The genomic origins of the Bronze Age Tarim Basin mummies.

The identity of the earliest inhabitants of Xinjiang, in the heart of Inner Asia, and the languages that they spoke have long been debated and remain contentious1. Here we present genomic data from 5 individuals dating to around 3000-2800 BC from the Dzungarian Basin and 13 individuals dating to around 2100-1700 BC from the Tarim Basin, representing the earliest yet discovered human remains from North and South Xinjiang, respectively. We find that the Early Bronze Age Dzungarian individuals exhibit a predominantly Afanasievo ancestry with an additional local contribution, and the Early-Middle Bronze Age Tarim individuals contain only a local ancestry. The Tarim individuals from the site of Xiaohe further exhibit strong evidence of milk proteins in their dental calculus, indicating a reliance on dairy pastoralism at the site since its founding. Our results do not support previous hypotheses for the origin of the Tarim mummies, who were argued to be Proto-Tocharian-speaking pastoralists descended from the Afanasievo1,2 or to have originated among the Bactria-Margiana Archaeological Complex3 or Inner Asian Mountain Corridor cultures4. Instead, although Tocharian may have been plausibly introduced to the Dzungarian Basin by Afanasievo migrants during the Early Bronze Age, we find that the earliest Tarim Basin cultures appear to have arisen from a genetically isolated local population that adopted neighbouring pastoralist and agriculturalist practices, which allowed them to settle and thrive along the shifting riverine oases of the Taklamakan Desert.

Polygenic risk score of metabolic dysfunction-associated steatotic liver disease amplifies the health impact on severe liver disease and metabolism-related outcomes.

BACKGROUND: Although the inherited risk factors associated with fatty liver disease are well understood, little is known about the genetic background of metabolic dysfunction-associated steatotic liver disease (MASLD) and its related health impacts. Compared to non-alcoholic fatty liver disease (NAFLD), MASLD presents significantly distinct diagnostic criteria, and epidemiological and clinical features, but the related genetic variants are yet to be investigated. Therefore, we conducted this study to assess the genetic background of MASLD and interactions between MASLD-related genetic variants and metabolism-related outcomes. METHODS: Participants from the UK Biobank were grouped into discovery and replication cohorts for an MASLD genome-wide association study (GWAS), and base and target cohorts for polygenic risk score (PRS) analysis. Autosomal genetic variants associated with NAFLD were compared with the MASLD GWAS results. Kaplan-Meier and Cox regression analyses were used to assess associations between MASLD and metabolism-related outcomes. RESULTS: Sixteen single-nucleotide polymorphisms (SNPs) were identified at genome-wide significance levels for MASLD and duplicated in the replication cohort. Differences were found after comparing these SNPs with the results of NAFLD-related genetic variants. MASLD cases with high PRS had a multivariate-adjusted hazard ratio of 3.15 (95% confidence interval, 2.54-3.90) for severe liver disease (SLD), and 2.81 (2.60-3.03) for type 2 diabetes mellitus. The high PRS amplified the impact of MASLD on SLD and extrahepatic outcomes. CONCLUSIONS: High PRS of MASLD GWAS amplified the impact of MASLD on SLD and metabolism-related outcomes, thereby refining the process of identification of individuals at high risk of MASLD. Supplementation of this process with relevant genetic backgrounds may lead to more effective MASLD prevention and management.

Association between fatty liver index and controlled attenuation parameters as markers of metabolic dysfunction-associated fatty liver disease and bone mineral density: observational and two-sample Mendelian randomization studies.

Previously observational studies did not draw a clear conclusion on the association between fatty liver diseases and bone mineral density (BMD). Our large-scale studies revealed that MAFLD and hepatic steatosis had no causal effect on BMD, while some metabolic factors were correlated with BMD. The findings have important implications for the relationship between fatty liver diseases and BMD, and may help direct the clinical management of MAFLD patients who experience osteoporosis and osteopenia. PURPOSE: Liver and bone are active endocrine organs with several metabolic functions. However, the link between metabolic dysfunction-associated fatty liver disease (MAFLD) and bone mineral density (BMD) is contradictory. METHODS: Using the UK Biobank and National Health and Nutrition Examination Survey (NHANES) dataset, we investigated the association between MAFLD, steatosis, and BMD in the observational analysis. We performed genome-wide association analysis to identify single-nucleotide polymorphisms associated with MAFLD. Large-scale two-sample Mendelian randomization (TSMR) analyses examined the potential causal relationship between MAFLD, hepatic steatosis, or major comorbid metabolic factors, and BMD. RESULTS: After adjusting for demographic factors and body mass index, logistic regression analysis demonstrated a significant association between MAFLD and reduced heel BMD. However, this association disappeared after adjusting for additional metabolic factors. MAFLD was not associated with total body, femur neck, and lumbar BMD in the NHANES dataset. Magnetic resonance imaging-measured steatosis did not show significant associations with reduced total body, femur neck, and lumbar BMD in multivariate analysis. TSMR analyses indicated that MAFLD and hepatic steatosis were not associated with BMD. Among all MAFLD-related comorbid factors, overweight and type 2 diabetes showed a causal relationship with increased BMD, while waist circumference and hyperlipidemia had the opposite effect. CONCLUSION: No causal effect of MAFLD and hepatic steatosis on BMD was observed in this study, while some metabolic factors were correlated with BMD. This has important implications for understanding the relationship between fatty liver disease and BMD, which may help direct the clinical management of MAFLD patients with osteoporosis.

Association between sarcopenia-related markers and cholelithiasis: A prospective and Mendelian randomization study.

Cholelithiasis is a common digestive disease that drives a myriad of adverse complications. The correlation between sarcopenia and various digestive disorders has been extensively researched, whereas its association with cholelithiasis remains unreported. We aimed to investigate the association through prospective and Mendelian randomization (MR) analyses and establish a quantitative score reflecting the impact of sarcopenia-related markers on cholelithiasis. The prospective study involved 448 627 participants from the UK Biobank. Cox proportional hazard models were employed to investigate the correlation between sarcopenia-related markers and cholelithiasis. To quantitatively assess cholelithiasis risk, the SARCHO score was derived from a multivariable Cox model. Bidirectional two-sample MR analysis was conducted to validate the causal association. A total of 16 738 individuals developed cholelithiasis during a median follow-up of 12 years. Hazard ratios (HRs) of cholelithiasis decreased stepwise over skeletal muscle index tertiles (highest tertile: reference; middle tertile: 1.23, p < .001; lowest tertile: 1.33, p < .001). The tertiles of grip strength showed a similar pattern. Individuals with slow walking pace had a higher risk of cholelithiasis compared to those with normal walking pace (HR 1.23; p < .001). Our SARCHO score better quantifies the risk of cholelithiasis. MR analysis showed a causal relationship between muscle mass and cholelithiasis (OR 0.81; p < .001). No causal effect of cholelithiasis on lean mass was observed. Prospective and MR analyses have consistently demonstrated an increased risk of cholelithiasis in individuals with decreased muscle mass. Additionally, SARCHO score further quantified the cholelithiasis occurrence risk. These findings provide compelling evidence for muscle strengthening in preventing cholelithiasis.

Safety and effectiveness of the three-dimensional-printed guide plate-assisted rotation axis positioning of a hinged external fixator for the elbow.

PURPOSE: We aimed to evaluate the safety and effectiveness of three-dimensional (3D)-printed guide plates for assisting in the positioning of the rotation axis of an elbow-hinged external fixator. METHODS: Terrible triad (TT) patients, who were screened using the predefined inclusion and exclusion criteria, underwent installation of a hinged external fixator on the basis of internal fixation; 3D-printed guide plates, generated from the patient's imaging data, assisted in positioning the rotation axis. All patients received the same peri-operative management and were followed up at six, 12, 24, and 48 weeks postoperatively. The duration of positioning pin placement, the number of fluoroscopies, pin placement success rate, types and incidence of post-operative complications, and the Mayo elbow performance score (MEPS) of the diseased elbow and range of motion (ROM) of both elbows were assessed. RESULTS: In 25 patients who completed the follow-up, the average time required for positioning pin placement was 329.32 ± 42.38 s (263-443 s), the average number of fluoroscopies was 2.32 ± 0.48 times (2-3 times), and the pin placement success rate was 100%. At the last follow-up, the mean MEPS of the diseased elbow was 97.50 ± 6.92 (75-100), with an excellent and good rate of 100%, and all patients demonstrated stable concentric reduction. The average range of flexion and extension was 135.08° ± 17.10° (77-146°), while the average range of rotation was 169.21° ± 18.14° (108-180°). No significant difference was observed in the average ROM between the both elbows (P > 0.05). Eight (32%) patients developed post-operative complications, including elbow stiffness due to heterotopic ossification in three (12%) patients, all of whom did not require secondary intervention. CONCLUSION: Utilizing 3D-printed guide plates for positioning the rotation axis of an elbow-hinged external fixator significantly reduced intra-operative positioning pin placement time and the number of fluoroscopies with excellent positioning results. Satisfactory results were also obtained in terms of post-operative complications, elbow ROM, and functional scores.

[Clinical Application of Microwave Ablation in Potentially Resectable Colorectal Cancer With Simultaneously Multiple Liver Metastases].

Objective To analyze the clinical efficacy of microwave ablation in the colorectal cancer with simultaneously multiple liver metastases that was initially evaluated as potentially resectable. Methods The patients with potentially resectable colorectal cancer with simultaneous multiple liver metastases treated in the Department of General Surgery of the First Affiliated Hospital of Hebei North University,the Center of Minimally Invasive Therapy in Oncology of Traditional Chinese and Western Medicine in Dongzhimen Hospital of Beijing University of Chinese Medicine,and the Second Department of General Surgery in the Fourth Hospital of Hebei Medical University from October 1,2018 to October 1,2020 were selected in this study.The general data,pathological features,treatment methods,and clinical efficacy of the patients were collected.According to the treatment methods,the patients were assigned into a surgical resection group(conversion therapy+laparoscopic primary resection+hepatectomy)and a microwave ablation group(conversion therapy+laparoscopic primary resection+microwave ablation).The surgical indicators(operation duration,time to first postoperative anal exhaust,hospital stay,etc.)and postoperative complications(anastomotic stenosis,anastomotic hemorrhage,incision infection,etc.)were compared between the two groups.The survival period was followed up,including the overall survival period and disease-free survival period,and the survival curves were drawn to analyze the clinical efficacy of the two treatment regimens. Results A total of 198 patients with potentially resectable colorectal cancer with simultaneous multiple liver metastases were included in this study.Sixty-six patients were cured by neoadjuvant chemotherapy(FOLFOX or FOLFIRI),including 30 patients in the surgical resection group and 36 patients in the microwave ablation group(with 57 tumors ablated).After the first ablation,54(94.74%)tumors achieved complete ablation,and all of them reached no evidence of disease status after re-ablation.The microwave ablation group had shorter operation duration,less intraoperative blood loss,shorter time to first postoperative anal exhaust,shorter time of taking a liquid diet,shorter hospital stay,and lower hospitalization cost than the surgical resection group(all P<0.001).In addition,the microwave ablation group had lower visual analogue scale score(P<0.001)than the surgical resection group.The incidences of complications such as incision infection(P=0.740),anastomotic fistula(P=1.000),and anastomotic stenosis(P=1.000),the overall survival period(P=0.191),and the disease-free survival period(P=0.934)showed no significant differences between the two groups. Conclusions For patients with colorectal cancer with simultaneous multiple liver metastases initially assessed as potentially resectable,laparoscopic primary resection+surgical resection/microwave ablation after conversion therapy was safe,effective,and had similar survival outcomes.Microwave ablation outperformed surgical resection in postoperative recovery,economy,and tolerability,being worthy of clinical promotion.

Rnf220/Zc4h2-mediated monoubiquitylation of Phox2 is required for noradrenergic neuron development.

Noradrenaline belongs to the monoamine system and is involved in cognition and emotional behaviors. Phox2a and Phox2b play essential but non-redundant roles during development of the locus coeruleus (LC), the main noradrenergic (NA) neuron center in the mammalian brain. The ubiquitin E3 ligase Rnf220 and its cofactor Zc4h2 participate in ventral neural tube patterning by modulating Shh/Gli signaling, and ZC4H2 mutation is associated with intellectual disability, although the mechanisms for this remain poorly understood. Here, we report that Zc4h2 and Rnf220 are required for the development of central NA neurons in the mouse brain. Both Zc4h2 and Rnf220 are expressed in developing LC-NA neurons. Although properly initiated at E10.5, the expression of genes associated with LC-NA neurons is not maintained at the later embryonic stages in mice with a deficiency of either Rnf220 or Zc4h2 In addition, we show that the Rnf220/Zc4h2 complex monoubiquitylates Phox2a/Phox2b, a process required for the full transcriptional activity of Phox2a/Phox2b. Our work reveals a role for Rnf220/Zc4h2 in regulating LC-NA neuron development, and this finding may be helpful for understanding the pathogenesis of ZC4H2 mutation-associated intellectual disability.

RNF220 is required for cerebellum development and regulates medulloblastoma progression through epigenetic modulation of Shh signaling.

Sonic hedgehog (Shh) signaling is essential for proliferation of cerebellar granule neuron progenitors (CGNPs) and its mis-regulation is linked to various disorders, including the cerebellar cancer medulloblastoma (MB). We recently identified RNF220, a ubiquitin E3 ligase promoting K63-linked polyubiquitylation and nuclear exportation of Gli transcription factors, as an Shh/Gli regulator involved in ventral neural patterning. Here, we report that RNF220 is required for the proliferation of CGNPs and Daoy cells (an Shh-grouped MB cell line), working as a positive regulator of Shh signaling. Mechanistic investigation demonstrated that RNF220 promotes Shh target gene expression by targeting the PRC2 component EED, and alters levels of epigenetic modification marks on Shh target promoters. We provided evidence that RNF220+/-; Ptch1+/- mice showed lower spontaneous MB occurrence compared with Ptch1+/- mice. Furthermore, in human clinical MB samples, RNF220 expression correlated well with that of GAB1, an Shh-group MB marker. Our findings provide new insights into the epigenetic regulation of Shh signaling and identify RNF220 as a potential new diagnostic marker and therapeutic target for Shh-group MB.

Noninvasive evaluation of PD-L1 expression in non-small cell lung cancer by immunoPET imaging using an acylating agent-modified antibody fragment.

PURPOSE: The aim of this study was to explore an effective 124I labeling strategy and improve the signal-to-noise ratio when evaluating the expression of PD-L1 using an 124I-iodinated durvalumab (durva) F(ab')2 fragment. METHODS: The prepared durva F(ab')2 fragments were incubated with N-succinimidyl-3-(4-hydroxyphenyl) propionate (SHPP); after purification, the HPP-durva F(ab')2 was iodinated using Iodo-Gen method. After the radiochemical purity, stability, and specific activities were determined, the binding affinities of probes prepared using different labeling strategies were compared in vitro. The clinical application value of [124I]I-HPP-durva-F(ab')2 was confirmed by PET imaging. To more objectively evaluate the in vivo distribution and clearance of tracers, the pharmacokinetics and biodistribution assays were also performed. RESULTS: After being modified with SHPP, the average conjugation number of SHPP per durva-F(ab')2 identified by LC-MS was about 8.92 ± 2.84. The prepared [124I]I-HPP-durva F(ab')2 was obtained with a satisfactory radiochemical purity of more than 98% and stability of more than 93% when incubated for 72 h. Compared with unmodified [124I]I-durva F(ab')2, the specific activity of [124I]I-HPP-durva-F(ab')2 was improved (52.91 ± 5.55 MBq/mg and 15.91 ± 0.74 MBq/mg), while the affinity did not significantly change. The biodistribution experiments and PET imaging showed that the prepared [124I]I-HPP-durva-F(ab')2 exhibited an accelerated clearance and improved tumor-to-background ratio compared with [124I]I-durva-F(ab')2. The specificity of [124I]I-HPP-durva-F(ab')2 to PD-L1 was well demonstrated both in vitro and in vivo. CONCLUSIONS: A PD-L1 PET imaging probe [124I]I-HPP-durva F(ab')2 was successfully synthesized through the SHPP modification strategy. The prepared probe was able to accurately evaluate the PD-L1 expression level through high-contrast noninvasive imaging.

Solving the two-decades-old murder case through joint application of ZooMS and ancient DNA approaches.

Bones are one of the most common biological types of evidence in forensic cases. Discriminating human bones from irrelevant species is important for the identification of victims; however, the highly degraded bones could be undiagnostic morphologically and difficult to analyze with standard DNA profiling approaches. The same challenge also exists in archaeological studies. Here, we present an initial study of an analytical strategy that involves zooarchaeology by mass spectrometry (ZooMS) and ancient DNA methods. Through the combined strategy, we managed to identify the only biological evidence of a two-decades-old murder case - a small piece of human bone out of 19 bone fragments - and confirmed the kinship between the victim and the putative parents through joint application of next-generation sequencing (NGS) and Sanger sequencing methods. ZooMS effectively screened out the target human bone while ancient DNA methods improve the DNA yields. The combined strategy in this case outperforms the standard DNA profiling approach with shorter time, less cost, as well as higher reliability for the genetic identification results. HIGHLIGHTS: • The first application of zooarchaeology by mass spectrometry technique in the forensic case for screening out human bones from bone fragment mixtures. • Application of ancient DNA technique to recover the highly degraded DNA sequence from the challenging sample that failed standard DNA profiling approaches. • A fast, sensitive, and low-cost strategy that combines the strengths of protein analysis and DNA analysis for kinship identification in forensic research.

Heterochiral ß-Peptide Polymers Combating Multidrug-Resistant Cancers Effectively without Inducing Drug Resistance.

Multidrug resistance to chemotherapeutic drugs is one of the major causes for the failure of cancer treatment. Therefore, there is an urgent need to develop anticancer agents that can combat multidrug-resistant cancers effectively and mitigate drug resistance. Here, we report a rational design of anticancer heterochiral ß-peptide polymers as synthetic mimics of host defense peptides to combat multidrug-resistant cancers. The optimal polymer shows potent and broad-spectrum anticancer activities against multidrug-resistant cancer cells and is insusceptible to anticancer drug resistance owing to its membrane-damaging mechanism. The in vivo study indicates that the optimal polymer efficiently inhibits the growth and distant transfer of solid tumors and the metastasis and seeding of circulating tumor cells. Moreover, the polymer shows excellent biocompatibility during anticancer treatment on animals. In addition, the ß-peptide polymers address those prominent shortcomings of anticancer peptides and have superior stability against proteolysis, easy synthesis in large scale, and low cost. Collectively, the structural diversity and superior anticancer performance of ß-peptide polymers imply an effective strategy in designing and finding anticancer agents to combat multidrug-resistant cancers effectively while mitigating drug resistance.

The many faces of the E3 ubiquitin ligase, RNF220, in neural development and beyond.

Ubiquitin modification plays important roles in many cellular processes that are fundamental for vertebrate embryo development, such as cell division, differentiation, and migration. Aberrant function or deregulation of ubiquitination enzymes can cause developmental disorders, cancer progression, and neurodegenerative diseases in humans. RING finger protein 220 (RNF220) is an evolutionarily conserved RING-type ubiquitin E3 ligase. Recent studies have revealed the roles and mechanisms of RNF220 and its partner protein, zinc finger C4H2-type containing protein (ZC4H2), in embryonic development and human diseases. Using mouse and zebrafish models, it has been shown that RNF220 regulates sonic hedgehog (Shh) signaling via Gli and embryonic ectoderm development (EED), a polycomb repressive complex 2 (PRC2) component, during ventral neural patterning and cerebellum development. In addition, RNF220 also regulates the development and functions of central noradrenergic and motor neurons in mice. By stabilizing ß-catenin and signal transducer and activator of transcription 1 (STAT1), RNF220 is also involved in Wnt and interferon (IFN)-STAT1 signaling and thus the regulation of tumorigenesis and immune response, respectively. In humans, both RNF220 and ZC4H2 mutations have been reported to be associated with diseases accompanied by complicated neural defects. In this review, we summarize the current knowledge of RNF220 with special emphasis on its roles and mechanisms of action in signal transduction, vertebrate neural development, and related human disorders.

Positive association of nap duration with risk of non-alcoholic fatty liver disease in an occupational population in Guangdong Province, China: a cross-sectional study.

BACKGROUND: A lack of sleep or disorder in sleep-wake cycles has been associated with metabolic impairments. However, few studies have investigated the association between daytime napping duration and the risk of non-alcoholic fatty liver disease. This study aimed to investigate the association of daytime napping duration with the risk of non-alcoholic fatty liver disease in a Chinese population. METHODS: This cross-sectional study analyzed data from the Health Management Center of Nanfang Hospital, Guangdong Province. A total of 3363 participants aged 20-79 years were recruited and admitted from January 20, 2018, to October 16, 2020. Non-alcoholic fatty liver disease was diagnosed using abdominal ultrasonography. The outcome was the association between daytime sleep duration and the risk of non-alcoholic fatty liver disease. RESULTS: Compared with non-nappers, long daytime nappers (≥ 60 min) were associated with a higher risk of non-alcoholic fatty liver disease in the crude model (odds ratio 2.138; 95% confidence interval 1.88-2.61, P < 0.05) and in the multivariable adjustment model (odds ratio 2.211; 95% confidence interval 1.042-4.690, P < 0.05) after adjusting for demographic, educational, and metabolic risk factors. The association was moderately enhanced with additional adjustments for night sleep duration and socioeconomic or other factors (odds ratio 2.253; 95% confidence interval 1.061-4.786, P = 0.035). CONCLUSION: In this cross-sectional study, daytime napping duration of ≥ 60 min was positively associated with the risk of non-alcoholic fatty liver disease in an occupational population of Guangdong Province after multivariable adjustment.

Breakfast consumption frequency is associated with dyslipidemia: a retrospective cohort study of a working population.

BACKGROUND: Dyslipidemia is a significant contributor to cardiovascular and cerebrovascular diseases. Research on the relationship between breakfast consumption frequency and dyslipidemia in the working population is lacking. Therefore, we aimed to investigate this relationship based on a retrospective cohort study of a large working population in China. METHODS: This retrospective cohort study used data from the physical examinations and questionnaire survey of working participants at Nanfang Hospital from January 20, 2015 to October 16, 2020. Univariate and multivariate analyses were conducted to explore the relationship between breakfast consumption frequency and dyslipidemia in this working population (n = 7644). RESULTS: The prevalence of dyslipidemia among the participants was 26.4%. The univariate logistic regression test showed that the breakfast consumption frequency was inversely correlated with dyslipidemia. After adjusting for multiple factors, such as sex, age, body mass index, hypertension, hyperuricaemia, diabetes, smoking status, alcohol consumption, education level, marital status, long-term exposure to kitchen oil fumes, attending business dinners, and sleep time, it was found that breakfast consumption remained inversely associated with dyslipidaemia. The odds ratio for daily breakfast consumption was 0.466 (95% confidence interval 0.283-0.770, P = 0.003). After adjusting for confounding factors, we found that the higher the frequency of breakfast consumption, the lower the odds ratios for hypertriglyceridaemia. CONCLUSIONS: This study demonstrated that breakfast consumption frequency was inversely correlated with dyslipidemia. The higher the frequency of breakfast, the lower the risk of hypertriglyceridaemia. This study provides a basis on which dietary suggestions for the working population and lifestyle guidance for patients with a clinical need to prevent dyslipidemia can be made.

The Role of Computed Tomography in The Diagnosis of Rare Congenital Heart Disease: Interrupted Aortic Arch.

Interrupted aortic arch (IAA) is a rare congenital anomaly of the aortic arch and an anatomical interruption of the lumen between the ascending and descending aorta. Computed tomography (CT) has become a reliable noninvasive diagnostic method for congenital IAA. The purpose of this study was to investigate the imaging features of IAA and improve the understanding and diagnosis of the disease. The imaging features and postoperative pathological data of 25 patients with IAA confirmed by dual-source computed tomography (DSCT) angiography were analyzed in this retrospective study. Among the 25 patients with IAA, 15 were type A, seven were type B, 0 were types C and D, and two were type E. The diameter of the pulmonary artery trunk in type A was larger than that in type B (P < 0.05). However, there were no significant differences between types A and B along the ascending aorta diameter, descending aorta, ascending aorta/descending aorta ratio, left pulmonary artery main trunk diameter, right pulmonary artery main trunk diameter, left pulmonary artery trunk/pulmonary artery trunk ratio, right pulmonary artery trunk/pulmonary artery trunk ratio, and left pulmonary artery trunk/right pulmonary artery trunk ratio. The imaging findings of IAA have typical and specific signs, and the types of IAA are not comprehensive. One type of patient identification can be added: Patients who are dissected between the left common carotid artery and left subclavian artery opening, and the descending aorta is circulated by the chest collaterals. Patients with a wide pulmonary artery in the IAA are usually type A patients. Patients with IAA after surgical repair require lifetime follow up, mainly to monitor left ventricular outflow tract obstruction and recurrent aortic coarctation. This study was approved by the Ethics Committee of Kunming Yan'an Hospital (Kunming City, Yunnan Province, China), and consent was waived because of the retrospective data collection.

RNF220-mediated ubiquitination promotes aggresomal accumulation and autophagic degradation of cytoplasmic Gli via HDAC6.

Sonic hedgehog acts as a key mitogen to drive cell proliferation and as a morphogen to direct cell differentiation during embryonic development and adult tissue maintenance by controlling the activities of its transcriptional effectors Glis. We previously reported that RNF220 controls the nuclear translocation and subcellular localization of Glis by promoting their K63-linked polyubiquitination, through which it fine tunes Shh/Gli gradients during ventral spinal cord patterning. RNF220 also epigenetically regulates Shh signaling by targeting epifactor EED in cerebellar development. Here, we continued to study the molecular events underlying RNF220-mediated Shh regulation in the cytoplasm. The results showed that HDAC6 is required for RNF220-induced Gli accumulation in the cytoskeletal fraction and inclusion in aggresomes. In the cytoplasm, Glis polyubiquitinated by RNF220 are prone to interact with p62 and destined for autophagy-mediated degradation. Additionally, we showed that RNF220 inhibits the processing of Gli2 and Gli3 both in vitro and in vivo. Collectively, our studies shed new light on Shh signaling regulation.

Shared paternal ancestry of Han, Tai-Kadai-speaking, and Austronesian-speaking populations as revealed by the high resolution phylogeny of O1a-M119 and distribution of its sub-lineages within China.

OBJECTIVES: The aim of this research was to explore the origin, diversification, and demographic history of O1a-M119 over the past 10,000 years, as well as its role during the formation of East Asian and Southeast Asian populations, particularly the Han, Tai-Kadai-speaking, and Austronesian-speaking populations. MATERIALS AND METHODS: Y-chromosome sequences (n = 141) of the O1a-M119 lineage, including 17 newly generated in this study, were used to reconstruct a revised phylogenetic tree with age estimates, and identify sub-lineages. The geographic distribution of 12 O1a-M119 sub-lineages was summarized, based on 7325 O1a-M119 individuals identified among 60,009 Chinese males. RESULTS: A revised phylogenetic tree, age estimation, and distribution maps indicated continuous expansion of haplogroup O1a-M119 over the past 10,000 years, and differences in demographic history across geographic regions. We propose several sub-lineages of O1a-M119 as founding paternal lineages of Han, Tai-Kadai-speaking, and Austronesian-speaking populations. The sharing of several young O1a-M119 sub-lineages with expansion times less than 6000 years between these three population groups supports a partial common ancestry for them in the Neolithic Age; however, the paternal genetic divergence pattern is much more complex than previous hypotheses based on ethnology, archeology, and linguistics. DISCUSSION: Our analyses contribute to a better understanding of the demographic history of O1a-M119 sub-lineages over the past 10,000 years during the emergence of Han, Austronesians, Tai-Kadai-speaking populations. The data described in this study will assist in understanding of the history of Han, Tai-Kadai-speaking, and Austronesian-speaking populations from ethnology, archeology, and linguistic perspectives in the future.

Post-last glacial maximum expansion of Y-chromosome haplogroup C2a-L1373 in northern Asia and its implications for the origin of Native Americans.

OBJECTIVES: Subbranches of Y-chromosome haplogroup C2a-L1373 are founding paternal lineages in northern Asia and Native American populations. Our objective was to investigate C2a-L1373 differentiation in northern Asia and its implications for Native American origins. MATERIALS AND METHODS: Sequences of rare subbranches (n = 43) and ancient individuals (n = 37) of C2a-L1373 (including P39 and MPB373), were used to construct phylogenetic trees with age estimation by BEAST software. RESULTS: C2a-L1373 expanded rapidly approximately 17.7,000-14.3,000 years ago (kya) after the last glacial maximum (LGM), generating numerous sublineages which became founding paternal lineages of modern northern Asian and Native American populations (C2a-P39 and C2a-MPB373). The divergence pattern supports possible initiation of differentiation in low latitude regions of northern Asia and northward diffusion after the LGM. There is a substantial gap between the divergence times of C2a-MPB373 (approximately 22.4 or 17.7 kya) and C2a-P39 (approximately 14.3 kya), indicating two possible migration waves. DISCUSSION: We discussed the decreasing time interval of "Beringian standstill" (2.5 ky or smaller) and its reduced significance. We also discussed the multiple possibilities for the peopling of the Americas: the "Long-term Beringian standstill model," the "Short-term Beringian standstill model," and the "Multiple waves of migration model." Our results support the argument from ancient DNA analyses that the direct ancestor group of Native Americans is an admixture of "Ancient Northern Siberians" and Paleolithic communities from the Amur region, which appeared during the post-LGM era, rather than ancient populations in greater Beringia, or an adjacent region, before the LGM.

Paternal origin of Tungusic-speaking populations: Insights from the updated phylogenetic tree of Y-chromosome haplogroup C2a-M86.

OBJECTIVES: Haplogroup C2a-M48 is the predominant paternal lineage of Tungusic-speaking populations, one of the largest population groups in Siberia. Up until now, the origins and dispersal of Tungusic-speaking populations have remained unclear. In this study, the demographic history of Tungusic-speaking populations was explored using the phylogenetic analysis of haplogroup C2a-M86, the major subbranch of C2a-M48. MATERIALS AND METHODS: In total, 18 newly generated Y chromosome sequences from C2a-M48 males and 20 previously available Y-chromosome sequences from this haplogroup were analyzed. A highly revised phylogenetic tree of haplogroup C2a-M86 with age estimates was reconstructed. Frequencies of this lineage in the literature were collected and a comprehensive analysis of this lineage in 13 022 individuals from 245 populations in Eurasia was performed. RESULTS: The distribution map of C2a-M48 indicated the most probable area of origin and diffusion route of this paternal lineage in North Eurasia. Most C2a-M86 samples from Tungusic-speaking populations belonged to the sublineage C2a-F5484, which emerged about 3300 years ago. We identified six unique sublineages corresponding to the Manchu, Evenks, Evens, Oroqen, and Daurpopulations; these sublineages diverged gradually over the past 1900 years. Notably, we observed a clear north-south dichotomous structure for sublineages derived from C2a-F5484, consistent with the internal north-south divergence of Tungusic languages and ethnic groups. CONCLUSIONS: We identified the important founding paternal haplogroup, C2a-F5484, for Tungusic-speaking populations as well as numerous unique subgroups of this haplogroup. We propose that the timeframe for the divergence of C2a-F5484 corresponds with the early differentiation of ancestral Tungusic-speaking populations.

JLGBMLoc-A Novel High-Precision Indoor Localization Method Based on LightGBM.

Wi-Fi based localization has become one of the most practical methods for mobile users in location-based services. However, due to the interference of multipath and high-dimensional sparseness of fingerprint data, with the localization system based on received signal strength (RSS), is hard to obtain high accuracy. In this paper, we propose a novel indoor positioning method, named JLGBMLoc (Joint denoising auto-encoder with LightGBM Localization). Firstly, because the noise and outliers may influence the dimensionality reduction on high-dimensional sparseness fingerprint data, we propose a novel feature extraction algorithm-named joint denoising auto-encoder (JDAE)-which reconstructs the sparseness fingerprint data for a better feature representation and restores the fingerprint data. Then, the LightGBM is introduced to the Wi-Fi localization by scattering the processed fingerprint data to histogram, and dividing the decision tree under leaf-wise algorithm with depth limitation. At last, we evaluated the proposed JLGBMLoc on the UJIIndoorLoc dataset and the Tampere dataset, the experimental results show that the proposed model increases the positioning accuracy dramatically compared with other existing methods.