Miracle-dz/UniFAR-FTUs huggingface dataset:
Structural analysis of the PTEN:P-Rex2 signaling complex reveals how cancer-associated mutations coordinate to hyperactivate Rac1

Mutations that dysregulate a protein complex may promote cancer metastasis by enhancing Rac1 activation. Ramping up Rac1 for metastasis The phosphatase and tumor suppressor PTEN hydrolyzes the lipid second messenger PI(3,4,5)P3, thereby suppressing cellular proliferation mediated by the PI3K-Akt pathway. The protein P-Rex2 activates Rac members of the Rho GTPase family to promote cell migration, invasion, and metastasis. Because PTEN and P-Rex2 bind to each other to form a coinhibitory complex, D’Andrea et al. used cross-linking mass spectrometry and functional studies to characterize the regions within each protein that were necessary for complex formation. The authors found that cancer-associated mutations in both proteins combined to enhance the activation of Rac1. Together, these findings enhance our understanding of the dysregulation of the PTEN:P-Rex2 complex that occurs in metastasis. The dual-specificity phosphatase PTEN functions as a tumor suppressor by hydrolyzing PI(3,4,5)P3 to PI(4,5)P2 to inhibit PI3K-AKT signaling and cellular proliferation. P-Rex2 is a guanine nucleotide exchange factor for Rho GTPases and can be activated by Gβγ subunits downstream of G protein–coupled receptor signaling and by PI(3,4,5)P3 downstream of receptor tyrosine kinases. The PTEN:P-Rex2 complex is a commonly mutated signaling node in metastatic cancer. Assembly of the PTEN:P-Rex2 complex inhibits the activity of both proteins, and its dysregulation can drive PI3K-AKT signaling and cellular proliferation. Here, using cross-linking mass spectrometry and functional studies, we gained mechanistic insights into PTEN:P-Rex2 complex assembly and coinhibition. We found that PTEN was anchored to P-Rex2 by interactions between the PDZ-interacting motif in the PTEN C-terminal tail and the second PDZ domain of P-Rex2. This interaction bridged PTEN across the P-Rex2 surface, preventing PI(3,4,5)P3 hydrolysis. Conversely, PTEN both allosterically promoted an autoinhibited conformation of P-Rex2 and blocked its binding to Gβγ. In addition, we observed that the PTEN-deactivating mutations and P-Rex2 truncations combined to drive Rac1 activation to a greater extent than did either single variant alone. These insights enabled us to propose a class of gain-of-function, cancer-associated mutations within the PTEN:P-Rex2 interface that uncouple PTEN from the inhibition of Rac1 signaling.
Population biology and phenology of the colour polymorphic damselfly Ischnura elegans at its southern range limit in Cyprus

1. Geographically widespread species provide excellent opportunities to investigate how phenotypes change across large‐scale environmental gradients. Temperature is a fundamental environmental variable and an important determinant of insect fitness. However, field research is often geographically restricted, and typically concentrated in northern latitudes. Basic population biology and phenotypic clines in relation to temperature therefore remain poorly known across the entire geographic range, even in otherwise well‐studied taxa.
Effects of hillside aspect, landscape features, and kleptoparasitism on the reproductive success of the solitary bee Osmia caerulescens

Osmia caerulescens is a generalist solitary bee well‐adapted to altered anthropogenic environments, and the kleptoparasitic wasp Sapyga quinquepunctata has been cited among its natural enemies. We analysed offspring characteristics of O. caerulescens and S. quinquepunctata, at population and individual levels, and compared these characteristics between sunny and shady aspects and between two zones within the valley that differed in landscape complexity (simple and complex zones). The offspring production of O. caerulescens was higher in sunny aspect at population and individual levels while S. quinquepunctata was positively associated with the zone with a lower proportion of agricultural land (complex zone). We did not detect a relationship between number of brood cells parasitised and number of brood cells established by host. Despite the parasitism being higher in the area with favourable characteristics for both species, the reproductive success of O. caerulescens did not show signs of reduction. At the individual level, nests with fewer brood cells were more likely to be parasitised. Studying the relationship of environmental factors and landscape features at population and individual levels provides a better understanding of how these characteristics could be driving the offspring production of the solitary bee and their ecological interactions.
Environment-driven Communication in Battery-free Smart Buildings

Recent years have witnessed the design and development of several smart devices that are wireless and battery-less. These devices exploit RFID backscattering-based computation and transmissions. Although singular devices can operate efficiently, their coexistence needs to be controlled, as they have widely varying communication requirements, depending on their interaction with the environment. The design of efficient communication protocols able to dynamically adapt to current device operation is quite a new problem that the existing work cannot solve well. In this article, we propose a new communication protocol, called ReLEDF, that dynamically discovers devices in smart buildings and their active and nonactive status and when active their current communication behavior (through a learning-based mechanism) and schedules transmission slots (through an Earliest Deadline First-- (EDF) based mechanism) adapt to different data transmission requirements. Combining learning and scheduling introduces a tag starvation problem, so we also propose a new mode-change scheduling approach. Extensive simulations clearly show the benefits of using ReLEDF, which successfully delivers over 95% of new data samples in a typical smart home scenario with up to 150 heterogeneous smart devices, outperforming related solutions. Real experiments are also conducted to demonstrate the applicability of ReLEDF and to validate the simulations.
Real-Time Multifrequency MR Elastography of the Human Brain Reveals Rapid Changes in Viscoelasticity in Response to the Valsalva Maneuver

Modulation of cerebral blood flow and vascular compliance plays an important role in the regulation of intracranial pressure (ICP) and also influences the viscoelastic properties of brain tissue. Therefore, magnetic resonance elastography (MRE), the gold standard for measuring in vivo viscoelasticity of brain tissue, is potentially sensitive to cerebral autoregulation. In this study, we developed a multifrequency MMRE technique that provides serial maps of viscoelasticity at a frame rate of nearly 6 Hz without gating, i.e., in quasi-real time (rt-MMRE). This novel method was used to monitor rapid changes in the viscoelastic properties of the brains of 17 volunteers performing the Valsalva maneuver (VM). rt-MMRE continuously sampled externally induced vibrations comprising three frequencies of 30.03, 30.91, and 31.8 Hz were over 90 s using a steady-state, spiral-readout gradient-echo sequence. Data were processed by multifrequency dual elasto-visco (MDEV) inversion to generate maps of magnitude shear modulus | G∗| (stiffness) and loss angle φ at a frame rate of 5.4 Hz. As controls, the volunteers were examined to study the effects of breath-hold following deep inspiration and breath-hold following expiration. We observed that | G∗| increased while φ decreased due to VM and, less markedly, due to breath-hold in inspiration. Group mean VM values showed an early overshoot of | G∗| 2.4 ± 1.2 s after the onset of the maneuver with peak values of 6.7 ± 4.1% above baseline, followed by a continuous increase in stiffness during VM. A second overshoot of | G∗| occurred 5.5 ± 2.0 s after the end of VM with peak values of 7.4 ± 2.8% above baseline, followed by 25-s sustained recovery until the end of image acquisition. φ was constantly reduced by approximately 2% during the entire VM without noticeable peak values. This is the first report of viscoelasticity changes in brain tissue induced by physiological maneuvers known to alter ICP and detected by clinically applicable rt-MMRE. Our results show that apnea and VM slightly alter brain properties toward a more rigid-solid behavior. Overshooting stiffening reactions seconds after onset and end of VM reveal rapid autoregulatory processes of brain tissue viscoelasticity.
iMAP: A Web Server for Metabolomics Data Integrative Analysis

Metabolomics data analysis depends on the utilization of bioinformatics tools. To meet the evolving needs of metabolomics research, several integrated platforms have been developed. Our group has developed a desktop platform IP4M (integrated Platform for Metabolomics Data Analysis) which allows users to perform a nearly complete metabolomics data analysis in one-stop. With the extensive usage of IP4M, more and more demands were raised from users worldwide for a web version and a more customized workflow. Thus, iMAP (integrated Metabolomics Analysis Platform) was developed with extended functions, improved performances, and redesigned structures. Compared with existing platforms, iMAP has more methods and usage modes. A new module was developed with an automatic pipeline for train-test set separation, feature selection, and predictive model construction and validation. A new module was incorporated with sufficient editable parameters for network construction, visualization, and analysis. Moreover, plenty of plotting tools have been upgraded for highly customized publication-ready figures. Overall, iMAP is a good alternative tool with complementary functions to existing metabolomics data analysis platforms. iMAP is freely available for academic usage at https://imap.metaboprofile. cloud/ (License MPL 2.0).
Profile of Circulatory Cytokines and Chemokines in Human Coronaviruses: A Systematic Review and Meta-Analysis

Background SARS, MERS, and COVID-19 share similar characteristics. For instance, the genetic homology of SARS-CoV-2 compared to SARS-CoV and MERS-CoV is 80% and 50%, respectively, which may cause similar clinical features. Moreover, uncontrolled release of proinflammatory mediators (also called a cytokine storm) by activated immune cells in SARS, MERS, and COVID-19 patients leads to severe phenotype development. Aim This systematic review and meta-analysis aimed to evaluate the inflammatory cytokine profile associated with three strains of severe human coronavirus diseases (MERS-CoV, SARS-CoV, and SARS-CoV-2). Method The PubMed, Embase, and Cochrane Library databases were searched for studies published until July 2020. Randomized and observational studies reporting the inflammatory cytokines associated with severe and non-severe human coronavirus diseases, including MERS-CoV, SARS-CoV, and SARS-CoV-2, were included. Two reviewers independently screened articles, extracted data, and assessed the quality of the included studies. Meta-analysis was performed using a random-effects model with a 95% confidence interval to estimate the pooled mean of inflammatory biomarkers. Results A high level of circulating IL-6 could be associated with the severity of infection of the three coronavirus strains. TNF, IL-10, and IL-8 are associated with the severity of COVID-19. Increased circulating levels of CXCL10/IP10 and CCL2/MCP-1 might also be related to the severity of MERS. Conclusion This study suggests that the immune response and immunopathology in the three severe human coronavirus strains are somewhat similar. The findings highlight that nearly all studies reporting severe cases of SARS, MERS, and COVID-19 have been associated with elevated levels of IL-6. This could be used as a potential therapeutic target to improve patients’ outcomes in severe cases. Systematic Review Registration PROSPERO registration 94 number: CRD42020209931.
Denitrification Biokinetics: Towards Optimization for Industrial Applications

Denitrification is a microbial process that converts nitrate (NO3–) to N2 and can play an important role in industrial applications such as souring control and microbially enhanced oil recovery (MEOR). The effectiveness of using NO3– in souring control depends on the partial reduction of NO3– to nitrite (NO2–) and/or N2O while in MEOR complete reduction of NO3– to N2 is desired. Thauera has been reported as a dominant taxon in such applications, but the impact of NO3– and NO2– concentrations, and pH on the kinetics of denitrification by this bacterium is not known. With the goal of better understanding the effects of such parameters on applications such as souring and MEOR, three strains of Thauera (K172, NS1 and TK001) were used to study denitrification kinetics when using acetate as an electron donor. At low initial NO3– concentrations (∼1 mmol L–1) and at pH 7.5, complete NO3– reduction by all strains was indicated by non-detectable NO3– concentrations and near-complete recovery (> 97%) of the initial NO3-N as N2 after 14 days of incubation. The relative rate of denitrification by NS1 was low, 0.071 mmol L–1 d–1, compared to that of K172 (0.431 mmol L–1 d–1) and TK001 (0.429 mmol L–1 d–1). Transient accumulation of up to 0.74 mmol L–1 NO2– was observed in cultures of NS1 only. Increased initial NO3– concentrations resulted in the accumulation of elevated concentrations of NO2– and N2O, particularly in incubations with K172 and NS1. Strain TK001 had the most extensive NO3– reduction under high initial NO3– concentrations, but still had only ∼78% of the initial NO3-N recovered as N2 after 90 days of incubation. As denitrification proceeded, increased pH substantially reduced denitrification rates when values exceeded ∼ 9. The rate and extent of NO3– reduction were also affected by NO2– accumulation, particularly in incubations with K172, where up to more than a 2-fold rate decrease was observed. The decrease in rate was associated with decreased transcript abundances of denitrification genes (nirS and nosZ) required to produce enzymes for reduction of NO2– and N2O. Conversely, high pH also contributed to the delayed expression of these gene transcripts rather than their abundances in strains NS1 and TK001. Increased NO2– concentrations, N2O levels and high pH appeared to cause higher stress on NS1 than on K172 and TK001 for N2 production. Collectively, these results indicate that increased pH can alter the kinetics of denitrification by Thauera strains used in this study, suggesting that liming could be a way to achieve partial denitrification to promote NO2– and N2O production (e.g., for souring control) while pH buffering would be desirable for achieving complete denitrification to N2 (e.g., for gas-mediated MEOR).
Effects of an Audiovisual Emotion Perception Training for Schizophrenia: A Preliminary Study

Individuals with schizophrenia show a reduced ability to integrate facial and vocal information in emotion perception. Although emotion perception has been a target for treatment, no study has yet examined the effect of multimodal training on emotion perception in schizophrenia. In the present study, we developed an audiovisual emotion perception training and test in which a voice and a face were simultaneously presented, and subjects were asked to judge whether the emotions of the voice and the face matched. The voices were either angry or happy, and the faces were morphed on a continuum ranging from angry to happy. Sixteen patients with schizophrenia participated in six training sessions and three test sessions (i.e., pre-training, post-training, and generalization). Eighteen healthy controls participated only in pre-training test session. Prior to training, the patients with schizophrenia performed significantly worse than did the controls in the recognition of anger; however, following the training, the patients showed a significant improvement in recognizing anger, which was maintained and generalized to a new set of stimuli. The patients also improved the recognition of happiness following the training, but this effect was not maintained or generalized. These results provide preliminary evidence that a multimodal, audiovisual training may yield improvements in anger perception for patients with schizophrenia.
Introduction of a New Pathology Workup Protocol for Glottic Cancer Treated With Transoral Laser Microsurgery (TLM): Prospective Analysis of Oncological Outcomes and Matched Case-Control Study

Background/Purpose The value of margin status after TLM for glottic cancer is debatable, due to difficulties in specimen orientation and margin analysis. To reduce these difficulties, we recently introduced a standardized protocol of oriented fixation of TLM specimens. This proved feasible and resulted in high margin evaluability rates and a decreased rate of false positive deep margins, when compared to a historical TLM cohort. For the patients whose specimens were processed according to this protocol, we prospectively analyzed oncological outcomes, identified prognostic factors and assessed the influence of the protocol introduction on outcomes compared with a historical TLM cohort. Methods Ninety-six patients with glottic malignancies treated with TLM were included. Resection specimens were processed according to the new protocol. Descriptive statistics and survival analyses were used to determine oncological outcomes. To assess the effect of the protocol introduction on outcomes, a matched-case-control analysis was performed, using a historical TLM-cohort as controls. The Cox proportional hazards model was used to analyze prognostic effects of patient and treatment characteristics, including the pathology protocol introduction, on overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS) and local recurrence-free survival (LRFS). Results Two-year outcomes were favorable: 88.5% OS, 97.0% DSS, and 87.6% LRFS. At multivariable analysis, the presence of multiple positive superficial margins was a negative prognosticator for OS (HR 4.102) and increasing cT classification proved a negative prognosticator for DFS (HR 2.828) and LRFS (HR 2.676). Matched case-control analysis did not reveal a significant difference in oncological outcomes between cohorts. Deep margin status had a strong differential effect for DFS (p-value for interaction = 0.0205) and for LRFS (p-value for interaction = 0.0176) between cohorts, indicating a prognostic effect of deep margin status on both outcomes in the current cohort, but not in the historical cohort. Discussion/Conclusion The introduction of a new standardized technique of oriented fixation of TLM specimens did not affect oncological outcomes when compared to a historical TLM cohort, but assigned a significant prognostic effect to deep margin status for DFS and LRFS, facilitating the decision making process with regards to planning of second-look procedures, administration of adjuvant radiotherapy or determination of follow-up intensity.
Intermittently Scanned and Continuous Glucose Monitor Systems: A Systematic Review on Psychological Outcomes in Pediatric Patients

Aim: To explore the impact of real-time continuous glucose monitoring (rtCGMs) or intermittently scanned/viewed CGM (isCGM) on psychological outcomes in children and caregivers, and to grade the level of evidence. Method: Systematic review of the literature from PubMed, Embase, Cochrane Library, Web of Science, CINAHL, Nursing reference center, Up to date, Google Scholar, and PsycINFO databases. The studies selected used validated questionnaires for investigating the psychological outcomes. We applied GRADE (Grading of Recommendations Assessment, Development and Evaluation) to rank the quality of a body of evidence. Results: A total of 192 studies were identified in the initial search and after the process of evaluation 25 studies were selected as appropriate to be included in this systematic review. We found in moderate quality studies that isCGM in adolescents can improve diabetes related distress, family conflicts, fear of hypoglycemia, and quality of life, while depression, anxiety, and quality of sleep have not yet been evaluated by validated questionnaires. In moderate—high quality studies, rtCGM technology does not impact on diabetes burden, diabetes specific family conflict, and depressive symptoms. The effect on fear of hypoglycemia, sleep quality, and anxiety is still debated and RCT studies powered to find significant results in psychological outcomes are lacking. RtCGM increases satisfaction and quality of life in parents and patients wearing rtCGM. Conclusion: these data present an interesting point to consider when families are deciding whether or not to start CGM use, choosing between rtCGM to reach a tighter metabolic control, or isCGM which allows greater benefits on psychological outcomes.
Autonomous Non Antioxidant Roles for Fasciola hepatica Secreted Thioredoxin-1 and Peroxiredoxin-1

Trematode parasites of the genus Fasciola are the cause of liver fluke disease (fasciolosis) in humans and their livestock. Infection of the host involves invasion through the intestinal wall followed by migration in the liver that results in extensive damage, before the parasite settles as a mature egg-laying adult in the bile ducts. Genomic and transcriptomic studies revealed that increased metabolic stress during the rapid growth and development of F. hepatica is balanced with the up-regulation of the thiol-independent antioxidant system. In this cascade system thioredoxin/glutathione reductase (TGR) reduces thioredoxin (Trx), which then reduces and activates peroxiredoxin (Prx), whose major function is to protect cells against the damaging hydrogen peroxide free radicals. F. hepatica expresses a single TGR, three Trx and three Prx genes; however, the transcriptional expression of Trx1 and Prx1 far out-weighs (>50-fold) other members of their family, and both are major components of the parasite secretome. While Prx1 possesses a leader signal peptide that directs its secretion through the classical pathway and explains why this enzyme is found freely soluble in the secretome, Trx1 lacks a leader peptide and is secreted via an alternative pathway that packages the majority of this enzyme into extracellular vesicles (EVs). Here we propose that F. hepatica Prx1 and Trx1 do not function as part of the parasite’s stress-inducible thiol-dependant cascade, but play autonomous roles in defence against the general anti-pathogen oxidative burst by innate immune cells, in the modulation of host immune responses and regulation of inflammation.