Miracle-dz/UniFAR-FTUs huggingface dataset:
The Identification of Prognostic and Metastatic Alternative Splicing in Skin Cutaneous Melanoma

Skin cutaneous melanoma (SKCM) is a type of highly invasive cancer originated from melanocytes. It is reported that aberrant alternative splicing (AS) plays an important role in the neoplasia and metastasis of many types of cancer. Therefore, we investigated whether ASEs of pre-RNA have such an influence on the prognosis of SKCM and the related mechanism of ASEs in SKCM. The RNA-seq data and ASEs data for SKCM patients were obtained from the TCGA and TCGASpliceSeq database. The univariate Cox regression revealed 1265 overall survival-related splicing events (OS-SEs). Screened by Lasso regression, 4 OS-SEs were identified and used to construct an effective prediction model (AUC: .904), whose risk score was proved to be an independent prognostic factor. Furthermore, Kruskal–Wallis test and Mann–Whitney–Wilcoxon test showed that an aberrant splicing type of aminoacyl tRNA synthetase complex-interacting multifunctional protein 2 (AIMP2) regulated by CDC-like kinase 1 (CLK1) was associated with the metastasis and stage of SKCM. Besides, the overlapped signal pathway for AIMP2 was galactose metabolism identified by the co-expression analysis. External database validation also confirmed that AIMP2, CLK1, and the galactose metabolism were associated with the metastasis and stage of SKCM patients. ChIP-seq and ATAC-seq methods further confirmed the transcription regulation of CLK1, AIMP2, and other key genes, whose cellular expression was detected by Single Cell Sequencing. In conclusion, we proposed that CLK1-regulated AIMP2-78704-ES might play a critical role in the tumorigenesis and metastasis of SKCM via galactose metabolism. Besides, we established an effective model with MTMR14-63114-ES, URI1-48867-ES, BATF2-16724-AP, and MED22-88025-AP to predict the metastasis and prognosis of SKCM patients.
Distinct populations of highly potent TAU seed conformers in rapidly progressing Alzheimer’s disease

Description Rapid replication in vitro implicates distinct populations of misfolded hippocampal 4R TAU protein in accelerated progression of Alzheimer’s disease. Shape matters The accumulation of TAU protein aggregates is one of the major hallmarks of Alzheimer’s disease (AD). Although TAU accumulation has been shown to be a predictor of cognitive decline in patients with AD, the correlation between AD progression and TAU remains to be elucidated. Here, Kim et al. isolated and analyzed TAU protein structure obtained from patients with different disease progression and showed an association between progression rate and distinct TAU conformers. Rapidly progressing AD was associated with mostly misfolded four-repeat (4R) TAU and high replication rate in vitro. The results suggest that the structure of TAU protein aggregates should be considered when developing potential treatment for slowing or halting AD progression. Although genetic factors play a main role in determining the risk of developing Alzheimer’s disease (AD), they do not explain extensive spectrum of clinicopathological phenotypes. Deposits of aggregated TAU proteins are one of the main predictors of cognitive decline in AD. We investigated the hypothesis that variabilities in AD progression could be due to diverse structural assemblies (strains) of TAU protein. Using sensitive biophysical methods in 40 patients with AD and markedly different disease durations, we identified populations of distinct TAU particles that differed in size, structural organization, and replication rate in vitro and in cell assay. The rapidly replicating, distinctly misfolded TAU conformers found in rapidly progressive AD were composed of ~80% misfolded four-repeat (4R) TAU and ~20% of misfolded 3R TAU isoform with the same conformational signatures. These biophysical observations suggest that distinctly misfolded population of 4R TAU conformers drive the rapid decline in AD and imply that effective therapeutic strategies might need to consider not a singular species but a cloud of differently misfolded TAU conformers.
Relatlimab and Nivolumab versus Nivolumab in Untreated Advanced Melanoma.

BACKGROUND Lymphocyte-activation gene 3 (LAG-3) and programmed death 1 (PD-1) are distinct inhibitory immune checkpoints that contribute to T-cell exhaustion. The combination of relatlimab, a LAG-3-blocking antibody, and nivolumab, a PD-1-blocking antibody, has been shown to be safe and to have antitumor activity in patients with previously treated melanoma, but the safety and activity in patients with previously untreated melanoma need investigation. METHODS In this phase 2-3, global, double-blind, randomized trial, we evaluated relatlimab and nivolumab as a fixed-dose combination as compared with nivolumab alone when administered intravenously every 4 weeks to patients with previously untreated metastatic or unresectable melanoma. The primary end point was progression-free survival as assessed by blinded independent central review. RESULTS The median progression-free survival was 10.1 months (95% confidence interval [CI], 6.4 to 15.7) with relatlimab-nivolumab as compared with 4.6 months (95% CI, 3.4 to 5.6) with nivolumab (hazard ratio for progression or death, 0.75 [95% CI, 0.62 to 0.92]; P = 0.006 by the log-rank test). Progression-free survival at 12 months was 47.7% (95% CI, 41.8 to 53.2) with relatlimab-nivolumab as compared with 36.0% (95% CI, 30.5 to 41.6) with nivolumab. Progression-free survival across key subgroups favored relatlimab-nivolumab over nivolumab. Grade 3 or 4 treatment-related adverse events occurred in 18.9% of patients in the relatlimab-nivolumab group and in 9.7% of patients in the nivolumab group. CONCLUSIONS The inhibition of two immune checkpoints, LAG-3 and PD-1, provided a greater benefit with regard to progression-free survival than inhibition of PD-1 alone in patients with previously untreated metastatic or unresectable melanoma. Relatlimab and nivolumab in combination showed no new safety signals. (Funded by Bristol Myers Squibb; RELATIVITY-047 ClinicalTrials.gov number, NCT03470922.).
Best additional management after non-curative endoscopic resection of esophageal squamous cell carcinoma: a systematic review and meta-analysis

Abstract Introduction Endoscopic resection (ER) is an accepted first-line treatment for superficial esophageal squamous cell carcinoma (ESCC), but when curative resection is not achieved, further treatment is not standardised. We aimed at evaluating outcomes of management strategies (esophagectomy, chemoradiotherapy/radiotherapy (CRT/RT) or follow-up (FUP)) after a non-curative ESCC ER. Methods A systematic review was performed evaluating outcomes of different management strategies after ESCC submitted to primary ER (T1a/T1b), without curative criteria (R1/Rx, T1a-m3/T1b, lymphovascular invasion (LVI) or poor differentiation). Primary outcomes included recurrence, overall survival (OS) and cancer-specific survival (CSS). Secondary outcomes consisted of treatment-related adverse events. Results Seventeen studies were included for qualitative analysis (16 observational and 1 randomized controlled trial) including 788 patients with ESCC submitted to ER, managed by additional CRT/RT (n = 530), surgery (n = 98) or FUP (n = 160). Eight studies suited quantitative analysis. Patients only followed up after ER experienced recurrence rates of 0–36.4% (OR 3.6 (95%CI 1.06–12.20) vs further treatments). When submitted to CRT/RT following non-curative ER, recurrence was observed in 0–27.2% (OR 8.00 (95%CI 1.74–36.80) whereas after surgery no recurrence was noticeable. Reported 5 y-OS after CRT/RT for non-curative ER ranged among 75–100% whereas, for those offered surgeries, 5 y-OS was 89.5%. OS ranged between 54.5% and 100% after FUP. CRT/RT and surgery-related adverse events ranged from 0% to 32% and 14% to 28.5%. Conclusions Additional treatment should be provided in ESCC after non-curative ER. Adjuvant esophagectomy might be the preferred treatment to medically fit patients with high-risk features (namely LVI). Properly designed trials assessing the role of CRT/RT are needed to manage these patients.
Research Priorities for Plasma and Platelet Transfusion Strategies in Critically Ill Children: From the Transfusion and Anemia EXpertise Initiative–Control/Avoidance of Bleeding

Objectives: To present a list of high-priority research initiatives for the study of plasma and platelet transfusions in critically ill children from the Transfusion and Anemia EXpertise Initiative–Control/Avoidance of Bleeding. Design: Systematic review and consensus conference of international, multidisciplinary experts in platelet and plasma transfusion management of critically ill children. Setting: Not applicable. Patients: Critically ill pediatric patients at risk of bleeding and receiving plasma and/or platelet transfusions. Interventions: None. Measurements and Main Results: A panel of 13 experts developed research priorities for the study of plasma and platelet transfusions in critically ill children which were reviewed and ratified by the 29 Transfusion and Anemia EXpertise Initiative–Control/Avoidance of Bleeding experts. The specific priorities focused on the following subpopulations: severe trauma, traumatic brain injury, intracranial hemorrhage, cardiopulmonary bypass surgery, extracorporeal membrane oxygenation, oncologic diagnosis or stem cell transplantation, acute liver failure and/or liver transplantation, noncardiac surgery, invasive procedures outside of the operating room, and sepsis and/or disseminated intravascular coagulation. In addition, tests to guide plasma and platelet transfusion, as well as component selection and processing, were addressed. We developed four general overarching themes and 14 specific research priorities using modified Research and Development/University of California, Los Angeles methodology. Conclusions: Studies are needed to focus on the efficacy/harm, dosing, timing, and outcomes of critically ill children who receive plasma and/or platelet transfusions. The completion of these studies will facilitate the development of evidence-based recommendations.
The role of exosomes in intercellular and inter‐organ communication of the peripheral nervous system

Exosomes, nano‐sized extracellular vesicles, are produced via the endosomal pathway and released in the extracellular space upon fusion of multivesicular bodies with the plasma membrane. Recent evidence shows that these extracellular vesicles play a key role in cell‐to‐cell communication. Exosomes transport bioactive proteins, mRNAs, and microRNA (miRNAs) in an active form to adjacent cells or to distant organs. In this review, we focus on the role of exosomes in peripheral nerve maintenance and repair, as well as peripheral nerve/organ crosstalk, and discuss the potential benefits of exploiting exosomes for treating PNS injuries. In addition, we will highlight the emerging role of exosomes as new important vehicles for physiological systemic crosstalk failures, which could lead to organ dysfunction during neuroinflammation or aging.
A novel current-mode instrumentation amplifier with Rail-to-Rail input and output

A current-mode instrumentation amplifier(CMIA) based on standard CMOS process is presented.The chopper pair used in the CMIA is for removing offset and 1/f noise.Moreover,associated with positive and negative charge pump the CMIA have true Rail-to-Rail input range.A prototype chip is designed and fabricated by using TSMC's 0. 25μm CMOS mixed-signal process.The system gain is determined by using two off-chip resistors.The measurement results show that the proposed CMIA with 60 kHz chopper and system gain of 40dB,have common-mode rejection ratio of 100dB,input-referred dc offset of-35μV,input-referred noise of 9nV/√Hz and input common mode range from-0.1V to 3.5V under the condition of 3V supply.
System Stability of Learning-Based Linear Optimal Control With General Discounted Value Iteration

For discounted optimal regulation design, the stability of the controlled system is affected by the discount factor. If an inappropriate discount factor is employed, the optimal control policy might be unstabilizing. Therefore, in this article, the effect of the discount factor on the stabilization of control strategies is discussed. We develop the system stability criterion and the selection rules of the discount factor with respect to the linear quadratic regulator problem under the general discounted value iteration algorithm. Based on the monotonicity of the value function sequence, the method to judge the stability of the controlled system is established during the iteration process. In addition, once some stability conditions are satisfied at a certain iteration step, all control policies after this iteration step are stabilizing. Furthermore, combined with the undiscounted optimal control problem, the practical rule of how to select an appropriate discount factor is constructed. Finally, several simulation examples with physical backgrounds are conducted to demonstrate the present theoretical results.
Models and methods to study Schwann cells

Schwann cells (SCs) are fundamental components of the peripheral nervous system (PNS) of all vertebrates and play essential roles in development, maintenance, function, and regeneration of peripheral nerves. There are distinct populations of SCs including: (1) myelinating SCs that ensheath axons by a specialized plasma membrane, called myelin, which enhances the conduction of electric impulses; (2) non‐myelinating SCs, including Remak SCs, which wrap bundles of multiple axons of small caliber, and perysinaptic SCs (PSCs), associated with motor axon terminals at the neuromuscular junction (NMJ). All types of SCs contribute to PNS regeneration through striking morphological and functional changes in response to nerve injury, are affected in peripheral neuropathies and show abnormalities and a diminished plasticity during aging. Therefore, methodological approaches to study and manipulate SCs in physiological and pathophysiological conditions are crucial to expand the present knowledge on SC biology and to devise new therapeutic strategies to counteract neurodegenerative conditions and age‐derived denervation. We present here an updated overview of traditional and emerging methodologies for the study of SCs for scientists approaching this research field.
Ecological thresholds under atmospheric nitrogen deposition for 1200 herbaceous species and 24 communities across the United States

Nitrogen (N) emissions and atmospheric deposition have increased significantly during the last century and become a stressor for many N‐sensitive plant species. Understanding individual and community herbaceous plant species thresholds to atmospheric N deposition can inform emissions reduction policy. Here, we present results using Threshold Indicator Taxa Analysis (TITAN) applied to more than 1200 unique plant species and 24 vegetation communities (i.e., alliances) across the United States (US) to assess vulnerability to N deposition. Alliance‐level thresholds (change points) for species decreasing in abundance along the gradient ranged from 1.8 to 14.3 kg N ha─1 year─1 and tended to be lower in the west than the east, which suggests that eastern communities, where N deposition has been historically higher, may have already lost many sensitive species. For the species that were present in more than one alliance, over half had a variable response to the N deposition gradient, suggesting that local factors affect vulnerability. Significant progress has been made during the past 30 years to reduce N emissions, which has reduced the percentage of plots at risk to N deposition from 72% to 35%. Nevertheless, over a third of plots remain at risk, and an average reduction of N deposition of 20% would protect half of the plots where N deposition exceeds community thresholds. Furthermore, the alliance‐ and species‐level change points determined in this study may be used to inform N critical loads.
Systems-level analysis of the plasticity of the maize metabolic network reveals novel hypotheses in the nitrogen-use efficiency of maize roots

This article comments on: Chowdhury NB, Schroeder WL, Sarkar D, Amiour N, Quilleré I, Hirel B, Maranas CD, Saha R. 2022. Dissecting the metabolic reprogramming of maize root under nitrogen-deficient stress conditions. Journal of Experimental Botany 73, 275–291.
Inpatient Early Intervention for Serious Mental Illnesses Is Associated With Fewer Rehospitalizations Compared With Treatment as Usual in a High-volume Public Psychiatric Hospital Setting

Objective: High-acuity publicly funded inpatient psychiatric settings usually feature short lengths of stay and high readmission rates. This study examined the influence of an early intervention program for serious mental illnesses (SMI) on readmissions at 6 and 12 months postdischarge at a high-volume, urban public inpatient psychiatric hospital. Methods: The Early Onset Treatment Program (EOTP) is a cost-free, 90-day inpatient multidisciplinary service intervention program for uninsured patients who are within 5 years of SMI onset, funded as a pilot program by the Texas state legislature. Rehospitalization rates at 6 and 12 months were extracted from electronic medical records for EOTP participants (n=165) and comparison patients matched on demographics and diagnosis (n=155). The comparison group received treatment as usual at the same psychiatric hospital. Group re-admission rates were compared using logistic and Poisson regression analyses. Results: Group membership was a significant predictor of rehospitalization (P<0.0001) at both 6 and 12 months. Expressed as 1/odds ratio (OR), the EOTP group was less likely to readmit once and more than once at 6 months postdischarge (1/OR=3.82 and 4.74, respectively) compared with the non-EOTP group. The EOTP group was also less likely to readmit once and more than once at 12 months postdischarge (1/OR=2.96 and 3.51, respectively). Conclusions: The results suggest that participation in the EOTP service in this high-acuity setting was significantly related to reduced likelihood of rehospitalization at 6 and 12 months. Several variables may account for this observation, including length of stay, longer medication adherence, environmental stability, and more individualized and extensive psychotherapy treatment.
Hyphae move matter and microbes to mineral microsites: Integrating the hyphosphere into conceptual models of soil organic matter stabilization

Associations between soil minerals and microbially derived organic matter (often referred to as mineral‐associated organic matter or MAOM) form a large pool of slowly cycling carbon (C). The rhizosphere, soil immediately adjacent to roots, is thought to control the spatial extent of MAOM formation because it is the dominant entry point of new C inputs to soil. However, emphasis on the rhizosphere implicitly assumes that microbial redistribution of C into bulk (non‐rhizosphere) soils is minimal. We question this assumption, arguing that because of extensive fungal exploration and rapid hyphal turnover, fungal redistribution of soil C from the rhizosphere to bulk soil minerals is common, and encourages MAOM formation. First, we summarize published estimates of fungal hyphal length density and turnover rates and demonstrate that fungal C inputs are high throughout the rhizosphere–bulk soil continuum. Second, because colonization of hyphal surfaces is a common dispersal mechanism for soil bacteria, we argue that hyphal exploration allows for the non‐random colonization of mineral surfaces by hyphae‐associated taxa. Third, these bacterial communities and their fungal hosts determine the chemical form of organic matter deposited on colonized mineral surfaces. Collectively, our analysis demonstrates that omission of the hyphosphere from conceptual models of soil C flow overlooks key mechanisms for MAOM formation in bulk soils. Moving forward, there is a clear need for spatially explicit, quantitative research characterizing the environmental drivers of hyphal exploration and hyphosphere community composition across systems, as these are important controls over the rate and organic chemistry of C deposited on minerals.
Do we need a more flexible use of Team Timeout calling? Evidence from the Handball Bundesliga

ABSTRACT Calling a Team Timeout (TTO) is one of the coaches’ most important tools. Given the key competitive advantage to determine your own timing, it is crucial to make a good decision when to use a TTO. Existing research shows that teams can benefit in general from TTOs and that they are called at the end of the game and when trailing (Gomes et al., 2014; Gutiérrez-Aguilar et al., 2016; Prieto et al., 2016). However, to generate relevant findings, situational variables must be included (Fernandez-Navarro et al., 2020; Gómez, Lago-Peñas et al., 2015). By integrating situational variables like scoring streak and player difference and higher-order interactions, this study aims to identify specific game situations where TTOs are most effective. Based on 850 games of the German Handball Bundesliga, game situations are identified by Classification Tree Analysis and efficacies are evaluated. Findings indicate a strong impact of timing. Frequently used TTOs, e.g., at the end of periods, are beneficial to the teams. However, strongest effect occurs for TTOs taken at the early stages of the game and with a positive run. Results indicate that TTO is a powerful tactical tool and an application at uncommon timings may even enhance the success rate.
Design of synchronous under-seal based on anti-shear strength between interlayers

The mechanistic-empirical design method of synchronous under-seal was studied based on its performance requirements.In this method the anti-shear strength between interlayers was taken as design index.The first step was to estimate asphalt content with McLeod empirical design method,and then 5 kinds of specimens were formed with different asphalt contents and the estimated content set as the middle value,then the shear strength tests of the 5 kinds of specimens were carried out.Finally,the asphalt content with the maximum shear strength was set as the optimum content.At the same time,the shear test,rutting test and seepage test were carried out to the two kinds of composite specimens: with only prime coat layer and with prime coat +synchronous under-seal.The results show that: the mechanistic-empirical design method can reduce the more asphalt content than the McLeod's,reduced by about 0.261 kg/m2;the synchronous under-seal can improve the interface resistance shear strength and dynamic stability,raised about 141% and 27.6% compared with the prime coat's;the impermeability of composite specimens can be significantly improved by using synchronous under-seal.4 tabs,3 figs,8 refs.
Hysteretic behavior of rectangular tube (box) sections based on Preisach model

In the present paper, the Preisach model of hysteresis is applied to model cyclic behavior of elas- to-plastic material. Rate of loading and viscous effects will not be considered. The problem of axial loading of rectangular cross-section and cyclic bending of rectangular tube (box) will be studied in details. Hysteretic stress-strain loop for prescribed history of stress change is plotted for material modeled by series connection of three unite element. Also moment-curvature hysteretic loop is obtained for a prescribed curvature change of rectangular tube (box). All obtained results clearly show advantages of the Preisach model for describing cyclic behavior of elasto-plastic material.
Characterization, genome analysis and in vitro activity of a novel phage vB_EcoA_RDN8.1 active against multi‐drug resistant and extensively drug‐resistant biofilm‐forming uropathogenic Escherichia coli isolates, India

We aimed to study host range, stability, genome and antibiofilm activity of a novel phage vB_EcoA_RDN8. 1 active against multi‐drug resistant (MDR) and extensively drug‐resistant (XDR) biofilm‐forming uropathogenic Escherichia coli isolates.