MAST: Phylogenetic Inference with Mixtures Across Sites and Trees.

Hundreds or thousands of loci are now routinely used in modern phylogenomic studies. Concatenation approaches to tree inference assume that there is a single topology for the entire dataset, but different loci may have different evolutionary histories due to incomplete lineage sorting, introgression, and/or horizontal gene transfer; even single loci may not be treelike due to recombination. To overcome this shortcoming, we introduce an implementation of a multi-tree mixture model that we call MAST. This model extends a prior implementation by Boussau et al. (2009) by allowing users to estimate the weight of each of a set of pre-specified bifurcating trees in a single alignment. The MAST model allows each tree to have its own weight, topology, branch lengths, substitution model, nucleotide or amino acid frequencies, and model of rate heterogeneity across sites. We implemented the MAST model in a maximum-likelihood framework in the popular phylogenetic software, IQ-TREE. Simulations show that we can accurately recover the true model parameters, including branch lengths and tree weights for a given set of tree topologies, under a wide range of biologically realistic scenarios. We also show that we can use standard statistical inference approaches to reject a single-tree model when data are simulated under multiple trees (and vice versa). We applied the MAST model to multiple primate datasets and found that it can recover the signal of incomplete lineage sorting in the Great Apes, as well as the asymmetry in minor trees caused by introgression among several macaque species. When applied to a dataset of four Platyrrhine species for which standard concatenated maximum likelihood and gene tree approaches disagree, we observe that MAST gives the highest weight (i.e. the largest proportion of sites) to the tree also supported by gene tree approaches. These results suggest that the MAST model is able to analyse a concatenated alignment using maximum likelihood, while avoiding some of the biases that come with assuming there is only a single tree. We discuss how the MAST model can be extended in the future.

Photochemical Organocatalytic Synthesis of Thioethers from Aryl Chlorides and Alcohols.

Thioethers, often found in pharmaceuticals and natural compounds, typically involve metal cross-coupling reactions, high temperatures, and the use of disagreeable thiols for their synthesis. Here we present a straightforward, thiol-free organocatalytic protocol that uses mild conditions to stitch together inexpensive alcohols and aryl chlorides, yielding a diverse array of aryl alkyl thioethers. Central to this approach was the discovery that tetramethylthiourea can serve as a simple sulfur source upon intercepting photochemically generated aryl radicals. To form radicals, we used a readily available indole thiolate organocatalyst that, when excited with 405 nm light, gained a strongly reducing power, enabling the activation of typically unreactive aryl chlorides via single-electron transfer. Radical trapping by the thiourea, followed by an alcohol attack via a polar path, resulted in the formation of thioether products.

DecentTree: scalable Neighbour-Joining for the genomic era.

MOTIVATION: Neighbour-Joining is one of the most widely used distance-based phylogenetic inference methods. However, current implementations do not scale well for datasets with more than 10 000 sequences. Given the increasing pace of generating new sequence data, particularly in outbreaks of emerging diseases, and the already enormous existing databases of sequence data for which Neighbour-Joining is a useful approach, new implementations of existing methods are warranted. RESULTS: Here, we present DecentTree, which provides highly optimized and parallel implementations of Neighbour-Joining and several of its variants. DecentTree is designed as a stand-alone application and a header-only library easily integrated with other phylogenetic software (e.g. it is integral in the popular IQ-TREE software). We show that DecentTree shows similar or improved performance over existing software (BIONJ, Quicktree, FastME, and RapidNJ), especially for handling very large alignments. For example, DecentTree is up to 6-fold faster than the fastest existing Neighbour-Joining software (e.g. RapidNJ) when generating a tree of 64 000 SARS-CoV-2 genomes. AVAILABILITY AND IMPLEMENTATION: DecentTree is open source and freely available at https://github.com/iqtree/decenttree. All code and data used in this analysis are available on Github (https://github.com/asdcid/Comparison-of-neighbour-joining-software).

Recurrent urinary tract infection genetic risk: a systematic review and gene network analysis.

INTRODUCTION AND HYPOTHESIS: The development of recurrent urinary tract infections (rUTIs) is not completely understood. This review is aimed at investigating the connection between genetics and rUTIs and summarizing the results of studies that have documented variations in gene expression among individuals with rUTIs compared with healthy individuals. METHODS: A systematic search was conducted in Cochrane, Ovid, and PubMed, limiting the results to articles published between 1 January 2000, and 5 July 2022. Only studies comparing the difference in gene expression between individuals with rUTI and healthy individuals utilizing molecular techniques to measure gene expression in blood or urine samples were included in this systematic review. Gene network and pathways analyses were performed using Cytoscape software, with input data obtained from our systematic review of differentially expressed genes in rUTIs. RESULTS: Six studies met our criteria for inclusion. The selected studies used molecular biology methods to quantify gene expression data from blood specimens. The analysis revealed that gene expressions of CXCR1 and TLR4 decreased, whereas CXCR2, TRIF, and SIGIRR increased in patients with rUTI compared with healthy controls. The analysis demonstrated that the most significant pathways were associated with TLR receptor signaling and tolerance, I-kappa B kinase/NF-kappa B signaling, and MyD88-independent TLR signaling. CONCLUSIONS: This systematic review uncovered gene expression variations in several candidate genes and identified a number of underlying biological pathways associated with rUTIs. These findings could shift the treatment and prevention strategies for rUTIs.

Mechanistic study of transcription factor Sox18 during heart development.

Heart development is a delicate and complex process regulated by coordination of various signaling pathways. In this study, we investigated the role of sox18 in heart development by modulating Wnt/ß-Catenin signaling pathways. Our spatiotemporal expression analysis revealed that sox18 is mainly expressed in the heart, branchial arch, pharyngeal arch, spinal cord, and intersegmental vessels at the tailbud stage of Xenopus tropicalis embryo. Overexpression of sox18 in the X. tropicalis embryos causes heart edema, while loss-of-function of sox18 can change the signal of developmental heart marker gata4 at different stages, suggesting that sox18 plays an essential role in the development of the heart. Knockdown of SOX18 in human umbilical vein endothelial cells suggests a link between Sox18 and ß-CATENIN, a key regulator of the Wnt signaling pathway. Sox18 negatively regulates islet1 and tbx3, the downstream factors of Wnt/ß-Catenin signaling, during the linear heart tube formation and the heart looping stage. Taken together, our findings highlight the crucial role of Sox18 in the development of the heart via inhibiting Wnt/ß-Catenin signaling.

Return to work following knee arthroplasty: a retrospective review in urban Asian population.

BACKGROUND: An increasing number of working adults undergo knee arthroplasty in Singapore. There is limited data concerning Southeast Asian patients returning to work (RTW) following knee replacement surgery. Our aim was to identify and study factors influencing patients RTW following total knee arthroplasty (TKA) or unicompartmental knee arthroplasty (UKA). METHODS: Patients who underwent TKA or UKA between August 2017 and March 2020 in our center were included in this study. Outcomes include RTW and duration prior to RTW. RESULTS: 441 patients underwent TKA (295 women, 146 men, mean age 67.3 years) and 69 underwent UKA (48 women, 21 men, mean age 61.1 years). Patients who underwent TKA returned to work earlier (mean 83.7 ± 27.1 days) compared to UKA (mean 94.4 ± 42.3 days). 90.0% of TKA patients RTW compared to 95.5% who underwent UKA. Of patients who RTW, 94.3% of the TKA group returned to employment of the same nature compared to 92.9% of UKA patients. Patients who RTW were of a younger age (p = 0.03), white collared workers (p = 0.04), and had independent preoperative ambulatory status (p < 0.01). CONCLUSION: Younger and independently ambulating patients may have better capacity for rehabilitation and RTW post arthroplasty surgery.

A systematic review and in silico study of potential genetic markers implicated in cases of overactive bladder.

OBJECTIVE: The contribution of genetic factors to the presence of an overactive bladder is recognized. This study aimed to (1) assemble and synthesize available data from studies assessing differential gene expression in patients with overactive bladder vs controls without overactive bladder and (2) determine possible correlations and functional pathways between genes. DATA SOURCES: We searched PubMed, Ovid or Medline, and Wiley Cochrane Central Register of Controlled Trials databases between January 1, 2000, and December 15, 2021. STUDY ELIGIBILITY CRITERIA: Studies were included if gene expression was detected and quantified using molecular approaches performed on human bladder tissue specimens directly and excluded if the gene expression analysis was carried out from blood and urine specimens alone. METHODS: A systematic review was completed to identify publications that reported differently expressed gene candidates among patients with overactive bladder vs healthy individuals. Gene networking connections and pathway analysis were performed employing Metascape software, where inputs were identified from our systematic review of differentially expressed genes in overactive bladder. RESULTS: A total of 9 studies were included in the final analysis and 11 genes were identified as being up-regulated (purinergic receptor P2X 2 [P2RX2], smoothelin [SMTN], growth-associated protein 43 [GAP43], transient receptor potential cation channel subfamily M member 8 [TRPM8], cadherin 11 [CDH1], gap junction protein gamma 1 [GJC1], cholinergic receptor muscarinic 2 [CHRM2], cholinergic receptor muscarinic 3 [CHRM3], and transient receptor potential cation channel subfamily V member 4 [TRPV4]) or down-regulated (purinergic receptor P2X 2 [P2RX3] and purinergic receptor P2X 5 [P2RX5]) in patients with overactive bladder. Gene network analysis showed that genes are involved in chemical synaptic transmission, smooth muscle contraction, blood circulation, and response to temperature stimulus. Network analysis demonstrated a significant genetic interaction between TRPV4, TRPM8, P2RX3, and PR2X2 genes. CONCLUSION: Outcomes of this systematic review highlighted potential biomarkers for treatment efficacy and have laid the groundwork for developing future gene therapies for overactive bladder in clinical settings.

Six-Year Evaluation of Same-Day Discharge following Conventional Transarterial Chemoembolization of Hepatocellular Carcinoma.

PURPOSE: To evaluate whether same-day discharge increased the incidence of 30-day readmission (30dR) after conventional transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) at a single institution. MATERIALS AND METHODS: In this retrospective study, 253 patients with HCC underwent 521 transarterial chemoembolization procedures between 2013 and 2020. TACE was performed with 50-mg doxorubicin/10-mg mitomycin C/5-10-mL ethiodized oil/particles. Patients not requiring intravenous pain medications were discharged after a 3-hour observation, and 30dR was tracked. The primary objective was to determine the incidence of 30dR in same-day discharge patients versus patients admitted for observation using the chi-square test. Secondary objectives assessed factors associated with overnight admission and factors predictive of 30dR using generalized estimated equation calculations and logistic regression. RESULTS: In the cohort, 24 readmissions occurred within 30 days (4.6%). Same-day discharge was completed after 331 TACE procedures with sixteen 30dRs (4.8%). Patients admitted overnight were readmitted 8 times after 190 TACE procedures (4.2%). This difference was not statistically significant (P = .4). Factors predicting overnight admission included female sex (58/190 [30.5%] vs 58/331 [17.5%], P < .001) and tumor size of ≥3.8 cm (104/190 [55%] vs 85/190 [45%]). Factors predicting 30dR included female sex (10/116 [8.6%] vs 14/405 [0.2%]) and younger age (median [interquartile range], 63 years [55-65 years] vs 65 years [59-71 years]). At regression, factors predictive of 30dR were Child-Pugh Class B/C (odds ratio [OR], 2.1; P = .04) and female sex (OR, 2.9; P = .004). CONCLUSIONS: Same-day discharge after conventional TACE is a safe and effective strategy with 30dR rate of <5%, similar to overnight observation.

Effects of posture on heart rate variability in non-frail and prefrail individuals: a cross-sectional study.

BACKGROUND: Frailty is an aging-related syndrome leading to high mortality in older adults. Without effective assessment and prevention of frailty, the incidence of frailty and relevant adverse outcomes will increase by 2050 as worldwide populations age. Although evidence suggested heart rate variability (HRV) is a potential measure of frailty, the role of HRV in frailty assessment remains unclear because of controversial findings. This study examined the effects of posture on HRV parameters in non-frail and prefrail individuals to understand the role of HRV in assessing frailty. METHODS: Forty-six participants aged ≥ 50 years were recruited between April and August 2022. Frailty was defined using Fried's criteria. HRV was measured in standing, sitting, and lying postures, respectively, using a Polar Watch, and analyzed using Kubios HRV Standard 3.5.0 (Kubios). The five most commonly used parameters were examined, including standard deviations of all normal-to-normal intervals (SDNN), root mean square of the successive differences (RMSSD), low frequency (LF), high frequency (HF), and LF/HF. Independent t-tests and Mann-Whitney tests were used for inter-group comparisons. Friedman tests were used for intra-group comparisons across postures. RESULTS: The non-frail group showed significant differences in HRV parameters across postures (all p < 0.05), whereas the prefrail group did not demonstrate any difference (all p > 0.05). The differences in the non-frail group included higher RMSSD and HF in the lying posture compared to those in the standing posture (29.54 vs 21.99 p = 0.003, 210.34 vs 96.34 p = 0.001, respectively), and higher LF and LF/HF in the sitting posture compared to those in the lying posture (248.40 vs 136.29 P = 0.024, 1.26 vs 0.77 p = 0.011, respectively). CONCLUSIONS: The effects of posture on HRV were blunted in the prefrail group, which suggests an impaired cardiac autonomic functioning. Measuring the effects of posture on HRV parameters may contribute to frailty assessment. However, further evidence from larger cohorts and including additional HRV parameters is needed.

Polylactic Acid-Based Biomaterials in Wound Healing: A Systematic Review.

OBJECTIVE: To examine (1) the effectiveness of polylactic acid (PLA)-based biomaterials in wound healing, (2) their effects on wound infection prevention, and (3) their safety compared with existing biomaterials. DATA SOURCES: Data sources included PubMed, MEDLINE, Cochrane Library, CINAHL (Cumulative Index to Nursing and Allied Health Literature), CNKI (China National Knowledge Infrastructure), WEIPU, and WANFANG databases. STUDY SELECTION: Investigators included 14 studies discussing the effects of PLA-based biomaterials in cutaneous wound healing published from 2000 to 2021. DATA EXTRACTION: Authors extracted the following information from the selected studies: general information, study type, type of wound, PLA-based biomaterials and techniques, study period, outcome measures, and results. DATA SYNTHESIS: Polylactic acid-based biomaterials may promote wound healing through wound area repair, collagen deposition, angiogenesis, and cell activities, which are related to the good biocompatibility, biodegradability, and moisture management properties of PLA. A proper product structure may also help. Both the native PLA materials and PLA blends seem to be antibacterial, although more evidence is needed for the native PLA products. Because there was no severe adverse event or obvious cytotoxicity observed in the included studies, PLA-based biomaterials are likely safe. CONCLUSIONS: Polylactic acid-based biomaterials may be good wound dressing materials, although more evidence is needed to support their broader application in wound care.

Exploring the impact of a compassion-oriented training program on personal care workers in a nursing home: A mixed-methods pilot study.

This pilot study aimed to explore the impact of a compassion-oriented training program on Personal Care Workers (PCWs) in a nursing home. A mixed-methods approach was used, including pre- and post-questionnaire surveys to measure changes in compassion, and in-depth interviews and daily diaries to explore PCWs' perceptions and experiences. A convenience sample of five female PCWs from a nursing home in Hong Kong participated in the study. The quantitative results showed that the PCWs experienced a decline in compassion after participating in the program. The qualitative data analysis identified three themes: (1) the multifaceted nature of compassion, (2) barriers and threats to compassion, and (3) transfer of skills at the workplace. Overall, These findings highlighted the complexity of implementing effective compassion training programs in nursing home, and emphasized the importance of recognizing the multifaceted nature of compassion and addressing barriers and threats to compassion in the workplace.

Fetal Loss and Preterm Birth Caused by Intraamniotic Haemophilus influenzae Infection, New Zealand.

Invasive Haemophilus influenzae infection during pregnancy can cause preterm birth and fetal loss, but the mechanism is unclear. We investigated 54 cases of pregnancy-associated invasive H. influenzae disease in 52 unique pregnancies in the Auckland region of New Zealand during October 1, 2008‒September 30, 2018. Intraamniotic infection was identified in 36 (66.7%) of 54 cases. Outcome data were available for 48 pregnancies. Adverse pregnancy outcomes, defined as fetal loss, preterm birth, or the birth of an infant requiring intensive/special care unit admission, occurred in 45 (93.8%) of 48 (pregnancies. Fetal loss occurred in 17 (35.4%) of 48 pregnancies, before 24 weeks' gestation in 13 cases, and at >24 weeks' gestation in 4 cases. The overall incidence of pregnancy-associated invasive H. influenzae disease was 19.9 cases/100,000 births, which exceeded the reported incidence of pregnancy-associated listeriosis in New Zealand. We also observed higher rates in younger women and women of Maori ethnicity.

Long-term outcomes following 90Y Radioembolization of neuroendocrine liver metastases: evaluation of the radiation-emitting SIR-spheres in non-resectable liver tumor (RESiN) registry.

BACKGROUND: The goal of this study was to evaluate efficacy and safety of 90Y radioembolization for neuroendocrine liver metastases (NELM) in a multicenter registry. METHODS: One hundred-seventy patients with NELM were enrolled in the registry (NCT02685631). Prior treatments included hepatic resection (n = 23, 14%), arterial therapy (n = 62, 36%), octreotide (n = 119, 83%), cytotoxic chemotherapy (n = 58, 41%), biologic therapy (n = 49, 33%) and immunotherapy (n = 10, 6%). Seventy-seven (45%) patients had extrahepatic disease. Seventy-eight (48%), 61 (37%), and 25 (15%) patients were Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or ≥ 2. Tumor grade was known in 81 (48%) patients: 57 (70%) were well-, 12 (15%) moderate-, and 12 (15%) poorly-differentiated. Kaplan-Meier analysis and log rank tests were performed to compare overall and progression-free survival (OS/PFS) by tumor location and grade. Toxicities were reported using Common Terminology Criteria for Adverse Events v.5. Cox Proportional Hazards were calculated for pancreatic primary, performance status, extrahepatic disease at treatment, unilobar treatment, baseline ascites, and > 25% tumor burden. RESULTS: One, 2, and 3-year OS rates were 75, 62 and 46%, respectively. Median OS was 33 months [(95% CI: 25-not reached (NR)]. The longest median OS was in patients with pancreatic (42 months, 95% CI: 33-NR) and hindgut 41 months, 95% CI: 12-NR) primaries. The shortest OS was in foregut primaries (26 months; 95% CI: 23-NR; X2 = 7, p = 0.1). Median OS of well-differentiated tumors was 36 months (95% CI: 10-NR), compared to 44 (95% CI: 7-NR) and 25 (95% CI: 3-NR) months for moderate and poorly differentiated tumors. Median progression-free survival (PFS) was 25 months with 1, 2, and 3-year PFS rates of 70, 54, and 35%, respectively. Thirteen patients (7.6%) developed grade 3 hepatic toxicity, most commonly new ascites (n = 8, 5%) at a median of 5.5 months. Performance status of ≥2 (HR 2.7, p = 0.01) and baseline ascites (HR 2.8, P = 0.049) predicted shorter OS. DISCUSSION: In a population with a high incidence of extrahepatic disease, 90Y was effective and safe in treatment of NELM, with median OS of 41 months for well differentiated tumors. Grade 3 or greater hepatic toxicity was developed in 7.6% of patients. TRIAL REGISTRATION: NCT02685631 .

An assembly-free method of phylogeny reconstruction using short-read sequences from pooled samples without barcodes.

A current strategy for obtaining haplotype information from several individuals involves short-read sequencing of pooled amplicons, where fragments from each individual is identified by a unique DNA barcode. In this paper, we report a new method to recover the phylogeny of haplotypes from short-read sequences obtained using pooled amplicons from a mixture of individuals, without barcoding. The method, AFPhyloMix, accepts an alignment of the mixture of reads against a reference sequence, obtains the single-nucleotide-polymorphisms (SNP) patterns along the alignment, and constructs the phylogenetic tree according to the SNP patterns. AFPhyloMix adopts a Bayesian inference model to estimate the phylogeny of the haplotypes and their relative abundances, given that the number of haplotypes is known. In our simulations, AFPhyloMix achieved at least 80% accuracy at recovering the phylogenies and relative abundances of the constituent haplotypes, for mixtures with up to 15 haplotypes. AFPhyloMix also worked well on a real data set of kangaroo mitochondrial DNA sequences.

Interventions for the prevention of acute phase chemotherapy-induced nausea and vomiting in adult and pediatric patients: a systematic review and meta-analysis.

PURPOSE: To identify effective and safe interventions to prevent acute phase chemotherapy-induced nausea and vomiting (CINV) in adult and pediatric patients. METHODS: We conducted a systematic review of randomized trials evaluating interventions to prevent acute CINV. Outcomes assessed were complete chemotherapy-induced vomiting (CIV) control, complete chemotherapy-induced nausea (CIN) control, complete CINV control, and discontinuation of antiemetics due to adverse effects. RESULTS: The search identified 65,172 citations; 744 were evaluated at full-text, and 295 (25 pediatric) met eligibility criteria. In patients receiving highly emetogenic chemotherapy (HEC), complete CIV (risk ratio (RR) 1.23, 95% confidence interval (CI) 1.05-1.44) and CIN (RR 1.34, 95% CI 1.10-1.62) control improved when olanzapine was added. The addition of a neurokinin-1 receptor antagonist (NK1RA) to a corticosteroid plus a serotonin-3 receptor antagonist (5HT3RA) also improved complete CIV (RR 1.11, 95% CI 1.08-1.14) and CIN (RR 1.05, 95% CI 1.01-1.08) control. Compared to granisetron/ondansetron, palonosetron provided improved complete CIV control when the 5HT3RA was given alone or when combined with dexamethasone. In patients receiving moderately emetogenic chemotherapy (MEC), dexamethasone plus a 5HT3RA improved complete CIV control compared to a 5HT3RA alone (RR 1.29, 95% CI 1.21-1.39). Only a single meta-analysis evaluating the safety outcome was possible. CONCLUSIONS: For patients receiving HEC, various antiemetic regimens improved CIV and CIN control. For patients receiving MEC, administration of a 5HT3RA plus dexamethasone improved CIV control. Analysis of antiemetic safety was constrained by lack of data.

3D Inductive Frequency Selective Structures Using Additive Manufacturing and Low-Cost Metallization.

The use of additive manufacturing and different metallization techniques for prototyping radio frequency components such as antennas and waveguides are rising owing to their high precision and low costs. Over time, additive manufacturing has improved so that its utilization is accepted in satellite payloads and military applications. However, there is no record of the frequency response in the millimeter-wave band for inductive 3D frequency selective structures implemented by different metallization techniques. For this reason, three different prototypes of dielectric 3D frequency selective structures working in the millimeter-wave band are designed, simulated, and manufactured using VAT photopolymerization. These prototypes are subsequently metallized using metallic paint atomization and electroplating. The manufactured prototypes have been carefully selected, considering their design complexity, starting with the simplest, the square aperture, the medium complexity, the woodpile structure, and the most complex, the torus structure. Then, each structure is measured before and after the metallization process using a measurement bench. The metallization used for the measurement is nickel spray flowed by the copper electroplating. For the electroplating, a detailed table showing the total area to be metallized and the current applied is also provided. Finally, the effectiveness of both metallization techniques is compared with the simulations performed using CST Microwave Studio. Results indicate that a shifted and reduced band-pass is obtained in some structures. On the other hand, for very complex structures, as in the torus case, band-pass with lower loss is obtained using copper electroplating, thus allowing the manufacturing of inductive 3D frequency selective structures in the millimeter-wave band at a low cost.

BAG3 Attenuates Ischemia-Induced Skeletal Muscle Necroptosis in Diabetic Experimental Peripheral Artery Disease.

Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities, resulting in ischemic limb injuries. Individuals with diabetes and PAD typically have more severe ischemic limb injuries and limb amputations, but the mechanisms involved are poorly understood. Previously, we identified BAG3 as a gene within a mouse genetic locus termed limb salvage QTL1 on mouse chromosome 7 that determined the extent of limb necrosis following ischemic injury in C57Bl/6 mice. Whether BAG3 deficiency plays a role in the severe ischemic injury observed in diabetic PAD is not known. In vitro, we found simulated ischemia enhanced BAG3 expression in primary human skeletal muscle cells, whereas BAG3 knockdown increased necroptosis markers and decreased cell viability. In vivo, ischemic skeletal muscles from hind limbs of high-fat diet (HFD)-fed mice showed poor BAG3 expression compared to normal chow diet (NCD)-fed mice, and this was associated with increased limb amputations. BAG3 overexpression in ischemic skeletal muscles from hind limbs of HFD mice rescued limb amputation and improved autophagy, necroptosis, skeletal muscle function and regeneration. Therefore, BAG3 deficiency in ischemic skeletal muscles contributes to the severity of ischemic limb injury in diabetic PAD, likely through autophagy and necroptosis pathways.

Elevated A20 promotes TNF-induced and RIPK1-dependent intestinal epithelial cell death.

Intestinal epithelial cell (IEC) death is a common feature of inflammatory bowel disease (IBD) that triggers inflammation by compromising barrier integrity. In many patients with IBD, epithelial damage and inflammation are TNF-dependent. Elevated TNF production in IBD is accompanied by increased expression of the TNFAIP3 gene, which encodes A20, a negative feedback regulator of NF-κB. A20 in intestinal epithelium from patients with IBD coincided with the presence of cleaved caspase-3, and A20 transgenic (Tg) mice, in which A20 is expressed from an IEC-specific promoter, were highly susceptible to TNF-induced IEC death, intestinal damage, and shock. A20-expressing intestinal organoids were also susceptible to TNF-induced death, demonstrating that enhanced TNF-induced apoptosis was a cell-autonomous property of A20. This effect was dependent on Receptor Interacting Protein Kinase 1 (RIPK1) activity, and A20 was found to associate with the Ripoptosome complex, potentiating its ability to activate caspase-8. A20-potentiated RIPK1-dependent apoptosis did not require the A20 deubiquitinase (DUB) domain and zinc finger 4 (ZnF4), which mediate NF-κB inhibition in fibroblasts, but was strictly dependent on ZnF7 and A20 dimerization. We suggest that A20 dimers bind linear ubiquitin to stabilize the Ripoptosome and potentiate its apoptosis-inducing activity.

Modulation of miR-29a and ADAM12 Reduces Post-Ischemic Skeletal Muscle Injury and Improves Perfusion Recovery and Skeletal Muscle Function in a Mouse Model of Type 2 Diabetes and Peripheral Artery Disease.

Both Type 1 diabetes mellitus (DM1) and type 2 diabetes mellitus (DM2) are associated with an increased risk of limb amputation in peripheral arterial disease (PAD). How diabetes contributes to poor PAD outcomes is poorly understood but may occur through different mechanisms in DM1 and DM2. Previously, we identified a disintegrin and metalloproteinase gene 12 (ADAM12) as a key genetic modifier of post-ischemic perfusion recovery. In an experimental PAD, we showed that ADAM12 is regulated by miR-29a and this regulation is impaired in ischemic endothelial cells in DM1, contributing to poor perfusion recovery. Here we investigated whether miR-29a regulation of ADAM12 is altered in experimental PAD in the setting of DM2. We also explored whether modulation of miR-29a and ADAM12 expression can improve perfusion recovery and limb function in mice with DM2. Our result showed that in the ischemic limb of mice with DM2, miR-29a expression is poorly downregulated and ADAM12 upregulation is impaired. Inhibition of miR-29a and overexpression of ADAM12 improved perfusion recovery, reduced skeletal muscle injury, improved muscle function, and increased cleaved Tie 2 and AKT phosphorylation. Thus, inhibition of miR-29a and or augmentation of ADAM12 improves experimental PAD outcomes in DM2 likely through modulation of Tie 2 and AKT signalling.

Correction to: Effective machine-learning assembly for next-generation amplicon sequencing with very low coverage.

Following publication of the original article [1], the author reported that there are several errors in the original article.