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Background: Inferring historical population admixture events yield essential insights in understanding a species demographic history. Methods are available to infer admixture events in demographic history with extant genetic data from multiple sources. Due to the deficiency in ancient population genetic data, there lacks a method for admixture inference from a single source. Pairwise Sequentially Markovian Coalescent (PSMC) estimates the historical effective population size from lineage genomes of a single individual, based on the distribution of the most recent common ancestor between the diploid's alleles. However, PSMC does not infer the admixture event. Results: Here, we proposed eSMC, an extended PSMC model for admixture inference from a single source. We evaluated our model's performance on both in silico data and real data. We simulated population admixture events at an admixture time range from 5 kya to 100 kya (5 years/generation) with population admix ratio at 1:1, 2:1, 3:1, and 4:1, respectively. The root means the square error is ± 7.61 kya for all experiments. Then we implemented our method to infer the historical admixture events in human, donkey and goat populations. The estimated admixture time for both Han and Tibetan individuals range from 60 kya to 80 kya (25 years/generation), while the estimated admixture time for the domesticated donkeys and the goats ranged from 40 kya to 60 kya (8 years/generation) and 40 kya to 100 kya (6 years/generation), respectively. The estimated admixture times were concordance to the time that domestication occurred in human history. Conclusion: Our eSMC effectively infers the time of the most recent admixture event in history from a single individual's genomics data. The source code of eSMC is hosted at https://github.com/zachary-zzc/eSMC. [ABSTRACT FROM AUTHOR]

Background: To investigate the clinical effects of a unilateral external fixator combined with bone transport and tibio-talar fusion in the treatment of severe postoperative infection of peri-ankle fractures. Methods: The clinical data of 32 patients (22 men and 10 women) with severe postoperative infection of peri-ankle fractures were retrospectively analyzed. Patients' age ranged from 26 to 62 (mean, 42 ± 9.5) years old. The types of fractures were distal tibia fracture (25 cases), distal tibia and fibula fracture (5 cases), and talus fracture (2 cases). All patients underwent treatment with unilateral external fixation combined with bone transport and tibio-talar fusion. 6 patients with severe infection received two-stage treatment involving focal debridement and external fixation, osteotomy, and bone transport. The remaining 26 patients underwent debridement, external fixation, and osteotomy simultaneously. The length of bone transport, total fixation time of the external fixator, and postoperative complications were recorded for all patients. The efficacy of the treatment was assessed using the American Association of Foot and Ankle Society (AOFAS) ankle–hindfoot score. Results: Patients were followed up for 16–36 months, with an average follow-up time of 24 months. The length of tibia bone transport ranged from 5 to 15 cm, with a mean length of 8.5 cm. The external fixator was applied for 12–24 months, with an average duration of 16 months. One patient suffered from refracture at tibio-talar fusion site, and one patient had external fixation pin-tract infection. No complications, such as recurrent infections (especially the MRSA infection), poor mineralization, refracture, iatrogenic nerve damage or fusion failure, were found in the remaining patients. The preoperative AOFAS ankle–hindfoot function score was 40.0 ± 3.8 (range, 30–52) points, and it increased to 75.0 ± 3.0 (range, 67–78) points at the last follow-up. Conclusion: A unilateral external fixator combined with bone transport and tibio-talar fusion is an effective method for treating severe postoperative infection of peri-ankle fractures. This approach is capable of reconstructing large bone defects that remain after clearing the infected lesion. Additionally, it provides stability to the ankle, enhances ankle–hindfoot function, and improves the patient's quality of life. [ABSTRACT FROM AUTHOR]

Background: Equine herpesvirus-8 (EHV-8) is one of the most economically significant viruses that infect mammals of the genus Equus worldwide, which cause severe respiratory diseases and abortion in horses. However, there is no report of abortion caused by EHV-8 in donkeys. Case presentation: The present case report is about a 4-year-old donkey having an abortion and showing a serious respiratory issue on the 296th day of pregnancy. Bacteriological and molecular tests were used to screen possible bacterial/viral pathogens to detect the etiological agent. Salmonella abortus equi, EHV-1, EHV-4, and EAV were all negative in the current study. EHV-8, on the other hand, was the only agent that was isolated and identified. Conclusions: This was for the first time that EHV-8 had been isolated from a donkey in China. EHV-8 infection can cause abortion in donkeys; therefore, veterinarians and breeders should be aware of it. [ABSTRACT FROM AUTHOR]

Background: Neonates possess an immature and plastic immune system, which is a major cause of some diseases in newborns. Necrotizing enterocolitis (NEC) is a severe and devastating intestinal disease that typically affects premature infants. However, the development of intestinal immune cells in neonates and their roles in the pathological process of NEC have not been elucidated. Results: We examined the ontogeny of intestinal lamina propria lymphocytes in the early life of mice and found a high percentage of RORγt+ cells (containing inflammatory Th17 and ILC3 populations) during the first week of life. Importantly, the proportion of RORγt+ cells of intestinal lamina propria further increased in both NEC mice and patients tissue than the control. Furthermore, the application of GSK805, a specific antagonist of RORγt, inhibited IL-17A release and ameliorated NEC severity. Conclusions: Our data reveal the high proportion of RORγt+ cells in newborn mice may directly contribute to the development of NEC. [ABSTRACT FROM AUTHOR]

Background: PCV3 is a pathogen associated with porcine dermatitis and nephropathy syndrome (PDNS)-like clinical signs, reproductive failure, and cardiac and multiorgan inflammation, which was newly identified in 2016 in sows in USA. Recently, PCV3 has also been identified from several non-porcine species like (cattle, dog, wild boar, deer, mice and ticks). However, PCV3 infection in donkey is not well established. Since 2019, 300 blood samples were collected from female donkey, which was characterized by abortion and sterility, in Liaocheng city of China. Results: In the present study, an investigation of PCV3 in donkey blood samples was undertaken employing by real time PCR. Positive rates of PCV3 in donkeys reach to 21.0 %. In addition, one full-length PCV3 genome sequence was obtained, and it had a highest identity with porcine circovirus 3 PCV3/CN/Nanjing2017 strain and is clustered to PCV3a genotype based on ORF2 sequences. Conclusions: This is the first report of detection of PCV3 from female donkeys presenting reproductive failure in large-scale donkey farms, China. In addition, the PCV3 strain identified in this study shared the closest relationship with those from porcine, suggesting that PCV3 may be transmitted from pigs to donkeys. Totally, PCV3 infection in donkey should be concerned although the association between it and reproductive failure are not better understood. [ABSTRACT FROM AUTHOR]

Background: The overall response rate to checkpoint blockade remains unsatisfactory, partially due to the immune-suppressive tumor microenvironment. A retinoic acid-related orphan receptor γt (RORγt) agonist (LYC-55716) is currently used in clinical trials combined with anti-PD-1, but how the Th17 cell transcription factor RORγt enhances antitumor immunity of PD-1 in the tumor microenvironment remains elusive. Methods: The expression of mRNA was analyzed using qPCR assays. Flow cytometry was used to sort and profile cells. Cell migration was analyzed using Transwell assays. Biacore was used to determine the binding affinity to the RORγt protein. The RORγt GAL4 cell-based reporter gene assay was used to measure activity in the RORγt driven luciferase reporter gene expression. Results: We designed a potent and selective small-molecule RORγt agonist (8-074) that shows robust antitumor efficacy in syngeneic tumor models and improves the efficacy of anti‑PD‑1 in a murine lung cancer model. RORγt agonist treatment increased intratumoral CD8+ T cells, which were correlated with CXCL10 and monocyte-derived dendritic cells (MoDCs). In addition, the RORγt agonist promoted Type 17 T cell migration by upregulating CCL20 and CCR6 expression, and Type 17 T cell tumor infiltration. CCL20 induces MoDCs migration, and CXCL10 derived from MoDCs promotes CD8+ T cell migration. Conclusion: Our results revealed that the RORγt agonist improved the efficacy of anti-PD-1. The RORγt agonist increased the migration of MoDCs, which increased the local levels of CXCL10, thus promoting CD8+ T cell tumor infiltration. Our findings provide the mechanistic insights implicating the RORγt agonist in immunotherapy and offer a strategy for targeting the RORγt agonist to improve PD-1 antibody efficacy in cancers. [ABSTRACT FROM AUTHOR]

Background: The overall response rate to checkpoint blockade remains unsatisfactory, partially due to the immune-suppressive tumor microenvironment. A retinoic acid-related orphan receptor γt (RORγt) agonist (LYC-55716) is currently used in clinical trials combined with anti-PD-1, but how the Th17 cell transcription factor RORγt enhances antitumor immunity of PD-1 in the tumor microenvironment remains elusive. Methods: The expression of mRNA was analyzed using qPCR assays. Flow cytometry was used to sort and profile cells. Cell migration was analyzed using Transwell assays. Biacore was used to determine the binding affinity to the RORγt protein. The RORγt GAL4 cell-based reporter gene assay was used to measure activity in the RORγt driven luciferase reporter gene expression. Results: We designed a potent and selective small-molecule RORγt agonist (8-074) that shows robust antitumor efficacy in syngeneic tumor models and improves the efficacy of anti‑PD‑1 in a murine lung cancer model. RORγt agonist treatment increased intratumoral CD8+ T cells, which were correlated with CXCL10 and monocyte-derived dendritic cells (MoDCs). In addition, the RORγt agonist promoted Type 17 T cell migration by upregulating CCL20 and CCR6 expression, and Type 17 T cell tumor infiltration. CCL20 induces MoDCs migration, and CXCL10 derived from MoDCs promotes CD8+ T cell migration. Conclusion: Our results revealed that the RORγt agonist improved the efficacy of anti-PD-1. The RORγt agonist increased the migration of MoDCs, which increased the local levels of CXCL10, thus promoting CD8+ T cell tumor infiltration. Our findings provide the mechanistic insights implicating the RORγt agonist in immunotherapy and offer a strategy for targeting the RORγt agonist to improve PD-1 antibody efficacy in cancers. [ABSTRACT FROM AUTHOR]

Objectives: This study is designed to generate and propagate human spermatogonial stem cells (SSCs) derived from human pluripotent stem cells (hPSCs). Methods: hPSCs were differentiated into SSC-like cells (SSCLCs) by a three-step strategy. The biological characteristics of SSCLCs were detected by immunostaining with antibodies against SSC markers. The ability of self-renewal was measured by propagating for a long time and still maintaining SSCs morphological property. The differentiation potential of SSCLCs was determined by the generation of spermatocytes and haploid cells, which were identified by immunostaining and flow cytometry. The transcriptome analysis of SSCLCs was performed by RNA sequencing. The biological function of SSCLCs was assessed by xeno-transplantation into busulfan-treated mouse testes. Results: SSCLCs were efficiently generated by a 3-step strategy. The SSCLCs displayed a grape-like morphology and expressed SSC markers. Moreover, SSCLCs could be propagated for approximately 4 months and still maintained their morphological properties. Furthermore, SSCLCs could differentiate into spermatocytes and haploid cells. In addition, SSCLCs displayed a similar gene expression pattern as human GPR125+ spermatogonia derived from human testicular tissues. And more, SSCLCs could survive and home at the base membrane of seminiferous tubules. Conclusion: SSCLCs were successfully derived from hPSCs and propagated for a long time. The SSCLCs resembled their counterpart human GPR125+ spermatogonia, as evidenced by the grape-like morphology, transcriptome, homing, and functional characteristics. Therefore, hPSC-derived SSCLCs may provide a reliable cell source for studying human SSCs biological properties, disease modeling, and drug toxicity screening. [ABSTRACT FROM AUTHOR]