Miracle-dz/UniFAR-FTUs huggingface dataset:
Single strand gap repair: The presynaptic phase plays a pivotal role in modulating lesion tolerance pathways

During replication, the presence of unrepaired lesions results in the formation of single stranded DNA (ssDNA) gaps that need to be repaired to preserve genome integrity and cell survival. All organisms have evolved two major lesion tolerance pathways to continue replication: Translesion Synthesis (TLS), potentially mutagenic, and Homology Directed Gap Repair (HDGR), that relies on homologous recombination. In Escherichia coli, the RecF pathway repairs such ssDNA gaps by processing them to produce a recombinogenic RecA nucleofilament during the presynaptic phase. In this study, we show that the presynaptic phase is crucial for modulating lesion tolerance pathways since the competition between TLS and HDGR occurs at this stage. Impairing either the extension of the ssDNA gap (mediated by the nuclease RecJ and the helicase RecQ) or the loading of RecA (mediated by RecFOR) leads to a decrease in HDGR and a concomitant increase in TLS. Hence, we conclude that defects in the presynaptic phase delay the formation of the D-loop and increase the time window allowed for TLS. In contrast, we show that a defect in the postsynaptic phase that impairs HDGR does not lead to an increase in TLS. Unexpectedly, we also reveal a strong genetic interaction between recF and recJ genes, that results in a recA deficient-like phenotype in which HDGR is almost completely abolished.
Endocannabinoids, Anandamide and 2-Arachidonoylglycerol, as Prognostic Markers of Sepsis Outcome and Complications

Background: One of the major challenges in improving sepsis care is early prediction of sepsis complications. The endocannabinoid system has been intensely studied in recent years; however, little is known about its role in sepsis in humans. This study aimed to assess the prognostic role of endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), as early predictors of mortality, invasive mechanical ventilation (IMV) requirement, and length of stay (LOS) in patients with sepsis. Materials and Methods: In total, 106 patients with confirmed sepsis were enrolled in this study. The patients were divided into groups according to mortality outcome (survival, N=53; nonsurvival, N=53), IMV requirement (IMV group, N=26; non-IMV group, N=80), and LOS (LOS <10 days, N=59; LOS ≥10 days, N=47). Patients' clinical status was assessed along with laboratory biomarkers as well as AEA and 2-AG concentration measurements early on admission to emergency units. AEA and 2-AG levels were measured by enzyme-linked immunosorbent assay (ELISA) using an ELISA processor, EtiMax 3000 (DiaSorin, Saluggia, Italy). The predictive value of AEA and 2-AG for the studied sepsis outcomes and complications was analyzed using univariate and multivariate analyses and receiver operating characteristic (ROC) curve analysis. Results: Two endocannabinoids showed no significant difference between survivors and nonsurvivors, although an AEA concentration <7.16 μg/L predicted mortality outcome with a sensitivity of 57% (95% confidence interval [CI] 42–71) and specificity of 80% (95% CI 66–91). AEA concentrations ≤17.84 μg/L predicted LOS ≥10 days with sensitivity of 98% (95% CI 89–100) and specificity of 34% (95% CI 22–47). When analyzing IMV requirement, levels of AEA and 2-AG were significantly lower within the IMV group compared with the non-IMV group (5.94 μg/L [2.04–9.44] and 6.70 μg/L [3.50–27.04], p=0.043, and 5.68 μg/L [2.30–8.60] and 9.58 μg/L [4.83–40.05], p=0.002, respectively). The 2-AG showed the best performance for IMV requirement prediction, with both sensitivity and specificity of 69% (p<0.001). Endocannabinoid AEA was an independent risk factor of LOS ≥10 days (odds ratio [OR] 23.59; 95% CI 3.03–183.83; p=0.003) and IMV requirement in sepsis (OR 0.79; 95% CI, 0.67–0.93; p=0.004). Conclusion: Low AEA concentration is a prognostic factor of hospital LOS longer than 10 days. Lower AEA and 2-AG concentrations obtained at the time of admission to the hospital are predictors of IMV requirement.
Striving for high reliability in healthcare: a qualitative study of the implementation of a hospital safety programme

Background Healthcare leaders look to high-reliability organisations (HROs) for strategies to improve safety, despite questions about how to translate these strategies into practice. Weick and Sutcliffe describe five principles exhibited by HROs. Interventions aiming to foster these principles are common in healthcare; however, there have been few examinations of the perceptions of those who have planned or experienced these efforts. Objective This single-site qualitative study explores how healthcare professionals understand and enact the HRO principles in response to an HRO-inspired hospital-wide safety programme. Methods We interviewed 71 participants representing hospital executives, programme leadership, and staff and physicians from three clinical services. We observed and collected data from unit and hospital-wide quality and safety meetings and activities. We used thematic analysis to code and analyse the data. Results Participants reported enactment of the HRO principles ‘preoccupation with failure’, ‘reluctance to simplify interpretations’ and ‘sensitivity to operations’, and described the programme as adding legitimacy, training, and support. However, the programme was more often targeted at, and taken up by, nurses compared with other groups. Participants were less able to identify interventions that supported the HRO principles ‘commitment to resilience’ and ‘deference to expertise’ and reported limited examples of changes in practices related to these principles. Moreover, we identified inconsistent, and even conflicting, understanding of concepts related to the HRO principles, often related to social and professional norms and practices. Finally, an individualised rather than systemic approach hindered collective actions underlying high reliability. Conclusion Our findings demonstrate that the safety programme supported some HRO principles more than others, and was targeted at, and perceived differently across professional groups leading to inconsistent understanding and enactments of the principles across the organisation. Combining HRO-inspired interventions with more targeted attention to each of the HRO principles could produce greater, more consistent high-reliability practices.
Efficacy and safety of outpatient parenteral antibiotic therapy in patients with infective endocarditis: a meta-analysis

Background To investigate the clinical outcome of patients with infective endocarditis (IE) during and after outpatient parenteral antimicrobial treatment (OPAT), and to further clarify the safety and efficacy of OPAT for IE patients. Methods Through December 20, 2021, a total of 331 articles were preliminarily searched in Pubmed, Web of Science, Cochrane Library and Embase, and 9 articles were eventually included in this study. Results A total of 9 articles comprising 1,116 patients were included in this study. The overall mortality rate of patients treated with OPAT was 0.04 (95% CI, 0.02-0.07), that means 4 deaths per 100 patients treated with OPAT. Separately, mortality was low during the follow-up period after OPAT treatment, with an effect size (ES) of 0.03 (95%CI, 0.02-0.07) and the mortality of patients during OPAT treatment was 0.04 (95% CI, 0.01-0.12). In addition, the readmission rate was found to be 0.14 (95% CI, 0.09-0.22) during the follow-up and 0.18 (95% CI, 0.08-0.39) during treatment, and 0.16 (95% CI, 0.10-0.24) for patients treated with OPAT in general. Regarding the relapse of IE in patients, our results showed a low overall relapse rate, with an ES of 0.03 (95% CI, 0.01-0.05). In addition, we found that the incidence of adverse events was low, with an ES of 0.26 (95% CI, 0.19-0.33). Conclusion In general, the incidence of adverse events and mortality, readmission, and relapse rates in IE patients treated with OPAT are low both during treatment and follow-up period after discharge, indicating that OPAT is safe and effective for IE patients. However, our study did not compare routine hospitalization as a control group, so conclusions should be drawn with caution. In order to obtain more scientific and rigorous conclusions and reduce clinical risks, it is still necessary to conduct more research in this field and improve the patient selection criteria for OPAT treatment, especially for IE patients. Finally, clinical monitoring and follow-up of OPAT-treated patients should be strengthened.
BETA: a comprehensive benchmark for computational drug–target prediction

Abstract Internal validation is the most popular evaluation strategy used for drug–target predictive models. The simple random shuffling in the cross-validation, however, is not always ideal to handle large, diverse and copious datasets as it could potentially introduce bias. Hence, these predictive models cannot be comprehensively evaluated to provide insight into their general performance on a variety of use-cases (e.g. permutations of different levels of connectiveness and categories in drug and target space, as well as validations based on different data sources). In this work, we introduce a benchmark, BETA, that aims to address this gap by (i) providing an extensive multipartite network consisting of 0.97 million biomedical concepts and 8.5 million associations, in addition to 62 million drug–drug and protein–protein similarities and (ii) presenting evaluation strategies that reflect seven cases (i.e. general, screening with different connectivity, target and drug screening based on categories, searching for specific drugs and targets and drug repurposing for specific diseases), a total of seven Tests (consisting of 344 Tasks in total) across multiple sampling and validation strategies. Six state-of-the-art methods covering two broad input data types (chemical structure- and gene sequence-based and network-based) were tested across all the developed Tasks. The best-worst performing cases have been analyzed to demonstrate the ability of the proposed benchmark to identify limitations of the tested methods for running over the benchmark tasks. The results highlight BETA as a benchmark in the selection of computational strategies for drug repurposing and target discovery.
Proteomic Analysis of Retinal Conditioned Medium: The Effect on Early Differentiation of Embyonic Stem Cells into Retina.

Stem cell replacement therapy has emerged as one of the most promising treatment options for retinal degenerative diseases, which are the main causes of irreversible vision loss. Three-dimensional (3D) retinal organoid culture is a cutting-edge technology for differentiating embryonic stem cells into retinal cells by forming a laminated retinal structure. However, 3D culture systems have strict requirements with respect to the experimental environment and culture technologies. Our study aimed to investigate the effect of retinal conditioned medium (RCM) at different developmental stages on the early differentiation of embryonic stem cells into retina in a 3D culture system. Here, we added RCM to the 3D culture system and found it could promote the differentiation of mouse embryonic stem cells (mESCs) into neuroretina. We further explored the possible mechanisms of RCM that regulate differentiation through proteomic analysis. RCM at different time points disclosed different protein profiles. Proteins which improved energy metabolism of mESCs might help improve the viability of embryonic bodies (EBs). We then screened out Snap25, Cntn1, Negr1, Dpysl2, Dpysl3, and Crmp1 as candidate proteins that might play roles in the differentiation and neurogenesis processes of mESCs, hoping to provide a basis for optimizing a retinal differentiation protocol from embryonic stem cells.
INTRUSION DETECTION IN HETEROGENEOUS NETWORK BY MULTIPATH ROUTING BASED TOLERNENCE PROTOCOL

The key theory of our redundancy management is to achieve the tradeoff between energy consumption vs. the gain in timeliness, security, and reliability to increase the system useful lifetime. A Innovative probability model to analyze the best redundancy level in terms of source redundancy, path redundancy and as well as the best intrusion detection settings in terms of the number of voters and the intrusion invocation break under which the lifetime of a HWSN [Heterogeneous Wireless Sensor Network] is maximized. In redundancy management “badmouthing” is the major problem in managing the redundancy. This badmouthing is malicious node which will never drop the packet even after knowing that the packet has been sent already. In this paper we propose a new scheme to overcome the problem of badmouthing by weighted based voting, this protocol will weight (Success Rate) all the nodes in the network to find the non-malicious node in the network which having more packet drop. In “weighted voting” main function is to find trust/reputation of neighbor nodes, as well as to tackle the “what paths to use” problem in multipath routing decision making for intrusion tolerance in WSNs.
TAR DNA-binding protein of 43 kDa (TDP-43) and amyotrophic lateral sclerosis (ALS): a promising therapeutic target

ABSTRACT Introduction Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that lacks an effective treatment. Aggregates of the TAR DNA-binding protein-43 (TDP-43) are observed in 97% of all ALS cases, thus making this protein a major therapeutic target in ALS. Areas covered The authors describe the major cellular functions of TDP-43 and the features and consequences of TDP-43 proteinopathy. Drawing from fundamental and preclinical studies on cellular and animal TDP-43 models of ALS and selected clinical trials, the major pathways that have been targeted for the mitigation of TDP-43 pathology in ALS are discussed. The authors provide insights on the approaches targeting the tendency of TDP-43 for aggregation, defective nucleocytoplasmic transport, dysfunctional proteostasis, abnormal stress granule dynamics, and pathological post-translational modifications of TDP-43. Expert opinion The complexity of ALS and TDP-43 proteinopathy generates challenges for the development of novel therapeutic approaches. However, the critical involvement of TDP-43 in the initiation and progression of ALS, makes it a promising therapeutic target. Further research should be centered on the development of precision strategies, consideration of patient subgroups, the prevention of the mislocalization of TDP-43 and restoration of the lost functions of TPD-43.
Pertuzumab Plus Trastuzumab for Treatment-Refractory HER2-Amplified Metastatic Colorectal Cancer: Comparison of the MyPathway Trial With a Real-World External Control Arm

PURPOSE We compared overall survival (OS) in patients with human epidermal growth factor receptor 2 (HER2)–amplified, treatment-refractory metastatic colorectal cancer (mCRC) receiving pertuzumab plus trastuzumab (PER-HER) in the phase IIa MyPathway multibasket study (ClinicalTrials.gov identifier: NCT02091141) with OS in those receiving routine clinical care in an electronic health record–derived external control arm. METHODS A noninterventional study was conducted using patient-level data from MyPathway participants receiving PER-HER and real-world patients with HER2-amplified treatment-refractory mCRC receiving routine clinical care. This study used a deidentified US-based clinico-genomic database (CGDB). For patients in the CGDB who met study eligibility criteria at multiple index dates (treatment initiation dates in the treatment-refractory setting), all eligible index dates were used for the analysis. Standardized mortality ratio weighting on the basis of propensity score derived a pseudopopulation (postweighting population) balancing key prognostic variables between arms. Multivariate Cox proportional hazards models were used for estimation of the hazard ratio (HR) in the primary OS analysis. A series of sensitivity analyses were conducted to investigate the robustness and consistency of the primary analysis. RESULTS The PER-HER arm comprised 57 patients enrolled in the MyPathway study by August 1, 2017 (data cutoff); the external control arm comprised 18 patients (27 index dates) with HER2-amplified mCRC who met the major MyPathway eligibility criteria in CGDB collected between 2011 and 2019. The estimated HR for OS from the multivariate Cox proportional hazards model in the postweighting population was 0.729 (95% CI, 0.184 to 3.900). The results of sensitivity analyses were consistent with the primary analysis in terms of the point estimate of HR. CONCLUSION Despite a small sample size, these findings suggest that PER-HER could have a potential OS benefit for this population.
DNA metabarcoding unveils the effects of habitat fragmentation on pollinator diversity, plant‐pollinator interactions, and pollination efficiency in Maldive islands

Habitat fragmentation affects biodiversity, but with unclear effects on pollinators and their interactions with plants in anthropized landscapes. Islands could serve as open air laboratories, suitable to disentangle how land‐use alteration impacts pollination ecology. In Maldive islands we investigated how pollinator richness, plant‐pollinator interactions and pollination efficiency are influenced by the green area fragmentation (i.e., gardens and semi‐natural patches). Moreover, we considered the mediating role of pollinator body size and the plant trait of being invasive in shaping interactions. To do this, we surveyed pollinator insects from 11 islands representing a gradient of green area fragmentation. A DNA metabarcoding approach was adopted to identify the pollen transported by pollinators and characterize the plant‐pollinator interactions. We found that intermediate levels of green area fragmentation characterized pollinator communities and increased their species richness, while decreasing interaction network complexity. Invasive plants were more frequently found on pollinator bodies than native or exotic noninvasive ones, indicating a concerningly higher potential for pollen dispersal and reproduction of the former ones. Intriguingly, pollinator body size mediated the effect of landscape alteration on interactions, as only the largest bees expanded the foraging diet in terms of plant richness in the transported pollen at increasing fragmentation. In parallel, the pollination efficiency increased with pollinator species richness in two sentinel plants. This study shows that moderate landscape fragmentation of green areas shapes many aspects of the pollination ecosystem service, where despite interactions being less complex and mediated by pollinator body size, pollinator insect biodiversity and potential plant reproduction are supported.
Targeted mitochondrial drugs for treatment of myocardial ischaemia-reperfusion injury

Abstract Myocardial ischaemia-reperfusion injury (MI/RI) refers to the further damage done to ischaemic cardiomyocytes when restoring blood flow. A large body of evidence shows that MI/RI is closely associated with excessive production of mitochondrial reactive oxygen species, mitochondrial calcium overload, disordered mitochondrial energy metabolism, mitophagy, mitochondrial fission, and mitochondrial fusion. According to the way it affects mitochondria, it can be divided into mitochondrial quality abnormalities and mitochondrial quantity abnormalities. Abnormal mitochondrial quality refers to the dysfunction caused by the severe destruction of mitochondria, which then affects the balance of mitochondrial density and number, causing an abnormal mitochondrial quantity. In the past, most of the reports were limited to the study of the mechanism of myocardial ischaemia-reperfusion injury, some of which involved mitochondria, but no specific countermeasures were proposed. In this review, we outline the mechanisms for treating myocardial ischaemia-reperfusion injury from the direction of mitochondria and focus on targeted interventions and drugs to restore mitochondrial health during abnormal mitochondrial quality control and abnormal mitochondrial quantity control. This is an update in the field of myocardial ischaemia-reperfusion injury.
A new test suggests hundreds of amino acid polymorphisms in humans are subject to balancing selection

The role that balancing selection plays in the maintenance of genetic diversity remains unresolved. Here, we introduce a new test, based on the McDonald–Kreitman test, in which the number of polymorphisms that are shared between populations is contrasted to those that are private at selected and neutral sites. We show that this simple test is robust to a variety of demographic changes, and that it can also give a direct estimate of the number of shared polymorphisms that are directly maintained by balancing selection. We apply our method to population genomic data from humans and provide some evidence that hundreds of nonsynonymous polymorphisms are subject to balancing selection.
Análisis gráficode la neuro-dinámica en un robot capaz de realizar aprendizaje imitativo Graphic analisys ofthe neural-dynamics in a robot able to do imitative learning

Multilayer Perceptron is an artificial neural network able to learn to work in a specific desired way through examples, and once it is trained, it is able to react correctly in situations for which it was not specifically trained, due to its generalization capability. These examples are specified by the designer or can be assimilated with the support of a self-organized map. This paper shows the training verification and the working analysis of the multilayer perceptron used during the development of an imitation learning model; which is focused to a mobile robot displacement over two-dimensional space. This was done designing a comparison method between the attractor’s graphs generated by the instructor robot and the apprentice robot. This method is supported in digital
Optimization of dynamic soaring in a flap-gliding seabird affects its large-scale distribution at sea

Dynamic soaring harvests energy from a spatiotemporal wind gradient, allowing albatrosses to glide over vast distances. However, its use is challenging to demonstrate empirically and has yet to be confirmed in other seabirds. Here, we investigate how flap-gliding Manx shearwaters optimize their flight for dynamic soaring. We do so by deriving a new metric, the horizontal wind effectiveness, that quantifies how effectively flight harvests energy from a shear layer. We evaluate this metric empirically for fine-scale trajectories reconstructed from bird-borne video data using a simplified flight dynamics model. We find that the birds’ undulations are phased with their horizontal turning to optimize energy harvesting. We also assess the opportunity for energy harvesting in long-range, GPS-logged foraging trajectories and find that Manx shearwaters optimize their flight to increase the opportunity for dynamic soaring during favorable wind conditions. Our results show how small-scale dynamic soaring affects large-scale Manx shearwater distribution at sea.