Ancient Mitogenomes Reveal the Maternal Genetic History of East Asian Dogs.

Recent studies have suggested that dogs were domesticated during the Last Glacial Maximum (LGM) in Siberia, which contrasts with previous proposed domestication centers (e.g. Europe, the Middle East, and East Asia). Ancient DNA provides a powerful resource for the study of mammalian evolution and has been widely used to understand the genetic history of domestic animals. To understand the maternal genetic history of East Asian dogs, we have made a complete mitogenome dataset of 120 East Asian canids from 38 archaeological sites, including 102 newly sequenced from 12.9 to 1 ka BP (1,000 years before present). The majority (112/119, 94.12%) belonged to haplogroup A, and half of these (55/112, 49.11%) belonged to sub-haplogroup A1b. Most existing mitochondrial haplogroups were present in ancient East Asian dogs. However, mitochondrial lineages in ancient northern dogs (northeastern Eurasia and northern East Asia) were deeper and older than those in southern East Asian dogs. Results suggests that East Asian dogs originated from northeastern Eurasian populations after the LGM, dispersing in two possible directions after domestication. Western Eurasian (Europe and the Middle East) dog maternal ancestries genetically influenced East Asian dogs from approximately 4 ka BP, dramatically increasing after 3 ka BP, and afterwards largely replaced most primary maternal lineages in northern East Asia. Additionally, at least three major mitogenome sub-haplogroups of haplogroup A (A1a, A1b, and A3) reveal at least two major dispersal waves onto the Qinghai-Tibet Plateau in ancient times, indicating eastern (A1b and A3) and western (A1a) Eurasian origins.

Origin of domesticated water chestnuts (Trapa bispinosa Roxb.) and genetic variation in wild water chestnuts.

The water chestnut Trapa bispinosa Roxb. has been domesticated in China and has been reported as the only domesticated species of this genus. To understand the origin of T. bispinosa and its evolution pathway, we compared the genetic similarity and seed morphology of domesticated water chestnut T. bispinosa with three wild species T. natans, T. incisa, and T. japonica along with archeological seed samples from the Tianluoshan site (approximately 7000-6300 cal BP) in China. The largest seed size was observed only in the domesticated species, whereas other wild species showed smaller size including T. natans L. genetically close to the domesticated type, and T. incisa was the smallest in size. The volumes of the seed capsule and endosperm were measured using X ray CT scans, showing the ratios of total volumes between T. bispinosa and wild species ranged from 4.2 to 4.5. The ratios of endosperm volume ranged from 3.3 to 3.7. Both measurements showed domesticated species have larger seed volume. Genome size was indirectly estimated by flow cytometry. Domesticated species with larger seed size was estimated as diploid, as were the wild species except for tetraploid species T. japonica. Domesticated species clearly showed the largest edible organs, but it was not a result of ploidy level changes. Maternal lineages traced using complete whole chloroplast sequences, suggested that T. natans is the closest to T. bispinosa, both of which are close to T. japonica. The result was confirmed by PCR genotyping with chloroplast insertion/deletion (cpINDEL) markers developed in the study. T. incisa showed distinct plastid types within the species, and T. japonica showed a unique plastid genotype. Our study concludes the largest volumes for the edible endosperm have been accomplished through nearly 6000 years of artificial selection, but the domestication did not involve ploidy level changes.

A retrospective study on the efficacy and safety of Envafolimab, a PD-L1 inhibitor, in the treatment of advanced malignant solid tumors.

Envafolimab, a PD-L1 inhibitor, has demonstrated potential in treating advanced malignant solid tumors (AMST). To study its' efficacy and safety in AMST, our retrospective study recruited 64 patients with various AMST, and treated with Envafolimab (400 mg every 3 weeks). We divided the patients into two cohorts: Cohort 1 (25 patients) receiving Envafolimab as first-line therapy, and Cohort 2 (39 patients) receiving it as second-line or subsequent therapy. Our analysis focused on Envafolimab's efficacy and safety. Over a median follow-up of 7.1 months, Cohort I reported a Disease Control Rate (DCR) of 72.0% and an Objective response rate (ORR) of 12.0%, while Cohort II had a DCR of 51.3% and an ORR of 5.1%. Notably, patients with more than four treatment cycles showed higher DCR and longer Progression-Free Survival (PFS) than those with fewer cycles. Adverse events were observed in 68.8% of patients, with severe events (CTCAE grade 3/4) in 14.1%. Most adverse events were mild, leading to treatment discontinuation in only 3.1% of patients, with no life-threatening events reported. In summary, Envafolimab is a safe and effective treatment for AMST, in both initial and later therapy stages, particularly with extended treatment duration, meriting further clinical trials.

Metagenome-assembled genome reveals species and functional composition of Jianghan chicken gut microbiota and isolation of Pediococcus acidilactic with probiotic properties.

BACKGROUND: Chickens are one of the most widely farmed animals worldwide and play a crucial role in meat and egg production. Gut microbiota is essential for chickens' health, disease, growth, and egg production. However, native chickens such as Jianghan chickens have better meat and egg production quality than centralized chickens, their intestinal microbial diversity is richer, and the potential gut microbial resources may bring health benefits to the host. RESULTS: The bacterial species composition in the gut microbiota of Jianghan chickens is similar to that of other chicken breeds, with Phocaeicola and Bacteroides being the most abundant bacterial genera. The LEfSe analysis revealed significant differences in species composition and functional profiles between samples from Jingzhou and the other three groups. Functional annotation indicated that the gut microbiota of Jianghan chickens were dominated by metabolic genes, with the highest number of genes related to carbohydrate metabolism. Several antibiotic resistance genes (ARGs) were found, and the composition of ARGs was similar to that of factory-farmed chickens, suggesting that antibiotics were widely present in the gut microbiota of Jianghan chickens. The resistance genes of Jianghan chickens are mainly carried by microorganisms of the Bacteroidota and Bacillota phylum. In addition, more than 829 isolates were selected from the microbiota of Jianghan chickens. Following three rounds of acid and bile tolerance experiments performed on all the isolated strains, it was determined that six strains of Pediococcus acidilactici exhibited consistent tolerance. Further experiments confirmed that three of these strains (A4, B9, and C2) held substantial probiotic potential, with P. acidilactici B9 displaying the highest probiotic potential. CONCLUSIONS: This study elucidates the composition of the intestinal microbiota and functional gene repertoire in Jianghan chickens. Despite the absence of antibiotic supplementation, the intestinal microbial community of Jianghan chickens still demonstrates a profile of antibiotic resistance genes similar to that of intensively reared chickens, suggesting resistance genes are prevalent in free-ranging poultry. Moreover, Jianghan and intensively reared chickens host major resistance genes differently, an aspect seldom explored between free-range and pastured chickens. Furthermore, among the 829 isolates, three strains of P. acidilatici exhibited strong probiotic potential. These findings provide insights into the unique gut microbiota of Jianghan chickens and highlight potential probiotic strains offering benefits to the host. Video Abstract.

Associations of circulating immunomarkers with the efficacy of immunotherapy for primary hepatic carcinoma.

BACKGROUND: Peripheral blood immunomarkers are associated with prognosis in patients with solid tumors receiving chemotherapy or immunotherapy. In this study, the associations of circulating neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), and platelet-to-lymphocyte ratio (PLR), as well as their dynamic changes were investigated in relation to the efficacy of immunotherapy in patients with primary liver cancer. METHODS: Comparisons were made between NLR, MLR, and PLR among individuals exhibiting disease control (defined as the best response of partial response [PR] or stable disease [SD]) and those with progressive disease (PD). Additionally, disease control rate (DCR), overall survival (OS), and progression-free survival (PFS) were compared between individuals with different NLR, MLR, and PLR levels before initiating palliative immunotherapy. Furthermore, comparisons were made between patients with different alterations in the ratios at the second cycle of immunotherapy compared to baseline. These analyses were performed using univariate and multivariate approaches. A total of 119 Chinese patients with liver cancer who underwent immunotherapy were included in this study, which focused on hepatocellular carcinoma (HCC). RESULTS: In cases with HCC (n = 104), the cutoffs of NLR, MLR, and PLR to differentiate treatment responders from nonresponders were 3.38, 0.28, and 227.18, respectively. Patients with the best response of PR or SD had significantly lower NLR and MLR. Patients with NLR <3.38 and those with MLR <0.28 significantly had longer OS and PFS than their counterparts, and those with PLR <227.18 had significantly longer PFS, both in overall patients and in various patient subgroups. Lower NLR, MLR, or PLR was associated with earlier BCLC stage, fewer metastatic sites, less frequent extrahepatic metastasis, or better performance status. For individuals who had an unfavorable baseline NLR ≥3.38, MLR ≥0.28, or a favorable baseline PLR <227.18 prior to first immunotherapy, a decrease in NLR, MLR, or PLR at Cycle 2 of immunotherapy was significantly associated with a higher DCR. CONCLUSIONS: Among patients with HCC who received immunotherapy, lower NLR, and MLR at baseline in overall patients were significantly associated with better disease control and more favorable survival outcomes (both OS and PFS), and lower PLR was significantly associated with longer PFS. The findings of this research may offer useful hints foranoptimized selection of patients with liver cancer who may benefit more from immunotherapy.

The variations of native plasmids greatly affect the cell surface hydrophobicity of sphingomonads.

IMPORTANCE: Microbial cell surface hydrophobicity (CSH) reflects nonspecific adhesion ability and affects various physiological processes, such as biofilm formation and pollutant biodegradation. Understanding the regulation mechanisms of CSH will contribute to illuminating microbial adaptation strategies and provide guidance for controlling CSH artificially to benefit humans. Sphingomonads, a common bacterial group with great xenobiotic-degrading ability, generally show higher CSH than typical Gram-negative bacteria, which plays a positive role in organic pollutant capture and cell colonization. This study verified that the variations of two native plasmids involved in synthesizing outer membrane proteins and polysaccharides greatly affected the CSH of sphingomonads. It is feasible to control their CSH by changing the plasmid copy number and sequences. Additionally, considering that plasmids are likely to evolve faster than chromosomes, the CSH of sphingomonads may evolve quickly to respond to environmental changes. Our results provide valuable insights into the CSH regulation and evolution of sphingomonads.

Explaining nitrogen turnover in sediments and water through variations in microbial community composition and potential function.

Anthropogenic activities greatly impact nitrogen (N) biogeochemical cycling in aquatic ecosystems. High N concentrations in coastal aquaculture waters threaten fishery production and aquaculture ecosystems and have become an urgent problem to be solved. Existing microbial flora and metabolic potential significantly regulate N turnover in aquatic ecosystems. To clarify the contribution of microorganisms to N turnover in sediment and water, we investigated three types of aquaculture ecosystems in coastal areas of Guangdong, China. Nitrate nitrogen (NO3--N) was the dominant component of total nitrogen in the sediment (interstitial water, 90.4%) and water (61.6%). This finding indicates that NO3--N (1.67-2.86 mg/L and 2.98-7.89 mg/L in the sediment and water) is a major pollutant in aquaculture ecosystems. In water, the relative abundances of assimilation nitrogen reduction and aerobic denitrifying bacteria, as well as the metabolic potentials of nitrogen fixation and dissimilated nitrogen in fish monoculture, were only 61.0%, 31.5%, 47.5%, and 27.2% of fish and shrimp polyculture, respectively. In addition, fish-shrimp polyculture reduced NO3--N content (2.86 mg/L) compared to fish monoculture (7.89 mg/L), which was consistent with changes in aerobic denitrification and nitrate assimilation, suggesting that polyculture could reduce TN concentrations in water bodies and alleviate nitrogen pollution risks. Further analysis via structural equation modeling (SEM) revealed that functional pathways (36% and 31%) explained TN changes better than microbial groups in sediment and water (13% and 11%), suggesting that microbial functional capabilities explain TN better than microbial community composition and other factors (pH, O2, and aquaculture type). This study enhances our understanding of nitrogen pollution characteristics and microbial community and functional capabilities related to sediment-water nitrogen turnover in three types of aquaculture ecosystems, which can contribute to the preservation of healthy coastal ecosystems.

Species' functional traits and interactions drive nitrate-mediated sulfur-oxidizing community structure and functioning.

IMPORTANCE: Understanding the processes and mechanisms governing microbial community assembly and their linkages to ecosystem functioning has long been a core issue in microbial ecology. An in-depth insight still requires combining with analyses of species' functional traits and microbial interactions. Our study showed how species' functional traits and interactions determined microbial community structure and functions by a well-controlled laboratory experiment with nitrate-mediated sulfur oxidation systems using high-throughput sequencing and culture-dependent technologies. The results provided solid evidences that species' functional traits and interactions were the intrinsic factors determining community structure and function. More importantly, our study established quantitative links between community structure and function based on species' functional traits and interactions, which would have important implications for the design and synthesis of microbiomes with expected functions.

Phase 2 Study of the PD-1 Inhibitor Serplulimab plus the Bevacizumab Biosimilar HLX04 in Patients with Previously Treated Advanced Hepatocellular Carcinoma.

Introduction: Current treatments for patients with previously treated advanced hepatocellular carcinoma (HCC) provide modest survival benefits. We evaluated the safety and antitumor activity of serplulimab, an anti-PD-1 antibody, plus the bevacizumab biosimilar HLX04 in this patient population. Methods: In this open-label, multicenter, phase 2 study in China, patients with advanced HCC who failed prior systemic therapy received serplulimab 3 mg/kg plus HLX04 5 mg/kg (group A) or 10 mg/kg (group B) intravenously every 2 weeks. The primary endpoint was safety. Results: As of April 8, 2021, 20 and 21 patients were enrolled into groups A and B, and they had received a median of 7 and 11 treatment cycles, respectively. Grade ≥3 treatment-emergent adverse events were reported by 14 (70.0%) patients in group A and 12 (57.1%) in group B. Most immune-related adverse events were grade ≤3. The objective response rate was 30.0% (95% confidence interval [CI], 11.9-54.3) in group A and 14.3% (95% CI, 3.0-36.3) in group B. Median duration of response was not reached (95% CI, 3.3-not evaluable [NE]) in group A and was 9.0 months (95% CI, 7.9-NE) in group B. Median progression-free survival was 2.2 months (95% CI, 1.4-5.5) and 4.1 months (95% CI, 1.5-NE), and median overall survival was 11.6 months (95% CI, 6.4-NE) and 14.3 months (95% CI, 8.2-NE) in groups A and B, respectively. Conclusion: Serplulimab plus HLX04 showed a manageable safety profile and promising antitumor activity in patients with previously treated advanced HCC.

Optimizing the scale-up production of fermented astragalus and its benefits to the performance and egg quality of laying hens.

Astragalus is a homologous medicine and food that benefits human beings and poultry rearing. Fermented astragalus (FA) is a valuable product obtained by fermentation, but its scale-up production requires optimization and expansion of solid-state fermentation (SSF). In this study, Lactobacillus pentosus Stm was screened as the most suitable LAB strain for fermenting astragalus due to its excellent capacity. After optimization and expansion of SSF, LAB count and lactic acid content reached 206 × 108 cfu/g and 15.0%, respectively. Meanwhile, the content of bioactive compounds in FA was significantly enhanced. Feeding experiments with laying hens indicated that supplementing FA in the diet significantly improved the performance and egg quality, as evidenced by reduced feed-to-egg ratio and egg cholesterol. This was due to the promotion of intestinal health by shifting intestinal microbiota. Therefore, this is a systematical endeavor of producing scaled-up FA with promising potential as a feed additive in the poultry breeding industry.

Role of NAT10-mediated ac4C-modified HSP90AA1 RNA acetylation in ER stress-mediated metastasis and lenvatinib resistance in hepatocellular carcinoma.

Emerging evidence showed that epigenetic regulation plays important role in the pathogenesis of HCC. N4-acetocytidine (ac4C) was an acetylation chemical modification of mRNA, and NAT10 is reported to regulate ac4C modification and enhance endoplasmic reticulum stress (ERS) in tumor metastasis. Here, we report a novel mechanism by which NAT10-mediated mRNA ac4C-modified HSP90AA1 regulates metastasis and tumor resistance in ERS of HCC. Immunohistochemical, bioinformatics analyses, and in vitro and in vivo experiments, e.g., acRIP-Seq, RNA-Seq, and double luciferase reporter experiment, were employed to investigate the effect of NAT10 on metastasis and drug resistance in HCC. The increased expression of NAT10 was associated with HCC risk and poor prognosis. Cell and animal experiments showed that NAT10 enhanced the metastasis ability and apoptosis resistance of HCC cells in ERS and ERS state. NAT10 could upregulate the modification level of HSP90AA1 mRNA ac4C, maintain the stability of HSP90AA1, and upregulate the expression of HSP90AA1, which further promotes the metastasis of ERS hepatoma cells and the resistance to apoptosis of Lenvatinib. This study proposes a novel mechanism by which NAT10-mediated mRNA ac4C modification regulates tumor metastasis. In addition, we demonstrated the regulatory effect of NAT10-HSP90AA1 on metastasis and drug resistance of ERS in HCC cells.

The influence of meteorological factors and total malignant tumor health risk in Wuhu city in the context of climate change.

With the increasing severity of the malignant tumors situation worldwide, the impacts of climate on them are receiving increasing attention. In this study, for the first time, all-malignant tumors were used as the dependent variable and absolute humidity (AH) was innovatively introduced into the independent variable to investigate the relationship between all-malignant tumors and meteorological factors. A total of 42,188 cases of malignant tumor deaths and meteorological factors in Wuhu City were collected over a 7-year (2014-2020) period. The analysis method combines distributed lagged nonlinear modeling (DLNM) as well as generalized additive modeling (GAM), with prior pre-analysis using structural equation modeling (SEM). The results showed that AH, temperature mean (T mean) and diurnal temperature range (DTR) all increased the malignant tumors mortality risk. Exposure to low and exceedingly low AH increases the malignant tumors mortality risk with maximum RR values of 1.008 (95% CI: 1.001, 1.015, lag 3) and 1.016 (95% CI: 1.001, 1.032, lag 1), respectively. In addition, low and exceedingly low T mean exposures also increased the risk of malignant tumors mortality, the maximum RR was 1.020 (95% CI: 1.006, 1.034) for low T mean and 1.035 (95% CI: 1.014, 1.058) for exceedingly low T mean. As for DTR, all four levels (exceedingly low, low, high, exceedingly high, from low to high) of exposure increased the risk of death from malignant tumors, from exceedingly low to exceedingly high maximum RR values of 1.018 (95% CI: 1.004, 1.032), 1.011 (95% CI: 1.005, 1.017), 1.006 (95% CI: 1.001, 1.012) and 1.019 (95% CI: 1.007, 1.031), respectively. The results of the stratified analysis suggested that female appear to be more sensitive to humidity, while male require additional attention to reduce exposure to high level of DTR.

KIAA1199 promotes oxaliplatin resistance and epithelial mesenchymal transition of colorectal cancer via protein O-GlcNAcylation.

Oxaliplatin is a commonly used platinum drug for colorectal cancer (CRC). However, the treatment of CRC by oxaliplatin usually fails because of drug resistance, which results in a huge challenge in the therapy of CRC. Elucidation of molecular mechanisms may help to overcome oxaliplatin resistance of CRC. In our study, we revealed that KIAA1199 can promote oxaliplatin resistance of CRC. Mechanistically, KIAA1199 prevents oxaliplatin mediated apoptosis via up-regulated PARP1 derived from reduced endoplasmic reticulum stress induced by protein O-GlcNAcylation. In the meantime, KIAA1199 can also trigger epithelial mesenchymal transition by stabilizing SNAI1 protein via O-GlcNAcylation. Therefore, KIAA1199 has great potential to be a novel biomarker, therapeutic target for oxaliplatin resistance and metastasis of CRC.

Complexing agents-free bioelectrochemical trickling systems for highly-efficient mesothermal NO removal: The role of extracellular polymer substances.

The biological treatments are promising for nitric oxide (NO) reduction, however, the biotechnology has long suffered from high demands of NO-complexing agents (i.e., Fe(II)EDTA), leading to extra operation costs. In this study, novel complexing agents-free bioelectrochemical systems have been developed for direct NO reduction. The electricity-driven bioelectrochemical trickling system (ED-BTS, a denitrifying biocathode driven by the external electricity and an acetate-consuming bioanode) achieved approximately 68% NO removal without any NO-complexing agents, superior to the bioanode-driven BTS and open-circuit BTS. The extracellular polymeric substances from the biofilms of ED-BTS contained more polysaccharides, humic substrates, and hydrophobic tryptophan that were beneficial for NO reduction. Additionally, the external electricity altered the microbial community toward more denitrifying bacteria and a higher abundance of NO reduction genes (nosZ and cnorB). This study provides a comprehensive understanding of microbial behaviors on the adsorption and reduction of NO and proposes a promising strategy for mesothermal NO biotreatment.

Exosomal NAMPT from chronic lymphocytic leukemia cells orchestrate monocyte survival and phenotype under endoplasmic reticulum stress.

Endoplasmic reticulum (ER) stress has been reported to be transmitted from tumor cells to immune cells via exosome and implicated in immune escape. However, the influence of ER stress on monocytes in chronic lymphocytic leukemia (CLL) cells is largely unknown. Here, we observed the expression of ER stress markers (GRP78, ATF6, PERK, IRE1a, and XBP1s) in CLL cells. The increasing mRNA expression of these ER stress response components was positively correlated with more aggressive disease. Exosome from ER stress inducer tunicamycin (TM)-primed CLL cells (ERS-exo) up-regulated the expression of ER stress marker on monocytes, indicating ER stress is transmissible in vitro via exosome. Treatment with ERS-exo promoted the survival of monocytes and induced phenotypic changes with a significantly larger percentage of CD14+ CD16+ monocytes. Finally, we identified exosome-mediated transfer of extracellular nicotinamide phosphoribosyltransferase (eNAMPT) from ER stressed CLL cells into monocytes as a novel mechanism through which ERS-exo regulated monocytes. Exosomal eNAMPT up-regulated nicotinamide adenine dinucleotide (NAD+ ) production which subsequently activated SIRT1-C/EBPß signaling pathway in monocytes. Our results suggest the role of ER stress in mediating immunological dysfunction in CLL.

A novel antimony-selective ArsR transcriptional repressor and its specific detection of antimony trioxide in environmental samples via bacterial biosensor.

Extensively industrial applications and ever-accelerated anthropogenic activities have resulted in the dramatic accumulation of Sb2O3 contaminant in the environment, leading to adverse health effects on humans and ecosystems. Although arsenite has been subjected to numerous studies and ArsR-based whole-cell biosensors have been successfully applied in field testing of arsenite, there is limited information on the biological recognition element of Sb2O3 and its actual application in biosensor construction and environmental monitoring. In this study, we identified a specific recognition element of Sb2O3, SxArsR, in Sphingobium xenophagum C1 by the induced bioluminescent signal analysis of gene expression in response to Sb2O3 exposure. Compared to the other four groups of characterized ArsRs, the novel SxArsR lacks the third cysteine residue for binding of arsenite and has a conserved histidine-cysteine "HCXC" binding site that directly and specifically binds for Sb2O3. Sb2O3 can remove SxArsR from the core operator/promoter binding sequence in the -79 region upstream of the start codon of sxarsR. Based on the specificity of SxArsR protein and the sensitivity of SxArsR-binding DNA sequence, SxArsR-based whole-cell biosensor was constructed and showed a linear relationship (R2 = 0.99) from 0.01 to 6.0 µM of Sb2O3 with a detection limit of 0.01 µM. The novel bacterial biosensor also exhibited a good performance in the detection of Sb2O3 in environmental water and sediment samples. Overall, SxArsR-based biosensor represents a promising strategy for Sb2O3 detection and may have a profound impact on further practical application of ArsR biosensor in the dual-signal simultaneous detection of arsenite and Sb2O3.

Genotypic Characterization of a Chinese Family with Osteogenesis Imperfecta and Generation of Disease-Specific Induced Pluripotent Stem Cells.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic disorder characterized by recurring bone fractures. Some OI patients have other clinical manifestations such as growth retardation, dental abnormalities, blue sclera, and hearing loss. The relationship between the phenotype and genotype of OI is indistinct, and there is no cure for OI. Therefore, an appropriate disease model is urgently needed to understand the pathophysiology of OI. Induced pluripotent stem cells (iPSCs) are capable of developing into three germ layers and have the same genetic background as the donor cells they were derived from; thus, they are an appropriate disease model. METHODS: Blood samples collected from the proband and her affected children and one unaffected child were used forgenotyping by whole genome sequencing. A patient-specific iPSC line and a healthy donor iPSC line were generated by reprogramming peripheral blood mononuclear cells with episomal plasmids containing seven transcription factors, namely, OCT4, SOX2, NANOG, LIN28, cMYC, KLF4, and SV40LT. RESULTS: The proband and her two affected children were homozygous for a mutation in collagen type I alpha 1 exon 10, c.725G>T, predicting a p.G242V substitution. A patient-specific iPSC line and a healthy donor iPSC line were generated and characterized in terms of their human embryonic stem cell-like morphology, expression of pluripotency markers, and the ability to differentiate into cells of three germ layers. CONCLUSIONS: Here, we report the phenotyping and iPSC disease modeling of an OI family. The detailed phenotyping of the OI family and establishment of iPSCs from an OI patient and healthy family member will provide a powerful tool to evaluate the pathophysiology of OI and develop targeted therapies.

Cysteine-Mediated Extracellular Electron Transfer of Lysinibacillus varians GY32.

Microbial extracellular electron transfer (EET) is essential in many natural and engineering processes. Compared with the versatile EET pathways of Gram-negative bacteria, the EET of Gram-positive bacteria has been studied much less and is mainly limited to the flavin-mediated pathway. Here, we investigate the EET pathway of a Gram-positive filamentous bacterium Lysinibacillus varians GY32. Strain GY32 has a wide electron donor spectrum (including lactate, acetate, formate, and some amino acids) in electrode respiration. Transcriptomic, proteomic, and electrochemical analyses show that the electrode respiration of GY32 mainly depends on electron mediators, and c-type cytochromes may be involved in its respiration. Fluorescent sensor and electrochemical analyses demonstrate that strain GY32 can secrete cysteine and flavins. Cysteine added shortly after inoculation into microbial fuel cells accelerated EET, showing cysteine is a new endogenous electron mediator of Gram-positive bacteria, which provides novel information to understand the EET networks in natural environments. IMPORTANCE Extracellular electron transport (EET) is a key driving force in biogeochemical element cycles and microbial chemical-electrical-optical energy conversion on the Earth. Gram-positive bacteria are ubiquitous and even dominant in EET-enriched environments. However, attention and knowledge of their EET pathways are largely lacking. Gram-positive bacterium Lysinibacillus varians GY32 has extremely long cells (>1 mm) and conductive nanowires, promising a unique and enormous role in the microenvironments where it lives. Its capability to secrete cysteine renders it not only an EET pathway to respire and survive, but also an electrochemical strategy to connect and shape the ambient microbial community at a millimeter scale. Moreover, its incapability of using flavins as an electron mediator suggests that the common electron mediator is species-dependent. Therefore, our results are important to understanding the EET networks in natural and engineering processes.

Development and validation of a nomogram to predict overall survival in young non-metastatic rectal cancer patients after curative resection: a population-based analysis.

PURPOSE: This study aimed to establish and validate a nomogram for predicting overall survival (OS) in young non-metastatic rectal cancer (RC) patients after curative resection. METHODS: Young RC patients (under 50 years of age) from 2010 to 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Those patients randomly assigned to a training cohort and a validation cohort at a ratio of 7:3. The independent prognostic factors for OS were identified by univariate and multivariate Cox regression analysis. A nomogram model was built based on the independent prognostic variables and was evaluated by concordance index (C-index), receiver operating characteristics (ROC) curves, calibration plot, and decision curve analysis (DCA). RESULTS: A total number of 3026 young RC patients were extracted from SEER database. OS nomogram was constructed based on race, histological type, tumor grade, T stage, N stage, carcinoembryonic antigen (CEA) level, and number of lymph nodes (LN) examined. C-index, ROC curves, calibration plot, and DCA curves presented satisfactory performance of the above nomogram in predicting the prognosis of young non-metastatic RC patients after curative resection. The nomogram can identify three subgroups of patients at different risks, which showed different prognostic outcomes both in the training cohort and validation cohort. CONCLUSION: We successfully established a reliable and insightful nomogram to predict OS for young non-metastatic RC patients after curative resection. The nomogram may provide accurate prognosis prediction to guide individualized follow-up and treatment plans.