Miracle-dz/UniFAR-FTUs huggingface dataset:
Spectrum of APC and MUTYH germ‐line mutations in Russian patients with colorectal malignancies

Distribution of cancer‐predisposing mutations demonstrates significant interethnic variations. This study aimed to evaluate patterns of APC and MUTYH germ‐line mutations in Russian patients with colorectal malignancies. APC gene defects were identified in 26/38 (68%) subjects with colon polyposis; 8/26 (31%) APC mutations were associated with 2 known mutational hotspots (p.E1309Dfs*4 [n = 5] and p.Q1062fs* [n = 3]), while 6/26 (23%) mutations were novel (p.K73Nfs*6, p.S254Hfs*12, p.S1072Kfs*9, p.E1547Kfs*11, p.L1564X and p.C1263Wfs*22). Biallelic mutations in MUTYH gene were detected in 3/12 (25%) remaining subjects with polyposis and in 6/90 (6.7%) patients with colorectal cancer (CRC) carrying KRAS p.G12C substitution, but not in 231 early‐onset CRC cases negative for KRAS p.G12C allele. In addition to known European founder alleles p.Y179C and p.G396D, this study revealed a recurrent character of MUTYH p.R245H germ‐line mutation. Besides that, 3 novel pathogenic MUTYH alleles (p.L111P, p.R245S and p.Q293X) were found. Targeted next‐generation sequencing of 7 APC/MUTYH mutation‐negative DNA samples identified novel potentially pathogenic POLD1 variant (p.L460R) in 1 patient and known low‐penetrant cancer‐associated allele CHEK2 p.I157T in 3 patients. The analysis of 1120 healthy subjects revealed 15 heterozygous carriers of recurrent MUTYH mutations, thus the expected incidence of MUTYH‐associated polyposis in Russia is likely to be 1:23 000.
Cancer risk and clinicopathological characteristics of thyroid nodules harboring thyroid‐stimulating hormone receptor gene mutations

Thyroid‐stimulating hormone receptor (TSHR) gene mutations play a critical role in thyroid cell proliferation and function. They are found in 20%‐82% of hyperfunctioning nodules, hyperfunctioning follicular thyroid cancers (FTC), and papillary thyroid cancers (PTC). The diagnostic importance of TSHR mutation testing in fine needle aspiration (FNA) specimens remains unstudied.
The role of basophils as innate immune regulatory cells in allergy and immunotherapy

ABSTRACT Basophils are circulating cells that are associated quite exclusively with allergy response and hypersensitivity reactions but their role in the immune network might be much more intriguing and complex than previously expected. The feasibility of testing their biology in vitro for allergy research and diagnosis, due fundamentally to their quite easy availability in the peripheral blood, made them the major source for assessing allergy in the laboratory assay, when yet many further cells such as mast cells and eosinophils are much more involved as effector cells in allergy than circulating basophils. Interestingly, basophil numbers change rarely in peripheral blood during an atopic response, while we might yet observe an increase in eosinophils and modification in the biology of mast cells in the tissue during an hypersensitivity response. Furthermore, the fact that basophils are very scanty in numbers suggests that they should mainly serve as regulatory cells in immunity, rather than effector leukocytes, as still believed by the majority of physicians. In this review we will try to describe and elucidate the possible role of these cells, known as “innate IL4-producing cells” in the immune regulation of allergy and their function in allergen immunotherapy.
Absence of TERT promoter mutations in colorectal precursor lesions and cancer

Abstract Hotspot mutations (c.-124bp G > A and c.-146bp G > A) in the promoter region of the TERT gene have been recently described in several types of solid tumors, including glioma, bladder, thyroid, liver and skin neoplasms. However, knowledge with respect to colorectal precursor lesions and cancer is scarce. In the present study we aimed to determine the frequency of hotspot TERT promoter mutations in 145 Brazilian patients, including 103 subjects with precursor lesions and 42 with colorectal carcinomas, and we associated the presence of such mutations with the patients clinical-pathological features. The mutation analysis was conclusive in 123 cases, and none of the precursor and colorectal carcinoma cases showed TERT promoter mutations. We conclude that TERT mutations are not a driving factor in colorectal carcinogenesis.
Virus-evolutionary genetic algorithm based selective ensemble classifier for pedestrian detection

In pedestrian detection system, it is critical to determine whether a candidate region contains a pedestrian both quickly and reliably. Therefore, an efficient classifier must be designed. In general, a well-organized assembly classifier outperforms than single classifiers. For pedestrian detection, due to the complexity of scene and vast number of candidate regions, an efficient ensemble method is needed. In this paper, we propose a virus evolutionary genetic algorithm (VEGA) based selective ensemble classifier for pedestrian detection system, in which only part of the trained learners are selected and participate the majority voting for the detection. Component learners are trained with diversity and then VEGA is employed to optimize the selection of component learners. Moreover, a time-spending factor is added to the fitness function so as to balance the detection rate and detection speed. Experiments show that, comparing with typical non-selective Bagging and GA-based selective ensemble method, the VEGA-based selective ensemble gets better performance not only in detecting accuracy but also in detection speed.
Cooperation between Strain-Specific and Broadly Neutralizing Responses Limited Viral Escape and Prolonged the Exposure of the Broadly Neutralizing Epitope

ABSTRACT V3-glycan-targeting broadly neutralizing antibodies (bNAbs) are a focus of HIV-1 vaccine development. Understanding the viral dynamics that stimulate the development of these antibodies can provide insights for immunogen design. We used a deep-sequencing approach, together with neutralization phenotyping, to investigate the rate and complexity of escape from V3-glycan-directed bNAbs compared to overlapping early strain-specific neutralizing antibody (ssNAb) responses to the V3/C3 region in donor CAP177. Escape from the ssNAb response occurred rapidly via an N334-to-N332 glycan switch, which took just 7.5 weeks to reach >50% frequency. In contrast, escape from the bNAbs was mediated via multiple pathways and took longer, with escape first occurring through an increase in V1 loop length, which took 46 weeks to reach 50% frequency, followed by an N332-to-N334 reversion, which took 66 weeks. Importantly, bNAb escape was incomplete, with contemporaneous neutralization observed up to 3 years postinfection. Both the ssNAb response and the bNAb response were modulated by the presence/absence of the N332 glycan, indicating an overlap between the two epitopes. Thus, selective pressure by ssNAbs to maintain the N332 glycan may have constrained the bNAb escape pathway. This slower and incomplete viral escape resulted in prolonged exposure of the bNAb epitope, which may in turn have aided the maturation of the bNAb lineage. IMPORTANCE The development of an HIV-1 vaccine is of paramount importance, and broadly neutralizing antibodies are likely to be a key component of a protective vaccine. The V3-glycan-targeting bNAb responses are among the most promising vaccine targets, as they are commonly elicited during infection. Understanding the interplay between viral evolution and the development of these antibodies provides insights that may guide immunogen design. Our work contrasted the dynamics of the early strain-specific antibodies and the later broadly neutralizing responses to a common Env target (V3C3), showing slower and more complex escape from bNAbs. Constrained bNAb escape, together with evidence of contemporaneous autologous virus neutralization, supports the proposal that prolonged exposure of the bNAb epitope enabled the maturation of the bNAb lineage.
Short and medium‐term efficacy of sodium glucose co‐transporter‐2 (SGLT‐2) inhibitors: A meta‐analysis of randomized clinical trials

Sodium glucose co‐transport‐2 (SGLT‐2) inhibitors reduce tubular glucose reabsorption, producing a reduction of blood glucose without stimulating insulin release. The aim of this meta‐analysis was the systematic collection of available data from randomized trials, in order to establish the durability of the efficacy of SGLT‐2 inhibitors on glycaemic control and body mass index.
Dual inhibition of MDMX and MDM2 as a therapeutic strategy in leukemia

Dual inhibition of MDMX and MDM2 by an α-helical p53-stapled peptide (ALRN-6924) results in robust antitumor activity in acute myeloid leukemia. A new staple of leukemia treatment? As suggested by their name, tumor suppressor genes prevent tumorigenesis, and their expression or activity is often lost in cancer cells. One of the best known tumor suppressors is p53, which is inactivated in a variety of cancer types, often through up-regulation of its endogenous suppressors. Despite numerous attempts to reactivate p53 by a variety of approaches, none have successfully advanced beyond clinical trials thus far. Now, Carvajal et al. applied yet another tactic to restore p53 activity by using a stapled peptide to inactivate both of its endogenous inhibitors, for situations where the tumor suppressor is inactive but not completely lost. The authors demonstrated the effectiveness of this approach in human acute myeloid leukemia using in vitro and in vivo models, along with preliminary testing in a patient with leukemia. The tumor suppressor p53 is often inactivated via its interaction with endogenous inhibitors mouse double minute 4 homolog (MDM4 or MDMX) or mouse double minute 2 homolog (MDM2), which are frequently overexpressed in patients with acute myeloid leukemia (AML) and other cancers. Pharmacological disruption of both of these interactions has long been sought after as an attractive strategy to fully restore p53-dependent tumor suppressor activity in cancers with wild-type p53. Selective targeting of this pathway has thus far been limited to MDM2-only small-molecule inhibitors, which lack affinity for MDMX. We demonstrate that dual MDMX/MDM2 inhibition with a stapled α-helical peptide (ALRN-6924), which has recently entered phase I clinical testing, produces marked antileukemic effects. ALRN-6924 robustly activates p53-dependent transcription at the single-cell and single-molecule levels and exhibits biochemical and molecular biological on-target activity in leukemia cells in vitro and in vivo. Dual MDMX/MDM2 inhibition by ALRN-6924 inhibits cellular proliferation by inducing cell cycle arrest and apoptosis in cell lines and primary AML patient cells, including leukemic stem cell–enriched populations, and disrupts functional clonogenic and serial replating capacity. Furthermore, ALRN-6924 markedly improves survival in AML xenograft models. Our study provides mechanistic insight to support further testing of ALRN-6924 as a therapeutic approach in AML and other cancers with wild-type p53.
N‐terminomics reveals control of Arabidopsis seed storage proteins and proteases by the Arg/N‐end rule pathway

Summary The N‐end rule pathway of targeted protein degradation is an important regulator of diverse processes in plants but detailed knowledge regarding its influence on the proteome is lacking. To investigate the impact of the Arg/N‐end rule pathway on the proteome of etiolated seedlings, we used terminal amine isotopic labelling of substrates with tandem mass tags (TMT‐TAILS) for relative quantification of N‐terminal peptides in prt6, an Arabidopsis thaliana N‐end rule mutant lacking the E3 ligase PROTEOLYSIS6 (PRT6). TMT‐TAILS identified over 4000 unique N‐terminal peptides representing c. 2000 protein groups. Forty‐five protein groups exhibited significantly increased N‐terminal peptide abundance in prt6 seedlings, including cruciferins, major seed storage proteins, which were regulated by Group VII Ethylene Response Factor (ERFVII) transcription factors, known substrates of PRT6. Mobilisation of endosperm α‐cruciferin was delayed in prt6 seedlings. N‐termini of several proteases were downregulated in prt6, including RD21A. RD21A transcript, protein and activity levels were downregulated in a largely ERFVII‐dependent manner. By contrast, cathepsin B3 protein and activity were upregulated by ERFVIIs independent of transcript. We propose that the PRT6 branch of the pathway regulates protease activities in a complex manner and optimises storage reserve mobilisation in the transition from seed to seedling via control of ERFVII action.
L1 coupling to ankyrin and the spectrin‐actin cytoskeleton modulates ethanol inhibition of L1 adhesion and ethanol teratogenesis

Ethanol causes fetal alcohol spectrum disorders (FASDs) partly by inhibiting cell adhesion mediated by the L1 neural cell adhesion molecule. Ethanol interacts with an alcohol binding pocket in the L1 extracellular domain (ECD), and dephosphorylation of S1248 in the L1 cytoplasmic domain (CD) renders L1 adhesion insensitive to inhibition by ethanol (L1 insensitive). The mechanism underlying this inside‐out signaling is unknown. Here we show that phosphorylation of the human L1‐CD at S1152, Y1176, S1181, and S1248 renders L1 sensitive to ethanol by promoting L1 coupling with ankyrin‐G and the spectrin‐actin cytoskeleton. Knockdown of ankyrin‐G or L1 mutations that uncouple L1 from ankyrin reduce L1 sensitivity to ethanol, but not methanol, consistent with a small conformational change in the extracellular alcohol binding pocket. Phosphorylation of Y1176 and ankyrin‐G coupling with L1 are higher in NIH/3T3 clonal cell lines in which ethanol inhibits L1 adhesion than in ethanol‐resistant NIH/3T3 clonal cell lines. Similarly, phosphorylation of Y1176 is higher in C57BL/6J mice that are sensitive to ethanol teratogenesis than in ethanol resistant C57BL/6N mice. Finally, polymorphisms in genes that encode ankyrin‐G and p90rsk, a kinase that phosphorylates S1152, are linked to facial dysmorphology in children with heavy prenatal ethanol exposure. These findings indicate that genes that regulate L1 coupling to ankyrin may influence susceptibility to FASD. —Dou, X. , Menkari, C. , Mitsuyama, R. , Foroud, T. , Wetherill, L. , Hammond, P., Suttie, M. , Chen, X. , Chen, S. ‐Y. , Charness, M. E. , Collaborative Initiative on Fetal Alcohol Spectrum Disorders. L1 coupling to ankyrin and the spectrin‐actin cytoskeleton modulates ethanol inhibition of L1 adhesion and ethanol teratogenesis. FASEB J. 32,1364‐1374 (2018). www.fasebj. org
The association between adult-type hypolactasia and symptoms of functional dyspepsia

Abstract Functional dyspepsia and lactose intolerance (adult-type hypolactasia, ATH) are common conditions that may coexist or even be confounded. Their clinical presentation can be similar, however, lactose intolerance does not form part of the diagnostic investigation of functional dyspepsia. Studies on the association between functional dyspepsia and ATH are scarce. This study aimed to evaluate whether ATH is associated with symptoms of functional dyspepsia. Patients fulfilling the Rome III diagnostic criteria for functional dyspepsia underwent genetic testing for ATH. Dyspeptic symptoms were evaluated and scored according to a validated questionnaire. The diagnostic criteria for ATH was a CC genotype for the -13910C/T polymorphism, located upstream of the lactase gene. The mean scores for dyspeptic symptoms were compared between patients with ATH and those with lactase persistence. A total of 197 functional dyspeptic patients were included in the study. Mean age was 47.7 years and 82.7% patients were women. Eighty-eight patients (44.7%) had a diagnosis of ATH. Abdominal bloating scores were higher in ATH patients compared to the lactase persistent patients (P=0.014). The remaining dyspeptic symptom scores were not significantly different between the two groups. The study results demonstrate an association between ATH and bloating in patients with functional dyspepsia.
Transcriptome Analysis of Short Fiber Mutant Ligon lintless-1 (Li1) Reveals Critical Genes and Key Pathways in Cotton Fiber Elongation and Leaf Development

For efficient spinning and superior fabric production, long fiber length is a desired trait for cotton production. To unveil the molecular basis of the cotton fiber length regulation, a short fiber mutant, Ligon lintless-1 (Li1), is selected to compare with its corresponding wild type (WT). Li1 is a monogenic dominant cotton mutant causing extremely short fibers (<6mm) on mature seeds with visible pleiotropic effects on vegetative growth and development. In this research, we compared the transcriptome of fiber bearing ovules at 1 DPA, 3 DPA, 8 DPA and leaf between Li1 mutant and WT. A total of 7,852 differentially expressed genes (DEGs) were detected in ovules and leaves, which mainly participated in sugar, secondary metabolite and lipid metabolism pathways based on KEGG analysis. The common DEGs at 1 DPA and 3 DPA were involved in the responses to endogenous stimulus, signal transduction and long-chain fatty acid biosynthesis. For 3 DPA, 8 DPA and leaf, the common DEGs were involved in the responses to auxin and receptor kinases related pathway. Further analysis showed that 37 genes involved in very-long-chain fatty acid biosynthesis were suppressed in Li1 mutant during fiber fast elongation development. Most of the DEGs involved in cell wall metabolism, such cellulose synthase, expansin family, and glycosyl hydrolase were differentially expressed at 3 DPA and 8 DPA. Our results provide new insights into the mechanisms of fiber elongation, and offer novel genes as potential objects for fiber length improvement.
Neuroscience and Biobehavioral Reviews Hearing voices in the resting brain: A review of intrinsic functional connectivity research on auditory verbal hallucinations

Resting state networks (RSNs) are thought to reﬂect the intrinsic functional connectivity of brain regions. Alterations to RSNs have been proposed to underpin various kinds of psychopathology, including the occurrence of auditory verbal hallucinations (AVH). This review outlines the main hypotheses linking AVH and the resting state, and assesses the evidence for alterations to intrinsic connectivity provided by studies of resting fMRI in AVH. The inﬂuence of hallucinations during data acquisition, medication confounds, and movement are also considered. Despite a large variety of analytic methods and designs being deployed, it is possible to conclude that resting connectivity in the left temporal lobe in general and left superior temporal gyrus in particular are disrupted in AVH. There is also preliminary evidence of atypical connectivity in the default mode network and its interaction with other RSNs. Recommendations for future research include the adoption of a common analysis protocol to allow for more overlapping datasets and replication of intrinsic functional connectivity alterations.
Application of Brown Planthopper Salivary Gland Extract to Rice Plants Induces Systemic Host mRNA Patterns Associated with Nutrient Remobilization

Insect saliva plays an important role in modulation of plant-insect interactions. Although this area of research has generated much attention in recent years, mechanisms of how saliva affects plant responses remain poorly understood. To address this void, the present study investigated the impact of the brown planthopper (Nilaparvata lugens, Stål; hereafter BPH) salivary gland extract (SGE) on rice (Oryza sativa) systemic responses at the mRNA level. Differentially expressed rice mRNAs were generated through suppression subtractive hybridization (SSH) and classified into six functional groups. Those with the most representatives were from the primary metabolism (28%), signaling-defense (22%) and transcription-translation-regulation group (16%). To validate SSH library results, six genes were further analyzed by One-Step Real-Time Reverse Transcriptase-PCR. Five of these genes exhibited up-regulation levels of more than 150% of those in the control group in at least one post-application time point. Results of this study allow assignment of at least two putative roles of BPH saliva: First, application of SGE induces immediate systemic responses at the mRNA level, suggesting that altering of the rice transcriptome at sites distant to hoppers feeding locations may play an important role in BPH-rice interactions. Second, 58% of SGE-responsive up-regulated genes have a secondary function associated with senescence, a process characterized by remobilization of nutrients. This suggests that BPH salivary secretions may reprogram the rice transcriptome for nutritional enhancement. When these findings are translated onto ‘whole plant’ scale, they indicate that BPH saliva may play the ‘wise investment’ role of ‘minimum input today, maximum output tomorrow’.
Multiobjective Flexible Job Shop Scheduling Using Memetic Algorithms

In this paper, we propose new memetic algorithms (MAs) for the multiobjective flexible job shop scheduling problem (MO-FJSP) with the objectives to minimize the makespan, total workload, and critical workload. The problem is addressed in a Pareto manner, which aims to search for a set of Pareto optimal solutions. First, by using well-designed chromosome encoding/decoding scheme and genetic operators, the nondominated sorting genetic algorithm II (NSGA-II) is adapted for the MO-FJSP. Then, our MAs are developed by incorporating a novel local search algorithm into the adapted NSGA-II, where some good individuals are chosen from the offspring population for local search using a selection mechanism. Furthermore, in the proposed local search, a hierarchical strategy is adopted to handle the three objectives, which mainly considers the minimization of makespan, while the concern of the other two objectives is reflected in the order of trying all the possible actions that could generate the acceptable neighbor. In the experimental studies, the influence of two alternative acceptance rules on the performance of the proposed MAs is first examined. Afterwards, the effectiveness of key components in our MAs is verified, including genetic search, local search, and the hierarchical strategy in local search. Finally, extensive comparisons are carried out with the state-of-the-art methods specially presented for the MO-FJSP on well-known benchmark instances. The results show that the proposed MAs perform much better than all the other algorithms.
Diet Overlap and Foraging Activity between Feral Pigs and Native Peccaries in the Pantanal

Inter-specific competition is considered one of the main selective pressures affecting species distribution and coexistence. Different species vary in the way they forage in order to minimize encounters with their competitors and with their predators. However, it is still poorly known whether and how native species change their foraging behavior in the presence of exotic species, particularly in South America. Here we compare diet overlap of fruits and foraging activity period of two sympatric native ungulates (the white-lipped peccary, Tayassu pecari, and the collared peccary, Pecari tajacu) with the invasive feral pig (Sus scrofa) in the Brazilian Pantanal. We found high diet overlap between white-lipped peccaries and feral pigs, but low overlap between collared peccaries and feral pigs. Furthermore, we found that feral pigs may influence the foraging period of both native peccaries, but in different ways. In the absence of feral pigs, collared peccary activity peaks in the early evening, possibly allowing them to avoid white-lipped peccary activity peaks, which occur in the morning. In the presence of feral pigs, collared peccaries forage mostly in early morning, while white-lipped peccaries forage throughout the day. Our results indicate that collared peccaries may avoid foraging at the same time as white-lipped peccaries. However, they forage during the same periods as feral pigs, with whom they have lower diet overlap. Our study highlights how an exotic species may alter interactions between native species by interfering in their foraging periods.