of bacterial infection; calcium and magnesium increase the risk of renal colic; iron increases while calcium decreases the risk of varicose veins. Unique clinical effects of each blood mineral were also pinpointed, such as iron enhancing the risk of glossitis and acquired foot deformities. CONCLUSIONS: Our comparative PheWAS-MR study of five circulating minerals comprehensively characterized their shared and unique clinical effects, highlighting the causal roles of specific minerals in hyperlipidemia and OA. Our findings emphasize managing blood minerals, probably through dietary adjustments, for disease prevention. FUNDING SOURCES: United States Department of Agriculture; National Institute of Food and Agriculture Hatch Funds; Allen Foundation Inc.; University of Georgia Research Foundation.

One of hot research foci has always been predicting amino acid residues underlying functional divergence after gene duplication, as those predicted sites can be used as candidates for further functional experimentations. It is important and interesting to know how many sites, on average, may have been responsible for the functional divergence between duplicate genes. In this article, we studied two basic types of functional divergence (type-I and type-II) in depth in order to give an accurate estimation of functional divergence-related sites. Type-I divergences result from altered functional constraints (i.e., different evolutionary rates) between duplicate genes, whereas type-II divergences refer to residues that are conserved by functional constraints but exhibit different physicochemical properties (e.g., charge or hydrophobicity) between duplicates. An effective site number (NE) strategy was applied in our study, which implements a stepwise regression model to calculate the minimum number of residues responsible for functional divergence without choosing preset threshold. We found that NE-determined cut-off value varies among different duplicate pairs, suggesting that empirical cutoff value is not suitable for every case. Under our standard NE calculation method, we estimated less than 15% of residues that are required for paralogous gene functional divergence. Finally, we established a database, DIVERGE-D, as a public resource for the predicted NE sites between two paralogs in this study, which can be used as candidates for further biological engineering and experimentation.

// Zhan Zhou 1, 4, * , Yangyun Zou 1, * , Gangbiao Liu 1 , Jingqi Zhou 1 , Jingcheng Wu 4 , Shimin Zhao 2 , Zhixi Su 1 and Xun Gu 3, 1 1 Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China 2 State Key Laboratory of Genetic Engineering, Collaborative Innovation Center of Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China 3 Department of Genetics, Development and Cell Biology, Program of Bioinformatics and Computational Biology, Iowa State University, Ames, Iowa, USA 4 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China * These authors have contributed equally to this work Correspondence to: Zhixi Su, email: zxsu@fudan.edu.cn Xun Gu, email: xgu@iastate.edu Keywords: cancer somatic mutations, mutation profile, natural selection, cancer-associated genes, evolution Received: October 26, 2016 Accepted: July 12, 2017 Published: July 19, 2017 ABSTRACT Human genes exhibit different effects on fitness in cancer and normal cells. Here, we present an evolutionary approach to measure the selection pressure on human genes, using the well-known ratio of the nonsynonymous to synonymous substitution rate in both cancer genomes ( C N / C S ) and normal populations ( p N / p S ). A new mutation-profile-based method that adopts sample-specific mutation rate profiles instead of conventional substitution models was developed. We found that cancer-specific selection pressure is quite different from the selection pressure at the species and population levels. Both the relaxation of purifying selection on passenger mutations and the positive selection of driver mutations may contribute to the increased C N / C S values of human genes in cancer genomes compared with the p N / p S values in human populations. The C N / C S values also contribute to the improved classification of cancer genes and a better understanding of the onco-functionalization of cancer genes during oncogenesis. The use of our computational pipeline to identify cancer-specific positively and negatively selected genes may provide useful information for understanding the evolution of cancers and identifying possible targets for therapeutic intervention.

Nanocomposite based on poly(vinylidene fluoride) (PVDF) polymer filled with surface functionalized core-shell structure BaTiO 3 @SiO 2 nanofibers (BT@SiO 2 NF) were prepared via the solution casting method. The effect of BT@SiO 2 NF filler introduction on the discharged energy density performance of the nanocomposite were investigated. The results indicated that the discharged energy density of nanocomposites is enhanced and the maximum discharged energy density in the nanocomposite with 2.5 vol% BT@SiO 2 NF is 6.6 J/cm 3 at 3500 kV/cm with an efficiency of above 62.7%. The reason of the enhancement of the discharged energy density performance is that coating SiO 2 layers on the surface of BT NF reduces the Maxwell–Wagner–Sillars interfacial polarization. This work may provide a novel route to enhance discharged energy density performance using core-shell nanofibers in polymer-based nanocomposites.

BackgroundOlfactory receptors (ORs) can bind odor molecules and play a crucial role in odor sensation. Due to the frequent gains and losses of genes during evolution, the number of OR members varies greatly among different species. However, whether the extent of gene gains/losses varies between marine mammals and related terrestrial mammals has not been clarified, and the factors that might underlie these variations are unknown.ResultsTo address these questions, we identified more than 10,000 members of the OR family in 23 mammals and classified them into 830 orthologous gene groups (OGGs) and 281 singletons. Significant differences occurred in the number of OR repertoires and OGGs among different species. We found that all marine mammals had fewer OR genes than their related terrestrial lineages, with the fewest OR genes found in cetaceans, which may be closely related to olfactory degradation. ORs with more gene duplications or loss events tended to be under weaker purifying selection. The average gain and loss rates of OR genes in terrestrial mammals were higher than those of mammalian gene families, while the average gain and loss rates of OR genes in marine mammals were significantly lower and much higher than those of mammalian gene families, respectively. Additionally, we failed to detect any one-to-one orthologous genes in the focal species, suggesting that OR genes are not well conserved among marine mammals.ConclusionsMarine mammals have experienced large numbers of OR gene losses compared with their related terrestrial lineages, which may result from the frequent birth-and-death evolution under varied functional constrains. Due to their independent degeneration, OR genes present in each lineage are not well conserved among marine mammals. Our study provides a basis for future research on the olfactory receptor function in mammals from the perspective of evolutionary trajectories.

Supplemental Digital Content is available in the text, Observational studies have reported that childhood obesity is positively associated with risks of type 2 diabetes (T2D) and coronary artery disease (CAD) in adults; however, whether this association is causal is still unclear. In the present study, we conducted the 2-sample Mendelian randomization (MR) studies to investigate whether childhood obesity is causally associated with T2D and CAD in adults. Seven single-nucleotide polymorphisms (SNPs) that significantly associated with childhood obesity were used as instrumental variables. The 2-sample MR analyses were performed with the summary-level data of large-sample genome-wide association studies to evaluate the causal effects of childhood obesity on adult T2D and CAD and the levels of cardiometabolic traits. The 2-sample MR analyses suggested that each 1-unit increase in the log-odds of having childhood obesity was causally associated with an increased risk of adult T2D (odds ratio [OR] = 1.16, 95% confidential interval [CI] = 1.06–1.28; P = 1.0 × 10–3) and CAD (OR = 1.07, 95% CI = 1.02–1.12; P = 4.0 × 10–3) based on the inverse-variance weighted method. The MR analyses also suggested that childhood obesity was positively associated with the levels of adult body mass index, waist circumference, hip circumference, waist and hip ratio, log-transformed fasting glucose, log-transformed homeostatic model assessment (HOMA) of insulin resistance (%), and triglycerides. The childhood obesity was negatively associated with the adult high-density lipoprotein cholesterol level; however, there was no evidence of a causal association between childhood obesity and the levels of fasting glucose, 2-hour glucose, HbA1c (%), log-transformed HOMA of ß-cell function (%), low-density lipoprotein cholesterol, or total cholesterol in adults. In conclusion, a genetic predisposition to childhood obesity was associated with an increased risk of adult T2D and CAD, providing causal relations between childhood obesity and the risks of T2D and CAD in adults; however, the results need to be validated with larger-scale intervention studies.

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