Sensitive responses among bacterial and fungal communities to pyrogenic organic matter (PyOM) (biochar) addition in rhizosphere and bulk soils are poorly understood. We conducted a pot experiment with manure and straw PyOMs added to an acidic paddy soil, and identified the sensitive "responders" whose relative abundance was significantly increased/decreased among the whole microbial community following PyOM addition. Results showed that PyOMs significantly (p < 0.05) increased root growth, and simultaneously changed soil chemical parameters by decreasing soil acidity and increasing biogenic resource. PyOM-induced acidity and biogenic resource co-determined bacterial responder community structure whereas biogenic resource was the dominant parameter structuring fungal responder community. Both number and proportion of responders in rhizosphere soil was larger than in bulk soil, regardless of PyOM types and microbial domains, indicating the microbial community in rhizosphere soil was sensitive to PyOM addition than bulk soil. The significant increased root biomass and length caused by PyOM addition, associated with physiological processes, e.g. C exudates secretion, likely favored more sensitive responders in rhizosphere soil than in bulk soil. Our study identified the responders at fine taxonomic resolution in PyOM amended soils, improved the understanding of their ecological phenomena associated with PyOM addition, and examined their interactions with plant roots.

The integrated analysis of the distribution characteristics, health risks, and source identification of heavy metals is crucial for formulating prevention and control strategies for soil contamination. In this study, the area around an abandoned electronic waste dismantling center in China was selected as the research area. The probabilistic health risks caused by heavy metals were evaluated by the Monte Carlo simulation. Random forest, partial least squares regression, and generalized linear models were utilized to predict heavy metal distributions and identify the potential driving factors affecting heavy metal accumulation in soil. The relationships of spatial variation between the heavy metal contents and environmental variables were further visualized. The results revealed that cadmium (Cd) and copper (Cu) were the primary soil pollutants in the study area and caused high ecological risks. The probabilistic health risk assessment indicated that the non-carcinogenic and carcinogenic risks for all populations were acceptable. However, children are more susceptible to heavy metal soil contamination than adults. The sensitivity analyses indicated that the total contents of soil heavy metals and soil ingestion rate were the dominant factors affecting human health. The random forest model, with R2 values of 0.41, 0.65, 0.57, 0.71, and 0.58 for Cd, Cu, Ni, Zn, and Pb, respectively, predicted the heavy metal concentrations better than the other two models. The distance to the nearest industrial enterprise, industrial output, and agricultural chemical input were the main factors affecting Cd, Cu, Zn, and Pb accumulations in the soil, and soil pH and soil parent material were the primary factors influencing Ni accumulation in the soil. The visualization results of the geographically weighted regression model showed a significant relationship between soil heavy metal contents and industrial activity level. This study could be utilized as a reference for policymakers to formulate prevention and control strategies for heavy metal pollution in agricultural areas.

Fine particulate matter (PM2.5) has been reported to be an important risk factor for asthma. This study was designed to evaluate the relationship between PM2.5 and lung function among children with asthma in Shanghai, China. From 2016 to 2019, a total of 70 Chinese children aged 4 to 14 in Shanghai were recruited for this panel study. The questionnaire was used to collect baseline information, and the lung function covering forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and peak expiratory flow (PEF) were carried out for each child more than twice during follow-up. Meanwhile, the simultaneous daily air atmospheric pollutants and meteorological data were collected. The linear mixed effect (LME) model was used to assess the relationship between air pollutants and lung function. A significantly negative association was found between PM2.5 and lung function in children with asthma. In the single-pollutant model, the largest effects of PM2.5 on lung function were found for lag 0-2, with FVC and FEV1 decreasing by 0.91% [95% confidence interval (CI): -1.75, -0.07] and 1.05% (95% CI: -2.09, 0.00), respectively, for each 10 μg/m3 increase in PM2.5. In the multi-pollution model (adjusted PM2.5 + SO2 + O3), the maximum effects of PM2.5 on FVC and FEV1 also appeared for lag 0-2, with FVC and FEV1 decreasing by 1.57% (95% CI: -2.69, -0.44) and 1.67% (95% CI: -3.05, -0.26), respectively, for each 10 μg/m3 increase in PM2.5. In the subgroup analysis, boys, preschoolers (<6 years old) and hot seasons (May to September) were more sensitive to changes. Our findings may contribute to a better understanding of the short-term exposure effects of PM2.5 on lung function in children with asthma.

It is difficult to predict normal-sized lymph node metastasis (LNM) in cervical cancer clinically. We aimed to investigate the feasibility of using deep learning (DL) nomogram based on readout segmentation of long variable echo-trains diffusion weighted imaging (RESOLVE-DWI) and related patient information to preoperatively predict normal-sized LNM in patients with cervical cancer.

Human activities have increased reactive nitrogen (Nr) input to terrestrial ecosystems compared with the pre-industrial era. However, the fate of such Nr input remains uncertain, leading to missing sink of the global nitrogen budget. By synthesizing records of Nr burial in sediments from 303 lakes worldwide, here we show that 9.6 ± 1.1 Tg N year-1 (Tg = 1012 g) accumulated in inland water sediments from 2000 to 2010, accounting for 3%-5% of global Nr input to the land from combined natural and anthropogenic pathways. The recent Nr burial flux doubles pre-industrial estimates, and Nr burial rate significantly increases with global increases in human population and air temperature. Sediment ratios of C:N decrease after 1950 while N:P ratios increase over time due to increasingly elevated Nr burial and other related processes in lakes. These findings imply that Nr burial in lakes is overlooked as an important global sink of Nr input to terrestrial ecosystems.

Steroid hormones play important roles in brain development and function. The signaling of steroid hormones depends on the interaction between steroid receptors and their coactivators. Although the function of steroid receptor coactivators has been extensively studied in other tissues, their functions in the central nervous system are less well investigated. In this study, we addressed the function of steroid receptor coactivator 3 (SRC3) - a member of the p160 SRC protein family that is expressed predominantly in the hippocampus. While hippocampal development was not altered in Src3+/- mice, hippocampus-dependent functions such as short-term memory and spatial memory were impaired. We further demonstrated that the deficient learning and memory in Src3+/- mice was strongly associated with the impairment of long-term potentiation (LTP) at Schaffer Collateral-CA1 synapses. Mechanistic studies indicated that Src3+/- mutation altered the composition of N-methyl-D-aspartate receptor subunits in the postsynaptic densities of hippocampal neurons. Finally, we showed that SRC3 regulated synaptic plasticity and learning mainly dependent on its lysine acetyltransferase activity. Taken together, these results reveal previously unknown functions of SRC3 in the hippocampus and thus may provide insight into how steroid hormones regulate brain function.

Developing low-cadmium (Cd) rice cultivars has emerged as a promising avenue for food safety in Cd-contaminated farmlands. The root-associated microbiomes of rice have been shown to enhance rice growth and alleviate Cd stress. However, the microbial taxon-specific Cd resistance mechanisms underlying different Cd accumulation characteristics between different rice cultivars remain largely unknown. This study compared low-Cd cultivar XS14 and hybrid rice cultivar YY17 for Cd accumulation with five soil amendments. The results showed that XS14 was characterized by more variable community structures and stable co-occurrence networks in the soil-root continuum compared to YY17. The stronger stochastic processes in assembly of the XS14 (~25%) rhizosphere community than that of YY17 (~12%) suggested XS14 may have higher resistance to changes in soil properties. Microbial co-occurrence networks and machine learning models jointly identified keystone indicator microbiota, such as Desulfobacteria in XS14 and Nitrospiraceae in YY17. Meanwhile, genes involved in sulfur cycling and nitrogen cycling were observed among the root-associated microbiome of these two cultivars, respectively. Microbiomes in the rhizosphere and root of XS14 showed a higher diversity in functioning, with the significant enrichment of functional genes related to amino acid and carbohydrate transport and metabolism, and sulfur cycling. Our findings revealed differences and similarities in the microbial communities associated with two rice cultivars, as well as bacterial biomarkers predictive of Cd-accumulation capacity. Thus, we provide new insights into taxon-specific recruitment strategies of two rice cultivars under Cd stress and highlight the utility of biomarkers in offering clues for enhancing crop resilience to Cd stresses in the future.

Antibiotic overuse and the subsequent environmental contamination of residual antibiotics poses a public health crisis via an acceleration in the spread of antibiotic resistance genes (ARGs) through horizontal gene transfer. Although the occurrence, distribution, and driving factors of ARGs in soils have been widely investigated, little is known about the antibiotic resistance of soilborne pathogens at a global scale. To explore this gap, contigs from 1643 globally sourced metagnomes are assembled, yielding 407 ARG-carrying pathogens (APs) with at least one ARG; APs are detected in 1443 samples (sample detection rate of 87.8%). The richness of APs is greater in agricultural soils (with a median of 20) than in non-agricultural ecosystems. Agricultural soils possess a high prevalence of clinical APs affiliated with Escherichia, Enterobacter, Streptococcus, and Enterococcus. The APs detected in agricultural soils tend to coexist with multidrug resistance genes and bacA. A global map of soil AP richness is generated, where anthropogenic and climatic factors explained AP hot spots in East Asia, South Asia, and the eastern United States. The results herein advance this understanding of the global distribution of soil APs and determine regions prioritized to control soilborne APs worldwide.

The interactions between soil microbiomes at various trophic levels are essential for restoring soil functions. Legumes are considered as "pioneer crops" in degraded or contaminated soils because they can fix nitrogen through symbiotic relationships with rhizobacteria, which promotes soil fertility. However, little is known about the abilities of legumes to contribute to the health of soil contaminated with cadmium (Cd). In this research, we applied a soil amendment (commercial Mg-Ca-Si conditioner, CMC) at two rates (1,500 and 3,000 kg/ha) in a Cd-contaminated soybean field. Bulk and rhizosphere soil samples were collected to assess the amendment-induced effects on four microbial lineages (bacteria, fungi, arbuscular mycorrhizal fungi [AMF], and nematodes) and their functions including Cd stabilization, nutrient cycling, and pathogen control. Compared with the control, both CMC application rates increased the pH and reduced labile Cd fraction in the bulk and rhizosphere soils. Although the total Cd concentrations in the soil were similar, the Cd accumulation in the grains was significantly reduced in treatments of soil amendments. It was observed that the application of CMC can significantly reduce the AMF diversity but increased the diversity of the other three communities. Moreover, the biodiversity within keystone modules (identified by co-occurrence network analysis) played key roles in driving soil multifunctionality. Specifically, key beneficial groups in module 2 such as Aggregicoccus (bacteria), Sordariomycetes (fungi), Glomus (AMF), and Bursaphelenchus (nematode) were strongly associated with soil multifunctionality. By co-culturing bacterial suspensions with the soybean root rot pathogen Fusarium solani in the in vitro assays, we experimentally validated that the application of CMC promoted the suppression of soil bacterial community on pathogens by inhibiting the mycelium growth and spore germination. Also, the bacterial community was more resistant to Cd stress in soils receiving CMC amendment. Our findings provide valuable theoretical references for enhancing soil functions and health via applying a soil amendment (CMC) during Cd-contaminated soil remediation. IMPORTANCE Restoration of microbiome-driven soil functions and health is of great importance during Cd-contaminated soil remediation via soil amendment. Soybean and its symbiotic mutualism can provide abundant nitrogen and phosphorus to relieve the nutrient deficiency of Cd-contaminated soil. This study provides a novel perspective on the potential role of applying a soil amendment (CMC) in enhancing the functions and health of Cd-contaminated soils. Our results showed the distinct differences in soil microbial community responding to amendment-induced changes in edaphic properties. The biodiversity within keystone modules had major contributions to the maintenance of the soil's multifunctionality and health. Additionally, a higher CMC application rate showed more beneficial effects. Collectively, our results enhance our understanding about the effects of applying CMC, together with soybean rotation, to enhance and maintain soil functions and health during the field Cd stabilization process.

Glucose is the basic fuel essential for maintenance of viability and functionality of all cells. However, some neurons - namely, glucose-inhibited (GI) neurons - paradoxically increase their firing activity in low-glucose conditions and decrease that activity in high-glucose conditions. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here, we showed that currents mediated by the anoctamin 4 (Ano4) channel are only detected in GI neurons in the ventromedial hypothalamic nucleus (VMH) and are functionally required for their activation in response to low glucose. Genetic disruption of the Ano4 gene in VMH neurons reduced blood glucose and impaired counterregulatory responses during hypoglycemia in mice. Activation of VMHAno4 neurons increased food intake and blood glucose, while chronic inhibition of VMHAno4 neurons ameliorated hyperglycemia in a type 1 diabetic mouse model. Finally, we showed that VMHAno4 neurons represent a unique orexigenic VMH population and transmit a positive valence, while stimulation of neurons that do not express Ano4 in the VMH (VMHnon-Ano4) suppress feeding and transmit a negative valence. Together, our results indicate that the Ano4 channel and VMHAno4 neurons are potential therapeutic targets for human diseases with abnormal feeding behavior or glucose imbalance.

Soil harbors a vast expanse of unidentified microbes, termed as microbial dark matter, presenting an untapped reservo)ir of microbial biodiversity and genetic resources, but has yet to be fully explored. In this study, we conduct a large-scale excavation of soil microbial dark matter by reconstructing 40,039 metagenome-assembled genome bins (the SMAG catalogue) from 3304 soil metagenomes. We identify 16,530 of 21,077 species-level genome bins (SGBs) as unknown SGBs (uSGBs), which expand archaeal and bacterial diversity across the tree of life. We also illustrate the pivotal role of uSGBs in augmenting soil microbiome's functional landscape and intra-species genome diversity, providing large proportions of the 43,169 biosynthetic gene clusters and 8545 CRISPR-Cas genes. Additionally, we determine that uSGBs contributed 84.6% of previously unexplored viral-host associations from the SMAG catalogue. The SMAG catalogue provides an useful genomic resource for further studies investigating soil microbial biodiversity and genetic resources.

Cetuximab in combination with chemotherapy is a standard-of-care first-line treatment regimen for patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC); however, the efficacy of cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX) has never before been proven in a controlled and randomized phase III trial. To our knowledge, the TAILOR trial ( ClinicalTrials.gov identifier: NCT01228734) is the first randomized, multicenter, phase III study of the addition of cetuximab to first-line FOLFOX prospectively choosing a RAS wt population and thus providing confirmative data for the efficacy and safety of cetuximab plus FOLFOX versus FOLFOX alone.

The mammalian stomach is structurally highly diverse and its organ functionality critically depends on a normal embryonic development. Although there have been several studies on the morphological changes during stomach development, a system-wide analysis of the underlying molecular changes is lacking. Here, we present a comprehensive, temporal proteome and transcriptome atlas of the mouse stomach at multiple developmental stages. Quantitative analysis of 12,108 gene products allows identifying three distinct phases based on changes in proteins and RNAs and the gain of stomach functions on a longitudinal time scale. The transcriptome indicates functionally important isoforms relevant to development and identifies several functionally unannotated novel splicing junction transcripts that we validate at the peptide level. Importantly, many proteins differentially expressed in stomach development are also significantly overexpressed in diffuse-type gastric cancer. Overall, our study provides a resource to understand stomach development and its connection to gastric cancer tumorigenesis.

Triple negative breast cancer (TNBC) has the poorest prognosis of all types of breast cancer and currently lacks efficient targeted therapy. Chemotherapy is the traditional standard-of-care for TNBC, but is frequently accompanied by severe side effects. Despite the fact that high expression of steroid receptor coactivator 3 (SRC-3) is correlated with poor survival in estrogen receptor positive breast cancer patients, its role in TNBC has not been extensively investigated. Here, we show that high expression of SRC-3 correlates with both poor overall survival and post progression survival in TNBC patients, suggesting that SRC-3 can serve as a prognostic marker for TNBC. Furthermore, we demonstrated that bufalin, a SRC-3 small molecule inhibitor, when introduced even at nM concentrations, can significantly reduce TNBC cell viability and motility. However, because bufalin has minimal water solubility, its in vivo application is limited. Therefore, we developed a water soluble prodrug, 3-phospho-bufalin, to facilitate its in vivo administration. In addition, we demonstrated that 3-phospho-bufalin can effectively inhibit tumor growth in an orthotopic TNBC mouse model, suggesting its potential application as a targeted therapy for TNBC treatment.

Soil microbiota play a critical role in soil biogeochemical processes and have a profound effect on soil functions. Recent studies have revealed microbial co-occurrence patterns in soil microbial communities, yet the geographic pattern of topological features in soil microbial co-occurrence networks at the continental scale are largely unknown. Here, we investigated the shifts of topological features in co-occurrence networks inferred from soil microbiota along a continental scale in eastern China. Integrating archaeal, bacterial and fungal community datasets, we inferred a meta-community co-occurrence network and analyzed node-level and network-level topological shifts associated with five climatic regions. Both node-level and network-level topological features revealed geographic patterns wherein microorganisms in the northern regions had closer relationships but had a lower interaction influence than those in the southern regions. We further identified topological differences associated with taxonomic groups and demonstrated that co-occurrence patterns were random for archaea and non-random for bacteria and fungi. Given that microbial interactions may contribute to soil functions more than species diversity, this geographic shift of topological features provides new insight into studying microbial biogeographic patterns, their organization and impacts on soil-associated function.

In soil microbiology, there is a "paradox" of soil organic carbon (SOC) mineralization, which is that even though chloroform fumigation destroys majority of the soil microbial biomass, SOC mineralization continues at the same rate as in the non-fumigated soil during the incubation period. Soil microeukaryotes as important SOC decomposers, however, their community-level responses to chloroform fumigation are not well understood. Using the 18S rRNA gene amplicon sequencing, we analyzed the composition, diversity, and C-metabolic functions of a grassland soil and an arable soil microeukaryotic community in response to fumigation followed by a 30-day incubation. The grassland and arable soil microeukaryotic communities were dominated by the fungal Ascomycota (80.5-93.1% of the fungal sequences), followed by the protistan Cercozoa and Apicomplexa. In the arable soil fungal community, the predominance of the class Sordariomycetes was replaced by the class Eurotiomycetes after fumigation at days 7 and 30 of the incubation. Fumigation changed the microeukaryotic α-diversity in the grassland soil at days 0 and 7, and β-diversity in the arable soil at days 7 and 30. Network analysis indicated that after fumigation fungi were important groups closely related to other taxa. Most phylotypes (especially Sordariomycetes, Dothideomycetes, Coccidia, and uncultured Chytridiomycota) were inhibited, and only a few were positively stimulated by fumigation. Despite the inhibited Sordariomycetes, the fumigated communities mainly consisted of Eurotiomycetes and Sordariomycetes (21.9 and 36.5% relative frequency, respectively), which are able to produce hydrolytic enzymes associated with SOC mineralization. Our study suggests that fumigation not only decreases biomass size, but modulates the composition and diversity of the soil microeukaryotic communities, which are capable of driving SOC mineralization by release of hydrolytic enzymes during short-term fumigation-incubation.

Peroxisome proliferator-activated receptor (PPAR)alpha, beta (also known as delta), and gamma function as sensors for fatty acids and fatty acid derivatives and control important metabolic pathways involved in the maintenance of energy balance. PPARs also regulate other diverse biological processes such as development, differentiation, inflammation, and neoplasia. In the nucleus, PPARs exist as heterodimers with retinoid X receptor-alpha bound to DNA with corepressor molecules. Upon ligand activation, PPARs undergo conformational changes that facilitate the dissociation of corepressor molecules and invoke a spatiotemporally orchestrated recruitment of transcription cofactors including coactivators and coactivator-associated proteins. While a given nuclear receptor regulates the expression of a prescribed set of target genes, coactivators are likely to influence the functioning of many regulators and thus affect the transcription of many genes. Evidence suggests that some of the coactivators such as PPAR-binding protein (PBP/PPARBP), thyroid hormone receptor-associated protein 220 (TRAP220), and mediator complex subunit 1 (MED1) may exert a broader influence on the functions of several nuclear receptors and their target genes. Investigations into the role of coactivators in the function of PPARs should strengthen our understanding of the complexities of metabolic diseases associated with energy metabolism.

The nuclear receptor coactivator-6 (NCOA6, AIB3, PRIP, ASC-2, TRBP, RAP250 or NRC) is a co-activator for nuclear hormone receptors and certain other transcription factors. NCOA6 plays an important role in embryonic development, adipocyte differentiation, metabolism and breast carcinogenesis. The human and mouse NCOA6 genes had 15 and 14 previously identified exons, respectively. This study further identified an alternatively spliced exon 11b (E11b) in human or E10b in mouse, which codes a short polypeptide and a Stop codon, resulting in splicing variants lacking the last four exon-coded polypeptide. Analyses of mouse testis NCOA6 mRNAs identified four alternatively spliced variants, NCOA6-α (without E10b), -β (without E10a and E10b), -γ (with E10a and E10b) and -δ (without E10a but with E10b). These isoforms were detected in multiple mouse tissues and in MDA-MB-435 human cells. NCOA6-α and -β are mainly located in the nucleus; NCOA6-γ is located in both cytoplasm and nucleus; and NCOA6-δ is mainly located in mitochondria. The C-terminus coded by the last four exons was responsible for locating NCOA6-α and -β into the nucleus. The human E11a or mouse E10a-coded region is responsible for distributing NCOA6-γ in both cytoplasm and nucleus, while the region coded by E8-E9 in human or E7-E8 in mouse is responsible for directing NCOA6-δ to mitochondria. Our assays also demonstrated that NCOA6-α and -β could significantly enhance estrogen receptor α-mediated transcription, but NCOA6-γ and -δ were unable to do so. These results suggest that the diverse physiological function of NCOA6 may be mediated by multiple isoforms expressed in different tissues and localized in different subcellular compartments.

Kdm3b is a JmjC domain-containing histone H3 (H3) demethylase and its physiological functions are largely unknown. In this study, we found that Kdm3b protein is highly expressed in multiple cell types in the mouse testes, including Leydig cells, Sertoli cells, spermatogonia and spermatocytes at different differentiation stages. We also observed Kdm3b protein in the epithelial cells of the caput epididymis, prostate and seminal vesicle. Breeding tests revealed that the number of pups produced by the breeding pairs with Kdm3b knockout (Kdm3bKO) males and wild type (WT) females was reduced 68% because of the decreased number of litters when compared with the breeding pairs with WT males and females. Further analysis demonstrated that Kdm3bKO male mice produced 44% fewer number of mature sperm in their cauda epididymides, displaying significantly reduced sperm motility. No significant differences in the circulating concentration of testosterone and the expression levels of androgen receptor and its representative target genes in the testis were observed. However, the circulating levels of 17β-estradiol, a modulator of sperm maturation and male sexual behaviors, was markedly reduced in Kdm3bKO male mice. Strikingly, abrogation of Kdm3b in male mice significantly increased the latencies to mount, intromit and ejaculate and decreased the number of mounts and intromissions, largely due to their loss of interest in female odors. These findings indicate that Kdm3b is required for normal spermatogenesis and sexual behaviors in male mice.

Although ductal carcinoma in situ (DCIS) is a non-invasive breast cancer, many DCIS lesions may progress to invasive cancer and the genes and pathways responsible for its progression are largely unknown. FGFR1 plays an important role in cell proliferation, differentiation and carcinogenesis. The purpose of this study is to examine the roles of FGFR1 signaling in gene expression, cell proliferation, tumor growth and progression in a non-invasive DCIS model.