Miracle-dz/UniFAR-FTUs huggingface dataset:
SIGNOR 2.0, the SIGnaling Network Open Resource 2.0: 2019 update

Abstract The SIGnaling Network Open Resource 2.0 (SIGNOR 2.0) is a public repository that stores signaling information as binary causal relationships between biological entities. The captured information is represented graphically as a signed directed graph. Each signaling relationship is associated to an effect (up/down-regulation) and to the mechanism (e.g. binding, phosphorylation, transcriptional activation, etc.) causing the up/down-regulation of the target entity. Since its first release, SIGNOR has undergone a significant content increase and the number of annotated causal interactions have almost doubled. SIGNOR 2.0 now stores almost 23 000 manually-annotated causal relationships between proteins and other biologically relevant entities: chemicals, phenotypes, complexes, etc. We describe here significant changes in curation policy and a new confidence score, which is assigned to each interaction. We have also improved the compliance to the FAIR data principles by providing (i) SIGNOR stable identifiers, (ii) programmatic access through REST APIs, (iii) bioschemas and (iv) downloadable data in standard-compliant formats, such as PSI-MI CausalTAB and GMT. The data are freely accessible and downloadable at https://signor.uniroma2. it/.
A computational approach for explaining the effect of the prl gene polymorphism on prolactin structure and biological activity in Japanese quails

Abstract Prolactin is a versatile hormone with multiple activities, including a negative control on egg production. This study was conducted to genotype all the coding portions of the prl gene using PCR-SSCP-sequencing, and to investigate the effects of amino acid substitutions of the prl gene on the structure and function of prolactin in quails using in silico approach. Though all genotyped exons exerted homogenous PCR-SSCP patterns, a total of 12 novel SNPs were detected in the investigated exons, including three SNPs in exon-1, 8 SNPs in exon-2, and one SNP in exon-4. Three adjacent missense SNPs were detected in exon-2, namely H69P, T70P, and S71F. Computational tools indicated obvious deleterious effects of T70P, with less extent to H69P and S71F on prolactin functions and activity, which may lead to limited participation of this hormone in the negative control of egg production. In conclusion, the introduction of in silico prediction has suggested an alternative solution for the breeders to evaluate the effect of each witnessed nsSNP in protein structure and function. The current study suggests three nsSNPs, T70P, T70P, and S71F as strong candidates for the negative effect on prolactin biological activity with a consequent reversal positive effect on egg productivity traits.
Nonlinear mixed‐effects models with misspecified random‐effects distribution

Nonlinear mixed‐effects models are being widely used for the analysis of longitudinal data, especially from pharmaceutical research. They use random effects which are latent and unobservable variables so the random‐effects distribution is subject to misspecification in practice. In this paper, we first study the consequences of misspecifying the random‐effects distribution in nonlinear mixed‐effects models. Our study is focused on Gauss‐Hermite quadrature, which is now the routine method for calculation of the marginal likelihood in mixed models. We then present a formal diagnostic test to check the appropriateness of the assumed random‐effects distribution in nonlinear mixed‐effects models, which is very useful for real data analysis. Our findings show that the estimates of fixed‐effects parameters in nonlinear mixed‐effects models are generally robust to deviations from normality of the random‐effects distribution, but the estimates of variance components are very sensitive to the distributional assumption of random effects. Furthermore, a misspecified random‐effects distribution will either overestimate or underestimate the predictions of random effects. We illustrate the results using a real data application from an intensive pharmacokinetic study.
Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke.

背景和目的 本指南旨在在单个文件中为治疗急性动脉性缺血性卒中患者的临床医生提供最新的全面系列推荐意见。 目标读者为院前急救人员、医生、综合医疗保健人员以及医院管理人员。 本指南将取代2013年版急性缺血性卒中(acute ischemic stroke, AIS)指南，同时也是对2018年版AIS指南的更新。 方法 写作组成员由美国心脏协会(American Heart Association, AHA)卒中委员会的科学声明监督委员会任命，代表各领域的医学专家。 写作组成员不得对存在企业利益关系的相关议题进行讨论或投票。 对2013年版AIS指南的更新最初于2018年1月发表，该版指南已经过AHA科学咨询与协调委员会以及AHA执行委员会批准。 2018年4月，在删除部分推荐意见后，该指南的修订版在AHA网站上在线发表。 要求写作组审查原始文件并在必要时进行修订。 2018年6月，写作组提交了一份经过细微更改并纳入新近发表的重要随机对照试验(受试者数量>100名且具有AIS发病后至少90 d的临床转归)的文件。 经过14位专家进行同行评议后，写作组根据同行评议专家的意见进行了适当修改。 目前的最终文件已经过写作组全体成员(除非企业利益关系妨碍了成员投票)以及AHA管理机构批准。 本指南采用了美国心脏病学学会/AHA 2015年推荐意见分类和证据级别标准以及新版AHA指南格式。 结果 本指南详细介绍了院前医疗、紧急和急诊评估、静脉和血管内治疗以及院内管理，包括在发病后最初2周内启用的二级预防措施。 本指南支持院前和院内卒中医疗系统的一体化概念。 结论 本指南基于现有证据提供了总体推荐意见，用于指导治疗成年急性动脉性缺血性卒中患者的临床医生。 然而，许多情况资料有限，迫切需要对AIS的治疗进行持续研究。
Pioneering a new approach to home exercise : physiotherapy for older adults through community television

The purpose of this case study was to describe my experience, as a physiotherapist, producing a chair exercise program for older adults through community television in Weyburn, Saskatchewan, between 1996 and 1998. Because television production by a physiotherapist has not been previously documented, I also sought to determine the acceptability of the television program by viewers and other physiotherapists. This study was based on a qualitative research design. I used documents, program video tapes, and personal journal entries to tell my story. Data was collected through interviews with twelve older adults and five physiotherapists. I represented the data as a town hall meeting. I created a "moderator" to facilitate the discussion, and a "panel expert" to provide analysis and interpretation based on the literature. The findings were highlighted throughout the discussion as "key points. " The older adult participants spoke about the convenience of televised exercises. They indicated that exercises on television were easier to follow than on handouts. The benefits of the exercise program were less stiffness and joint pain resulting in greater ease ofmovement. Another key point was ongoing motivation and adherence: some viewers continued to follow the exercise program three to four years later. They indicated they would like to see the television program continue; the production ofnew shows was recommended. These findings were of interest to the physiotherapists. Even though they accepted televised exercises within the scope of physiotherapy, they expressed concern for the safety of the participant. They discussed the importance of being able to screen and monitor viewers, and evaluate the program. The results of this study indicate that community television is an effective and appropriate means of delivering an exercise program for older adults; this program could be ofvalue in other communities with an aging population. Finally, the use of television expands the delivery ofphysiotherapy beyond the traditional treatment paradigm to one ofhealth promotion and prevention.
The expression of HLA class I molecules and complement regulatory proteins in ovarian cancer

Over recent decades, translational ovarian cancer research has been impeded by its underappreciated molecular heterogeneity and five-year survival has remained poor. One strategy for addressing this problem is to search for molecular biomarkers that can better inform the development and targeting of novel treatments. The aim of this thesis was to construct and validate a tissue microarray of ovarian cancer cases and to survey the expression and prognostic capabilities of immunological molecular markers: specifically HLA class I and the membrane bound complement regulatory proteins CD46, CD55 and CD59. These are central to the efficacy of certain immunotherapies and while they have been shown to have prognostic power in breast and colorectal cancer, they have been investigated less in ovarian cancer. Five copies of a tissue microarray representing 339 cases of ovarian cancer which presented to Derby City General Hospital between 1982 and 1997 were made. The array was stained for CK7, CK20, CA125, CEA, p53 and Bcl-2 following a standard immunohistochemical protocol. A linked clinical database was adapted and assessed for data consistency and subsequently used to analyse the prognostic and clinicopathological associations of the expression data. The array was then stained for HLA class I, B2microglobulin and CD59 using commercial antibodies and for CD55 and CD46 using in-house antibodies. Retained expression of HLA class I molecules independently predicted improved prognosis. High expression of CD55 and CD59 were associated with worse prognosis, though not independently of other factors. CD55 expression was more widespread than previously appreciated. This thesis describes the discovery of a new independent marker of prognosis which suggests that immunoediting occurs in ovarian cancer, describes the distribution of markers known to have a negative impact on immunotherapy in ovarian cancer in a large series for the first time and documents the production of a valuable resource for future studies.
One-step efficient generation of dual-function conditional knockout and geno-tagging alleles in zebrafish

CRISPR/Cas systems are widely used to knock out genes by inducing indel mutations, which are prone to genetic compensation. Complex genome modifications such as knockin (KI) might bypass compensation, though difficult to practice due to low efficiency. Moreover, no ‘two-in-one’ KI strategy combining conditional knockout (CKO) with fluorescent gene-labeling or further allele-labeling has been reported. Here, we developed a dual-cassette-donor strategy and achieved one-step and efficient generation of dual-function KI alleles at tbx5a and kctd10 loci in zebrafish via targeted insertion. These alleles display fluorescent gene-tagging and CKO effects before and after Cre induction, respectively. By introducing a second fluorescent reporter, geno-tagging effects were achieved at tbx5a and sox10 loci, exhibiting CKO coupled with fluorescent reporter switch upon Cre induction, enabling tracing of three distinct genotypes. We found that LiCl purification of gRNA is critical for highly efficient KI, and preselection of founders allows the efficient germline recovery of KI events.
Accounting for respiratory motion in small serial structures during radiotherapy planning: proof of concept in virtual bronchoscopy-guided lung functional avoidance radiotherapy

Respiratory motion management techniques in radiotherapy (RT) planning are primarily focused on maintaining tumor target coverage. An inadequately addressed need is accounting for motion in dosimetric estimations in smaller serial structures. Accurate dose estimations in such structures are more sensitive to motion because respiration can cause them to move completely in or out of a high dose-gradient field. In this work, we study three motion management strategies (m1–m3) to find an accurate method to estimate the dosimetry in airways. To validate these methods, we generated a ‘ground truth’ digital breathing model based on a 4DCT scan from a lung stereotactic ablative radiotherapy (SAbR) patient. We simulated 225 breathing cycles with ±10% perturbations in amplitude, respiratory period, and time per respiratory phase. A high-resolution breath-hold CT (BHCT) was also acquired and used with a research virtual bronchoscopy software to autosegment 239 airways. Contours for planning target volume (PTV) and organs at risk (OARs) were defined on the maximum intensity projection of the 4DCT (CTMIP) and transferred to the average of the 10 4DCT phases (CTAVG). To design the motion management methods, the RT plan was recreated using different images and structure definitions. Methods m1 and m2 recreated the plan using the CTAVG image. In method m1, airways were deformed to the CTAVG. In m2, airways were deformed to each of the 4DCT phases, and union structures were transferred onto the CTAVG. In m3, the RT plan was recreated on each of the 10 phases, and the dose distribution from each phase was deformed to the BHCT and summed. Dose errors (mean [min, max]) in airways were: m1: 21% (0.001%, 93%); m2: 45% (0.1%, 179%); and m3: 4% (0.006%, 14%). Our work suggests that accurate dose estimation in moving small serial structures requires customized motion management techniques (like m3 in this work) rather than current clinical and investigational approaches.
Kinetic Models of Secondary Active Transporters

Kinetic models have been employed to understand the logic of substrate transport through transporters of the Solute Carrier (SLC) family. All SLC transporters operate according to the alternate access model, which posits that substrate transport occurs in a closed loop of partial reactions (i.e., a transport cycle). Kinetic models can help to find realistic estimates for conformational transitions between individual states of the transport cycle. When constrained by experimental results, kinetic models can faithfully describe the function of a candidate transporter at a pre-steady state. In addition, we show that kinetic models can accurately predict the intra- and extracellular substrate concentrations maintained by the transporter at a steady state, even under the premise of loose coupling between the electrochemical gradient of the driving ion and of the substrate. We define the criteria for the design of a credible kinetic model of the SLC transporter. Parsimony is the guiding principle of kinetic modeling. We argue, however, that the level of acceptable parsimony is limited by the need to account for the substrate gradient established by a secondary active transporter, and for random order binding of co-substrates and substrate. Random order binding has consistently been observed in transporters of the SLC group.
The role of TRIM family proteins in the regulation of cancer stem cell self‐renewal

The tripartite‐motif (TRIM) family of proteins represents one of the largest classes of putative single protein RING‐finger E3 ubiquitin ligases. The members of this family are characterized by an N‐terminal TRIM motif containing one RING‐finger domain, one or two zinc‐finger domains called B boxes (B1 box and B2 box), and a coiled‐coil region. The TRIM motif can be found in isolation or in combination with a variety of C‐terminal domains, and based on C‐terminus, TRIM proteins are classified into 11 distinct groups. Because of the complex nature of TRIM proteins, they are implicated in a variety of cellular functions and biological processes, including regulation of cell proliferation, cell division and developmental processes, cancer transformation, regulation of cell metabolism, autophagocytosis, modification of chromatin status, regulation of gene transcription, post‐translational modifications, and interactions with pathogens. Here, we demonstrate the specific activities of TRIM family proteins that contribute to the cancer stem cell phenotype. A growing body of evidence demonstrates that several TRIM members guarantee the acquisition of stem cell properties and the ability to sustain stem‐like phenotype by cancer cells using distinct mechanisms. For other members, further work is needed to understand their full contribution to stem cell self‐renewal. Identification of TRIM proteins that possess the potential to serve as therapeutic targets may result in the development of new therapeutic strategies. Finally, these strategies may result in the disruption of the machinery of stemness acquisition, which may prevent tumor growth, progression, and overcome the resistance to anticancer therapies.
The Kempen study : aspects of maternal well-being and obstetrical outcome in relation to gestational thyroid function

Objective: To investigate whether women who give birth at home are less prone to mood disturbances during the early puerperium than those who give birth in hospital. Design: A prospective study of 303 pregnant women who registered for antenatal care. Setting: The antenatal clinic at St Joseph's Hospital, Veldhoven. The Netherlands, and five antenatal consultation programmes of local midwives working in the surrounding region. Subjects: Three hundred and eighty-two consecutive caucasían women registering for antenatal care were approached. Of these, 303 consented to participate and 293 completed the study.
A lightweight structure detector on cardiac ultrasound images of multiple views with tailored NMS algorithm

American Society of Echocardiography (ASE) has established guidelines for performing Transthoracic Echocardiographic exams in adults. 2D imaging protocols [1] are defined for multiple views that consist of several key structures. In practice, it can be difficult to determine whether qualified views have been achieved. In many cases, cardiac ultrasound images suffer from missing structures and incomplete chambers. This can lead to diagnostic errors and adversely alter patient treatment. Thus, we proposed a method that combines automatic cardiac view classification and detection of key structures with a tailored non-maximum suppression (NMS) algorithm. The multi-task method on different views is merged into a single light-weight model that has the potential to be deployed for real-time applications.
Cradles and museums of generic plant diversity across tropical Africa

Summary Determining where species diversify (cradles) and persist (museums) over evolutionary time is fundamental to understanding the distribution of biodiversity and for conservation prioritization. Here, we identify cradles and museums of angiosperm generic diversity across tropical Africa, one of the most biodiverse regions on Earth. Regions containing nonrandom concentrations of young (neo‐) and old (paleo‐) endemic taxa were identified using distribution data of 1719 genera combined with a newly generated time‐calibrated mega‐phylogenetic tree. We then compared the identified regions with the current network of African protected areas (PAs). At the generic level, phylogenetic diversity and endemism are mainly concentrated in the biogeographically complex region of Eastern Africa. We show that mountainous areas are centres of both neo‐ and paleo‐endemism. By contrast, the Guineo‐Congolian lowland rain forest region is characterized by widespread and old lineages. We found that the overlap between centres of phylogenetic endemism and PAs is high (> 85%). We show the vital role played by mountains acting simultaneously as cradles and museums of tropical African plant biodiversity. By contrast, lowland rainforests act mainly as museums for generic diversity. Our study shows that incorporating large‐scale taxonomically verified distribution datasets and mega‐phylogenies lead to an improved understanding of tropical plant biodiversity evolution.
End-of-Life Communication Between Providers and Family Caregivers of Home Hospice Patients in a Rural US-Mexico Border Community: Caregivers’ Retrospective Perspectives

Introduction: Family caregiver–provider communication is essential to making an effective hospice care transition for patients. Despite the importance of this topic, there is little information about how caregivers in rural US-Mexico border regions navigate hospice care transition and their needs. This study explores the family caregivers’ experience relating to their end-of-life (EOL) communication and needs for hospice care transition. Methods: In-depth interviews using qualitative methods were conducted with 28 informal caregivers of patients who are enrolled in home hospice care in a rural US-Mexico border region. Thematic analysis was applied to analyze the data. Results: Qualitative themes that emerged include (1) lack of/insufficient EOL communication and (2) informational needs, including (a) signs of symptom changes, (b) EOL treatment options and goals of care, and (c) hospice care and its benefits. Limited caregiver–provider EOL communication was observed, in which the majority of the caregivers (n = 22, 78.6%) were informed of the patient’s terminal condition, but only half (n = 15, 53.6%) had a discussion with the providers about hospice care. Conclusion: Timely EOL communication between caregivers and the providers is key to the patient’s optimal transition to hospice care. Providers need to be aware of the caregivers’ informational needs relating to patient symptoms and health condition as well as hospice care. It is important to be aware of the impact of cultural values on hospice care placement. A clear explanation about the purpose and functions of hospice care and its benefit can better guide the family caregivers in making hospice care decisions.
An Efficient Parallel Triangle Enumeration on the MapReduce Framework

SUMMARY A triangle enumerating problem is one of fundamental problems of graph data. Although several triangle enumerating algorithms based on MapReduce have been proposed, they still su ﬀ er from generating a lot of intermediate data. In this paper, we propose the e ﬃ cient MapReduce algorithms to enumerate every triangle in the massive graph based on a vertex partition. Since a triangle is composed of an edge and a wedge, our algorithms check the existence of an edge connecting the end-nodes of each wedge. To generate every triangle from a graph in parallel, we ﬁrst split a graph into several vertex partitions and group the edges and wedges in the graph for each pair of vertex partitions. Then, we form the triangles appearing in each group. Furthermore, to enhance the performance of our al-gorithm, we remove the duplicated wedges existing in several groups. Our experimental evaluation shows the performance of our proposed algorithm is better than that of the state-of-the-art algorithm in diverse environments.
A metacognitive intervention model to promote independence among individuals with autism spectrum disorder: Implementation on a shopping task in the community

ABSTRACT Adolescents with autism spectrum disorder show low independence levels and difficulty performing complex daily activities. The many intervention approaches for these individuals include deconstructing complex activities into basic components, processing and practicing tasks, and developing compensation strategies. The aim of this study was to examine the effectiveness of a short-term metacognitive intervention combined with virtual supermarket practice to improve the independent implementation of a shopping task among adolescents with autism spectrum disorder. The study included 56 adolescents with autism spectrum disorder, of whom 33 performed the metacognitive intervention and 23 served as controls. Outcome measures included assessments of cognitive and metacognitive functions and a performance-based evaluation of a shopping task in the natural environment. Compared to the control group, the intervention group experienced significant improvement in accuracy and efficiency while performing a shopping task. In addition, the executive functions domain was found to be the main predictor of accuracy and efficiency in performing the shopping task. These findings indicate the short-term metacognitive intervention, reinforced by a technology-based training programme, may effectively enhance the independent execution of a shopping task by adolescents with autism spectrum disorder and expand their potential participation in the community.