Machine-assisted pathological recognition has been focused on supervised learning (SL) that suffers from a significant annotation bottleneck. We propose a semi-supervised learning (SSL) method based ...on the mean teacher architecture using 13,111 whole slide images of colorectal cancer from 8803 subjects from 13 independent centers. SSL (~3150 labeled, ~40,950 unlabeled; ~6300 labeled, ~37,800 unlabeled patches) performs significantly better than the SL. No significant difference is found between SSL (~6300 labeled, ~37,800 unlabeled) and SL (~44,100 labeled) at patch-level diagnoses (area under the curve (AUC): 0.980 ± 0.014 vs. 0.987 ± 0.008, P value = 0.134) and patient-level diagnoses (AUC: 0.974 ± 0.013 vs. 0.980 ± 0.010, P value = 0.117), which is close to human pathologists (average AUC: 0.969). The evaluation on 15,000 lung and 294,912 lymph node images also confirm SSL can achieve similar performance as that of SL with massive annotations. SSL dramatically reduces the annotations, which has great potential to effectively build expert-level pathological artificial intelligence platforms in practice.
The perceived inability of climate change mitigation goals alone to mobilize sufficient climate change mitigation efforts has, among other factors, led to growing research on the co-benefits of ...reducing greenhouse gas (GHG) emissions. This study conducts a systematic review (SR) of the literature on the co-benefits of mitigating GHG emissions resulting in 1554 papers. We analyze these papers using bibliometric analysis, including a keyword co-occurrence analysis. We then iteratively develop and present a typology of co-benefits, mitigation sectors, geographic scope, and methods based on the manual double coding of the papers resulting from the SR. We find that the co-benefits from GHG mitigation that have received the largest attention of researchers are impacts on ecosystems, economic activity, health, air pollution, and resource efficiency. The co-benefits that have received the least attention include the impacts on conflict and disaster resilience, poverty alleviation (or exacerbation), energy security, technological spillovers and innovation, and food security. Most research has investigated co-benefits from GHG mitigation in the agriculture, forestry and other land use (AFOLU), electricity, transport, and residential sectors, with the industrial sector being the subject of significantly less research. The largest number of co-benefits publications provide analysis at a global level, with relatively few studies providing local (city) level analysis or studying co-benefits in Oceanian or African contexts. Finally, science and engineering methods, in contrast to economic or social science methods, are the methods most commonly employed in co-benefits papers. We conclude that given the potential mobilizing power of understudied co-benefits (e.g. poverty alleviation) and local impacts, the magnitude of GHG emissions from the industrial sector, and the fact that Africa and South America are likely to be severely affected by climate change, there is an opportunity for the research community to fill these gaps.
Mutant ZP1 in Familial Infertility Huang, Hua-Lin; Lv, Chao; Zhao, Ying-Chun ...
The New England journal of medicine,
03/2014, Volume:
370, Issue:
13
Journal Article
Peer reviewed
Open access
The zona pellucida is a clear, gelatinous matrix that surrounds the ovum and is essential to fertilization. Four sisters with primary infertility were found to harbor a mutation affecting one of the ...ZP proteins.
Summary
The human zona pellucida is composed of four glycoproteins (ZP1, ZP2, ZP3, and ZP4) and has an important role in reproduction. Here we describe a form of infertility with an autosomal recessive mode of inheritance, characterized by abnormal eggs that lack a zona pellucida. We identified a homozygous frameshift mutation in
ZP1
in six family members. In vitro studies showed that defective ZP1 proteins and normal ZP3 proteins colocalized throughout the cells and were not expressed at the cell surface, suggesting that the aberrant ZP1 results in the sequestration of ZP3 in the cytoplasm, thereby preventing the formation of . . .
Background
Increasing evidence suggests that human gut microbiome plays an important role in variation of skeletal muscle mass (SMM). However, specific causal mechanistic relationship of human gut ...microbiome with SMM remains largely unresolved. Understanding the causal mechanistic relationship may provide a basis for novel interventions for loss of SMM. This study investigated whether human gut microbiome has a causal effect on SMM among Chinese community‐dwelling healthy menopausal women.
Methods
Estimated SMM was derived from whole‐body dual‐energy X‐ray absorptiometry. We performed integrated analyses on whole‐genome sequencing, shotgun metagenomic sequencing, and serum short‐chain fatty acids (SCFAs), as well as available host SMM measurements among community‐dwelling healthy menopausal women (N = 482). We combined the results with summary statistics from genome‐wide association analyses for human gut microbiome (N = 952) and SMM traits (N = 28 330). As a prerequisite for causality, we used a computational protocol that was proposed to measure correlations among gut metagenome, metabolome, and the host trait to investigate the relationship between human gut microbiome and SMM. Causal inference methods were applied to assess the potential causal effects of gut microbial features on SMM, through one‐sample and two‐sample Mendelian randomization (MR) analyses, respectively.
Results
In metagenomic association analyses, the increased capacity for gut microbial synthesis of the SCFA butyrate was significantly associated with serum butyrate levels Spearman correlation coefficient (SCC) = 0.13, P = 0.02 and skeletal muscle index (SCC = 0.084, P = 0.002). Of interest was the finding that two main butyrate‐producing bacterial species were both positively associated with the increased capacity for gut microbial synthesis of butyrate Faecalibacterium prausnitzii (SCC = 0.25, P = 6.6 × 10−7) and Butyricimonas virosa (SCC = 0.15, P = 0.001) and for skeletal muscle index F. prausnitzii (SCC = 0.16, P = 6.2 × 10−4) and B. virosa (SCC = 0.17, P = 2.4 × 10−4). One‐sample MR results showed a causal effect between gut microbial synthesis of the SCFA butyrate and appendicular lean mass (β = 0.04, 95% confidence interval 0.029 to 0.051, P = 0.003). Two‐sample MR results further confirmed the causal effect between gut microbial synthesis of the SCFA butyrate and appendicular lean mass (β = 0.06, 95% confidence interval 0 to 0.13, P = 0.06).
Conclusions
Our results may help the future development of novel intervention approaches for preventing or alleviating loss of SMM.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Although previous studies have explored the gene expression profiles of human oocytes and granulosa cells by single‐cell RNA sequencing (scRNA‐seq), the dynamic regulatory network at a single‐cell ...resolution during folliculogenesis remains largely unknown. We identified 10 functional modules by WGCNA, four of which were significantly correlated with primary/antral oocyte and antral/pre‐ovulatory granulosa cells. Functional enrichment analysis showed that the brown module, which was correlated with antral oocyte, was enriched in oocyte differentiation, and two core subnetworks identified by MCODE were involved in cell cycle (blue subnetwork) and oogenesis (red subnetwork). The cell‐specific network (CSN) analysis demonstrated a distinct gene network structure associated with the antral follicular stage, which was notably different from other developmental stages. To our knowledge, this is the first study to explore gene functions during folliculogenesis at single‐cell network level. We uncovered two potential gene subnetworks, which may play an important role in oocyte function beginning at the antral stage, and further established their rewiring process at intra‐network/whole transcriptome level. The findings provide crucial insights from a novel network perspective to be further explored in functional mechanistic studies.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Plasma low-density lipoprotein (LDL) is primarily cleared by LDL receptor (LDLR). LDLR can be proteolytically cleaved to release its soluble ectodomain (sLDLR) into extracellular milieu. However, the ...proteinase responsible for LDLR cleavage is unknown. Here we report that membrane type 1-matrix metalloproteinase (MT1-MMP) co-immunoprecipitates and co-localizes with LDLR and promotes LDLR cleavage. Plasma sLDLR and cholesterol levels are reduced while hepatic LDLR is increased in mice lacking hepatic MT1-MMP. Opposite effects are observed when MT1-MMP is overexpressed. MT1-MMP overexpression significantly increases atherosclerotic lesions, while MT1-MMP knockdown significantly reduces cholesteryl ester accumulation in the aortas of apolipoprotein E (apoE) knockout mice. Furthermore, sLDLR is associated with apoB and apoE-containing lipoproteins in mouse and human plasma. Plasma levels of sLDLR are significantly increased in subjects with high plasma LDL cholesterol levels. Thus, we demonstrate that MT1-MMP promotes ectodomain shedding of hepatic LDLR, thereby regulating plasma cholesterol levels and the development of atherosclerosis.
The rapid population growth in China has increased the demand for limited water, energy and food resources. Because the resource supply is constrained by future uncertainties such as climate change, ...it is necessary to examine the connections among water, energy and food resources from the perspective of the relevant final demands. Based on an input-output model and structural path analysis, this study aims to explore the hidden connections among water, energy and food resources by identifying important final demands and examine how these resources are embodied in upstream production and downstream consumption processes along the supply chain. The water-energy-food nexus approach in this research identifies where and how these resources intersect in economic sectors. By simultaneously considering the water, energy and food footprints, synergistic effects can be maximized among these resource systems. The results reveal that urban household consumption and fixed capital formation have large impacts on water-energy-food resources. Besides, agriculture, construction and service sectors have the largest water-energy-food footprints. For each resource, we rank the top-20 supply chain paths from the final demands to the upstream production sectors, and six critical supply chain paths are identified as important contributors to the consumption of all these resources. Compared with independent approach to manage water, energy and food resources, the nexus approach identifies the critical linkages of the water, energy and food systems and helps to formulate integrated policies to effectively manage these resources across sectors and actors. Synergistic strategies for conserving water, energy, and food resources can be achieved through avoiding unnecessary waste in end uses and improving resource use efficiency along critical supply chains. This research can help consumers, industries and the government make responsible consumption and production decisions to conserve water, energy and food resources.
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•The hidden connections among water, energy and food consumptions are examined.•Maximizing the synergy of the water-energy-food nexus management.•Urban household consumption and fixed capital formation have large resource impacts.•Agriculture, construction and service sectors have the largest resource footprints.•Six key supply chains that consume these resources simultaneously are recognized.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A randomized, parallel controlled, open-label clinical trial was conducted to evaluate the effect of a botanic compound berberine (BBR) on NAFLD.
A randomized, parallel controlled, open-label ...clinical trial was conducted in three medical centers (NIH Registration number: NCT00633282). A total of 184 eligible patients with NAFLD were enrolled and randomly received (i) lifestyle intervention (LSI), (ii) LSI plus pioglitazone (PGZ) 15mg qd, and (iii) LSI plus BBR 0.5g tid, respectively, for 16 weeks. Hepatic fat content (HFC), serum glucose and lipid profiles, liver enzymes and serum and urine BBR concentrations were assessed before and after treatment. We also analyzed hepatic BBR content and expression of genes related to glucose and lipid metabolism in an animal model of NAFLD treated with BBR.
As compared with LSI, BBR treatment plus LSI resulted in a significant reduction of HFC (52.7% vs 36.4%, p = 0.008), paralleled with better improvement in body weight, HOMA-IR, and serum lipid profiles (all p<0.05). BBR was more effective than PGZ 15mg qd in reducing body weight and improving lipid profile. BBR-related adverse events were mild and mainly occurred in digestive system. Serum and urine BBR concentrations were 6.99ng/ml and 79.2ng/ml, respectively, in the BBR-treated subjects. Animal experiments showed that BBR located favorably in the liver and altered hepatic metabolism-related gene expression.
BBR ameliorates NAFLD and related metabolic disorders. The therapeutic effect of BBR on NAFLD may involve a direct regulation of hepatic lipid metabolism.
ClinicalTrials.gov NCT00633282.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Concern about rising rates of obesity has prompted searches for obesity-related single nucleotide polymorphisms (SNPs) in genome-wide association studies (GWAS). Identifying plausible regulatory SNPs ...is very difficult partially because of linkage disequilibrium. We used an unusual epigenomic and transcriptomic analysis of obesity GWAS-derived SNPs in adipose versus heterologous tissues. From 50 GWAS and 121,064 expanded SNPs, we prioritized 47 potential causal regulatory SNPs (Tier-1 SNPs) for 14 gene loci. A detailed examination of seven loci revealed that four (
,
,
, and
) had Tier-1 SNPs positioned so that they could regulate use of alternative transcription start sites, resulting in different polypeptides being generated or different amounts of an intronic microRNA gene being expressed.
and long noncoding RNA gene
had Tier-1 SNPs in their 3' or promoter region, respectively, and strong preferences for expression in subcutaneous versus visceral adipose tissue.
had two intragenic Tier-1 SNPs, each of which could contribute to mediating obesity risk through modulating long-distance chromatin interactions. Our approach not only revealed especially credible novel regulatory SNPs, but also helped evaluate previously highlighted obesity GWAS SNPs that were candidates for transcription regulation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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