Miracle-dz/UniFAR-FTUs huggingface dataset:
Blind prediction of homo‐ and hetero‐protein complexes: The CASP13‐CAPRI experiment

We present the results for CAPRI Round 46, the third joint CASP‐CAPRI protein assembly prediction challenge. The Round comprised a total of 20 targets including 14 homo‐oligomers and 6 heterocomplexes. Eight of the homo‐oligomer targets and one heterodimer comprised proteins that could be readily modeled using templates from the Protein Data Bank, often available for the full assembly. The remaining 11 targets comprised 5 homodimers, 3 heterodimers, and two higher‐order assemblies. These were more difficult to model, as their prediction mainly involved “ab‐initio” docking of subunit models derived from distantly related templates. A total of ~30 CAPRI groups, including 9 automatic servers, submitted on average ~2000 models per target. About 17 groups participated in the CAPRI scoring rounds, offered for most targets, submitting ~170 models per target. The prediction performance, measured by the fraction of models of acceptable quality or higher submitted across all predictors groups, was very good to excellent for the nine easy targets. Poorer performance was achieved by predictors for the 11 difficult targets, with medium and high quality models submitted for only 3 of these targets. A similar performance “gap” was displayed by scorer groups, highlighting yet again the unmet challenge of modeling the conformational changes of the protein components that occur upon binding or that must be accounted for in template‐based modeling. Our analysis also indicates that residues in binding interfaces were less well predicted in this set of targets than in previous Rounds, providing useful insights for directions of future improvements.
Regulation and Anaerobic Function of the Clostridioides difficile β-Lactamase

Clostridioides difficile causes severe antibiotic-associated diarrhea and colitis. C. difficile is an anaerobic, Gram-positive sporeformer that is highly resistant to β-lactams, the most commonly prescribed antibiotics. The resistance of C. difficile to β-lactam antibiotics allows the pathogen to replicate and cause disease in antibiotic-treated patients. However, the mechanisms of β-lactam resistance in C. difficile are not fully understood. ABSTRACT Clostridioides difficile causes severe antibiotic-associated diarrhea and colitis. C. difficile is an anaerobic, Gram-positive sporeformer that is highly resistant to β-lactams, the most commonly prescribed antibiotics. The resistance of C. difficile to β-lactam antibiotics allows the pathogen to replicate and cause disease in antibiotic-treated patients. However, the mechanisms of β-lactam resistance in C. difficile are not fully understood. Our data reinforce prior evidence that C. difficile produces a β-lactamase, which is a common β-lactam resistance mechanism found in other bacterial species. Here, we characterize the C. difficile bla operon that encodes a lipoprotein of unknown function and a β-lactamase that was greatly induced in response to several classes of β-lactam antibiotics. An in-frame deletion of the operon abolished β-lactamase activity in C. difficile strain 630Δerm and resulted in decreased resistance to the β-lactam ampicillin. We found that the activity of this β-lactamase, BlaCDD, is dependent upon the redox state of the enzyme. In addition, we observed that transport of BlaCDD out of the cytosol and to the cell surface is facilitated by an N-terminal signal sequence. Our data demonstrate that a cotranscribed lipoprotein, BlaX, aids in BlaCDD activity. Further, we identified a conserved BlaRI regulatory system and demonstrated via insertional disruption that BlaRI controls transcription of the blaXCDD genes in response to β-lactams. These results provide support for the function of a β-lactamase in C. difficile antibiotic resistance and reveal the unique roles of a coregulated lipoprotein and reducing environment in C. difficile β-lactamase activity.
Highly ABA-Induced 1 (HAI1)-Interacting protein HIN1 and drought acclimation-enhanced splicing efficiency at intron retention sites

Significance The ability of plants to acclimate and maintain productivity under changing environmental conditions is a topic of heightened concern because of climate change and increasing demands on agriculture. Plant stress acclimation involves multiple layers of gene regulation and posttranslational protein modifications. Pre-mRNA splicing patterns are greatly altered by stress, yet little is known about how stress signaling impinges upon the splicing machinery to mediate such changes. We found that one of the key stress signaling protein phosphatases can interact with and dephosphorylate a newly identified splicing regulator. This splicing regulator promotes growth during moderate-severity drought stress and mediates a dramatic shift toward increased splicing efficiency of stress and signaling-related genes which are prone to intron retention. The Highly ABA-Induced 1 (HAI1) protein phosphatase is a central component of drought-related signaling. A screen for HAI1-interacting proteins identified HAI1-Interactor 1 (HIN1), a nuclear protein of unknown function which could be dephosphorylated by HAI1 in vitro. HIN1 colocalization and interaction with serine-arginine rich (SR) splicing factors and appearance of nuclear speckle-localized HIN1 during low water potential (ψw) stress suggested a pre-mRNA splicing-related function. RNA sequencing of Arabidopsis Col-0 wild type identified more than 500 introns where moderate severity low ψw altered intron retention (IR) frequency. Surprisingly, nearly 90% of these had increased splicing efficiency (decreased IR) during stress. For one-third of these introns, ectopic HIN1 expression (35S:HIN1) in unstressed plants mimicked the increased splicing efficiency seen in stress-treated wild type. HIN1 bound to a GAA-repeat, Exonic Splicing Enhancer-like RNA motif enriched in flanking sequence around HIN1-regulated introns. Genes with stress and HIN1-affected splicing efficiency were enriched for abiotic stress and signaling-related functions. The 35S:HIN1 plants had enhanced growth maintenance during low ψw, while hin1 mutants had reduced growth, further indicating the role of HIN1 in drought response. HIN1 is annotated as an MYB/SANT domain protein but has limited homology to other MYB/SANT proteins and is not related to known yeast or metazoan RNA-binding proteins or splicing regulators. Together these data identify HIN1 as a plant-specific RNA-binding protein, show a specific effect of drought acclimation to promote splicing efficiency of IR-prone introns, and also discover HAI1–HIN1 interaction and dephosphorylation that connects stress signaling to splicing regulation.
Self-Controlled Practice to Achieve Neuro-Cognitive Engagement: Underlying Brain Processes to Enhance Cognitive-Motor Learning and Performance

Abstract While self-controlled practice has been shown to be an effective practice methodology, the neuro-cognitive correlates of its effectiveness are unclear. We investigated whether learners participating in self-controlled practice exhibit increased neuro-cognitive engagement compared to externally controlled practice. Two groups (self-controlled and yoked) of 16 participants practiced and performed a golf putting task over 3 days. Working memory engagement, central executive activity, and cortical activation were assessed via electroencephalography as indicators of neuro-cognitive engagement. The self-controlled group exhibited more consistent working memory engagement, and greater central executive activity, compared to the yoked group during practice. Relationships were also observed between neuro-cognitive engagement during self-controlled practice and performance improvement, indicating that self-controlled practice uniquely benefitted from increased neuro-cognitive engagement.
Object stiffness recognition using haptic feedback delivered through transcutaneous proximal nerve stimulation

Objective. Haptic feedback is crucial when we manipulate objects. Information pertaining to an object’s stiffness in particular can help facilitate fine motor control. In this study, we seek to determine whether objects of different stiffness levels can be recognized using haptic feedback provided by transcutaneous electrical stimulation of peripheral nerves. Approach. Using a stimulation electrode grid placed along the medial side of the upper arm, the median and ulnar nerve bundles were targeted to evoke haptic sensation on the palmar side of the hand. Stimulation current amplitude was modulated in real-time with the fingertip force recorded from a sensorized prosthetic hand. In order to evaluate which stimulation pattern was more critical, object stiffness was encoded either by the rate of change of the stimulus amplitude or the level of peak stimulus amplitude, as the prosthesis grasped the objects. Main results. Both encoding methods allowed the subjects to differentiate objects of different stiffness levels with >90% accuracy. No significant difference was observed between the two encoding methods, which indicated that both the rate of change of the stimulation amplitude and the peak stimulation amplitude could effectively provide stiffness information of the objects. Significance. The outcomes suggest that it is possible to elicit haptic sensations describing various object stiffness levels using transcutaneous nerve stimulation. The haptic feedback associated with object stiffness can facilitate object manipulation/interactions. It may also improve user experience during human–machine interactions, when object stiffness information is incorporated.
What we say and what we mean when we say redundancy and robustness of the chemokine system – how CCR5 challenges these concepts

Classically, robustness and redundancy are features that define the intricate and connected functioning of the chemokine system. Following these ideas, the lack of a particular chemokine or chemokine receptor could be compensated by the presence of other molecules with similar functions, ensuring robustness to the systems. Although these concepts are generally accepted, they represent an oversimplification of a highly complex system that works in a context‐dependent manner. Based on different studies, and taking as an example the chemokine receptor CCR5 (C–C chemokine receptor type 5) and the genetic variant CCR5Δ32, which on several occasions challenge the classical concepts of redundancy and robustness of the chemokine system, we will discuss and question this general and oversimplified point of view.
Front‐line treatment of ceritinib improves efficacy over crizotinib for Asian patients with anaplastic lymphoma kinase fusion NSCLC: The role of systemic progression control

Approximately 3%–5% of lung adenocarcinoma is driven by anaplastic lymphoma kinase (ALK) fusion oncogene, whose activity can be suppressed by multiple ALK inhibitors. Crizotinib and ceritinib have demonstrated superior efficacy to platinum‐based chemotherapy as front‐line treatment for patients with ALK‐positive advanced non‐small cell lung cancer (NSCLC). However, the direct comparison between them in the front‐line setting remains lacking.
Local anaesthetic delivery regimens for peripheral nerve catheters: a systematic review and network meta‐analysis

There are numerous possible techniques for delivering local anaesthetic through peripheral nerve catheters. These include continuous infusions, patient‐controlled boluses and programmed intermittent boluses. The optimal delivery regimen of local anaesthetic is yet to be conclusively established. In this review, we identified prospective trials of delivery regimens through peripheral nerve catheters. Our primary outcome was visual analogue scale scores for pain at 48 h. Secondary outcomes were: visual analogue scores at 24 h; patient satisfaction scores; rescue opioid use; local anaesthetic consumption; and nausea and vomiting. Network meta‐analysis was used to compare these outcomes. Predefined sub‐group analyses were performed. Thirty‐three studies enrolling 1934 participants were included. In comparison with continuous infusion, programmed intermittent boluses improved visual analogue pain scores at both 48 and 24 h, the weighted mean difference (95%CI) being −0.63 (−1.12 to −0.14), p = 0.012 and −0.48 (−0.92 to −0.03), p = 0.034, respectively. Programmed intermittent boluses also improved satisfaction scores, the weighted mean difference (95%CI) being 0.70 (0.10–1.31), p = 0.023, and reduced rescue opioid use, the weighted mean difference (95%CI) in oral morphine equivalent at 24 h being −23.84 mg (−43.90 mg to −3.77 mg), p = 0.020. Sub‐group analysis revealed that these findings were mostly confined to lower limb and truncal catheter studies; there were few studies of programmed intermittent boluses for upper limb catheters. Programmed intermittent boluses may provide optimal delivery of a local anaesthetic through peripheral nerve catheters. Further research is warranted, particularly to delineate the differences between upper and lower limb catheter locations, which will help clarify the clinical relevance of these findings.
Myeloid cells activate iNKT cells to produce IL-4 in the thymic medulla

Significance T cells, essential components of the immune system, are developed in the thymus. Various effector cytokines are produced in the thymus in the steady state, which affect T cell development and tolerance. Interleukin-4 (IL-4) produced by a unique subset of lipid-specific invariant natural killer T (iNKT) cells (NKT2) in the steady state influences a series of immune events to alter thymic development. However, the underling mechanisms for this steady-state IL-4 production are not completely understood. In this study, we show that steady-state IL-4–producing NKT2 cells predominantly localize to the thymic medulla. Furthermore, this steady-state IL-4 production requires continuous T cell receptor (TCR) signaling in NKT2 cells majorly stimulated by thymic macrophages. Interleukin-4 (IL-4) is produced by a unique subset of invariant natural killer T (iNKT) cells (NKT2) in the thymus in the steady state, where it conditions CD8+ T cells to become “memory-like” among other effects. However, the signals that cause NKT2 cells to constitutively produce IL-4 remain poorly defined. Using histocytometry, we observed IL-4–producing NKT2 cells localized to the thymic medulla, suggesting that medullary signals might instruct NKT2 cells to produce IL-4. Moreover, NKT2 cells receive and require T cell receptor (TCR) stimulation for continuous IL-4 production in the steady state, since NKT2 cells lost IL-4 production when intrathymically transferred into CD1d-deficient recipients. In bone marrow chimeric recipients, only hematopoietic, not stromal, antigen-presenting cells (APCs), provided such stimulation. Furthermore, using different Cre-recombinase transgenic mouse strains to specifically target CD1d deficiency to various APCs, together with the use of diphtheria toxin receptor (DTR) transgenic mouse strains to deplete various APCs, we found that macrophages were the predominant cell to stimulate NKT2 IL-4 production. Thus, NKT2 cells appear to encounter and require different activating ligands for selection in the cortex and activation in the medulla.
Primary Cutaneous Gamma-Delta T-cell Lymphoma: Not an Aggressive Disease in All Cases

peripheral neuropathy. This latter therapy was efficient and remained well tolerated after 9 cycles (7 CHOP and 2 COP) with no worsening of peripheral neurotoxicity. No skin progression nor extracutaneous involvement was observed 24 months after the last course of chemotherapy and more than 5 years after the first occurrence of cutaneous nodules.
Stressors, psychological distress, and mental health problems amongst Brazilian medical students

Abstract In line with studies from around the world, several studies have shown equal or higher rates of anxiety, depression, alcohol and other drug use, and burnout in medical students in Brazil. The aim of the present study was to identify difficulties Brazilian medical students face regarding stressors, psychological distress, and psychiatric morbidity using standardized reliable and valid instruments. In addition, this study also investigated differences associated with sex. Students (n = 129) were asked to complete a one-off survey from January to June 2019, including demographics, previous mental health issues, CAGE, GHQ-12, and OLBI. A higher prevalence of previous mental disorders was found in comparison to during the medical course. This may suggest that perhaps students are under more stress or that they form a more vulnerable sub-population in medical school in comparison with the general population. However, the types of mental disorders before and during the undergraduate course appear to vary. During the course, they show higher levels of anxiety rather than that of depression. Before commencing the course, they showed higher levels of depression rather than anxiety. Cannabis and ecstasy experimentation levels were higher than those of students from other courses in previous studies. The opposite was true for stimulants. Just over a quarter reported alcohol abuse above the CAGE cut-off point. The levels of psychological distress and burnout were extremely high, and women had even higher levels. Male respondents were more likely to have a history of mental ill-health, but female subjects scored higher on burnout. Overall over 80% students reported burnout. These findings are discussed in the context of Brazilian culture.
The long-term outcomes of CIS patients in the Barcelona inception cohort: Looking back to recognize aggressive MS

Objective: To explore the long-term outcomes of patients with clinically isolated syndromes from the Barcelona cohort. Methods: We selected patients with a follow-up longer than 10 years to (1) estimate the risks of multiple sclerosis (MS) and disability accumulation according to the baseline number of T2 lesions and to compare treated versus untreated patients and early versus delayed treatment, and (2) to study baseline features of patients with aggressive MS (Expanded Disability Status Scale (EDSS) ⩾6.0 at 10 years). Results: In all, 401 patients were included (mean follow-up of 14.4 (standard deviation of 2.9) years). A higher number of T2 lesions was associated with an earlier MS diagnosis and an earlier risk of irreversible disability. Early treatment was associated with a decreased risk of EDSS of 3.0: adjusted hazard ratio = 0.4, 95% confidence interval = (0.2, 0.7). Patients with aggressive MS differed in their baseline brain magnetic resonance images: The median (interquartile range) number of T2 lesions and contrast-enhancing lesions (CEL) was 71 (28–95) versus 7 (1–19) and 3 (1–24) versus 0 (0–1), respectively. The cut-offs that better classified patients with aggressive MS were 20 for T2 lesions and 2 for CEL. Conclusion: Although MS natural history is changing, a high lesion load at onset is helpful to identify patients at risk of presenting an aggressive MS.
Follow-Up of Patients With Complete Remission of Locally Advanced Basal Cell Carcinoma After Vismodegib Discontinuation: A Multicenter French Study of 116 Patients.

PURPOSE Vismodegib is a hedgehog pathway inhibitor indicated for the treatment of locally advanced basal cell carcinoma (laBCC), with an objective response rate of 65%, including a 32% complete response (CR). However, adverse effects often lead to drug discontinuation. The objective of our study was to evaluate long-term responses, predictive factors, and management of relapse after vismodegib discontinuation. METHODS An observational retrospective study was conducted in nine French oncodermatology units. We included patients with laBCC with CR on vismodegib who discontinued treatment between March 2012 and January 2016; we reviewed charts up to June 2016. The primary objective was to evaluate median relapse-free survival (RFS). Secondary objectives were risk factors associated with RFS, relapse, and death and treatment modalities after relapse and their efficacy. RESULTS One hundred sixteen patients with laBCC were included. The median RFS was 18.4 months (95% CI, 13.5 to 24.8 months). The RFS rate at 36 months was 35.4% (95% CI, 22.5% to 47.9%) for the total population and 40.0% (95% CI, 25.7% to 53.7%) for patients without Gorlin syndrome. LaBCC to the limbs and trunk was the only variable independently associated with a higher risk of relapse (hazard ratio, 2.77; 95% CI, 1.23 to 6.22; P = .019). Twenty-seven patients (50%) who experienced relapse during follow-up were retreated with vismodegib, with an objective response in 23 (objective response rate, 85%; CR rate, 37%; partial response rate, 48%) and eligibility for surgery in 24 (42%). CONCLUSION Long-term response after vismodegib discontinuation is frequent. Most patients who experience a relapse still respond to vismodegib rechallenge.
Comparison of effects of different long-term iron-chelation regimens on myocardial and hepatic iron concentrations assessed with T2* magnetic resonance imaging in patients with β-thalassemia major

The aim of this study was to compare the effect of different long-term chelation regimens on heart and liver iron stores with the use of T2* magnetic resonance imaging (MRI) in patients with transfusion-dependent β-thalassemia major. Sixty-four patients (28 men, 36 women; mean age, 26.49 ± 5.8 years) were enrolled in the study. The 3 groups were based on the chelation therapy received. The first group (19 patients) received deferiprone (DFP) (75 mg/kg per day orally), the second group (23 patients) received deferoxamine (DFO) (30–50 mg/kg per day subcutaneously at least 5 times/week), and the third group (22 patients) received a combination of DFO (30–50 mg/kg per day, 2–3 days/week) and DFP (75 mg/kg per day, 7 days/week). MRI scans were acquired with an imager equipped with a 1.5 T magnet, and the data included myocardial and hepatic iron measurements obtained by means of T2*, and ventricular volumes and ejection fractions obtained with standard cardiovascular MRI techniques. The results revealed that the DFP and the combined groups had significantly less myocardial iron than the DFO group (mean myocardial T2*, 35.77 ± 18.3 milliseconds and 38.05 ± 15.3 milliseconds versus 23.77 ± 13 milliseconds [P =.02, andP =.001], respectively). On the contrary, the DFP group had a significantly higher hepatic iron content than the DFO and combined groups (mean hepatic T2*, 3.29 ± 2.5 milliseconds versus 8.16 ± 8.4 milliseconds and 11.3 ±10.9 milliseconds [P =.014, andP =.003], respectively). No correlation was observed between myocardial T2* and hepatic T2* values (r =-0.043;P =.37). Myocardial T2* values were inversely correlated with age (r =-0.249;P =.024) and positively correlated with both left and right ventricular ejection fractions (r = 0.33 [P =.004], andr = 0.279 [P =.014], respectively). Finally, liver T2* was strongly and inversely correlated with serum ferritin concentration (r =-0.465;P =.001). In conclusion, combined chelation therapy seems to sum the beneficial effects of DFO and DFP with respect to hepatic and myocardial iron. Because myocardial iron is not related to measurements of serum ferritin or hepatic T2*, important decisions on clinical management relating to cardiac risk should not rely on these conventional parameters. Thus, the use of MRI for assessing myocardial iron should be adopted in the routine clinical management of patients with β-thalassemia major.