Miracle-dz/UniFAR-FTUs huggingface dataset:
Randomness, Structural Uniqueness, Modularity and Neutral Evolution in Sequence Space of Model Proteins

The genotype-phenotype map for short chains of a protein-like hetero-polymer model has been characterised [9, 12]. Hydrophobic-Polar (HP) sequences on a square lattice, their structures and partition functions have been exhaustively enumerated and analysed. Homologous sequences folding uniquely into the same structure are interconnected by point mutations. These neutral nets arrange in superfunnel topology as they are centred around prototype sequences which tolerate the largest number of neutral mutations, are thermodynamically most stable, and correspond to what is known as consensus sequences of real protein families. This work briefly summarises the superfunnel concept and reports new results on the non-randomness of sequences, modularity and well-definedness of structures, and variations of sequence positions in nets. Essentially, these features vary smoothly along evolutionarily plausible trajectories and can be qualitatively related to experimental evidence from real world proteins. In summary, results can be understood in the context of the designing-out principle and structural isolation in shape space. The resulting picture offers a unified perspective on evolutionary design, thermodynamic and mutational stability.
Methodological considerations in measuring specific force in human single skinned muscle fibres

Chemically skinned fibres allow the study of human muscle contractile function in vitro. A particularly important parameter is specific force (SF), that is, maximal isometric force divided by cross‐sectional area, representing contractile quality. Although SF varies substantially between studies, the magnitude and cause of this variability remains puzzling. Here, we aimed to summarize and explore the cause of variability in SF between studies. A systematic search was conducted in Medline, Embase and Web of Science databases in June 2020, yielding 137 data sets from 61 publications which studied healthy, young adults. Five‐fold differences in mean SF data were observed. Adjustments to the reported data for key methodological differences allowed between‐study comparisons to be made. However, adjustment for fibre shape, swelling and sarcomere length failed to significantly reduce SF variance (I2 = 96%). Interestingly, grouping papers based on shared authorship did reveal consistency within research groups. In addition, lower SF was found to be associated with higher phosphocreatine concentrations in the fibre activating solution and with Triton X‐100 being used as a skinning agent. Although the analysis showed variance across the literature, the ratio of SF in single fibres containing myosin heavy chain isoforms IIA or I was found to be consistent across research groups. In conclusion, whilst the skinned fibre technique is reliable for studying in vitro force generation of single fibres, the composition of the solution used to activate fibres, which differs between research groups, is likely to heavily influence SF values.
Neutrophils in pregnancy: New insights into innate and adaptive immune regulation

The immunology of pregnancy has been the focus of many studies to better understand how the mother is able to tolerate the presence of a semi‐allogeneic fetus. Far from the initial view of pregnancy as a state of immunosuppression, successful fetal development from implantation to birth is now known to be under the control of an intricate balance of immune cells. The balance between pro‐inflammatory functions used to promote embryo implantation and placental development and immunosuppressive activity to maintain maternal tolerance of the fetus is an immunological phenotype unique to pregnancy, which is dependent on the time of gestation. Neutrophils are one of a host of innate immune cells detected at the maternal–fetal interface, but very little is known of their function. In this review, we explore the emerging functions of neutrophils during pregnancy and their interactions with and regulation of T cells, a key adaptive immune cell population essential for the establishment of fetal–maternal tolerance.
A Relationship between the Characteristics of the Oval Nucleus of the Mesopallium and Parrot Vocal Response to Playback

Correlations between differences in animal behavior and brain structures have been used to infer function of those structures. Brain region size has especially been suggested to be important for an animal’s behavioral capability, controlled by specific brain regions. The oval nucleus of the mesopallium (MO) is part of the anterior forebrain vocal learning pathway in the parrot brain. Here, we compare brain volume and total number of neurons in MO of three parrot species (the peach-fronted conure, Eupsittula aurea, the peach-faced lovebird, Agapornis roseicollis, and the budgerigar, Melopsittacus undulatus), relating the total neuron numbers with the vocal response to playbacks of each species. We find that individuals with the highest number of neurons in MO had the shortest vocal latency. The peach-fronted conures showed the shortest vocal latency and largest number of MO neurons, the peach-faced lovebird had intermediary levels of both, and the budgerigar had the longest latency and least number of neurons. These findings indicate the MO nucleus as one candidate region that may be part of what controls the vocal capacity of parrots.
Long‐term safety and efficacy of add‐on cannabidiol in patients with Lennox–Gastaut syndrome: Results of a long‐term open‐label extension trial

Lennox–Gastaut syndrome (LGS) is an epileptic encephalopathy that is often treatment resistant. Efficacy and safety of add‐on cannabidiol (CBD) to treat seizures associated with LGS was demonstrated in two randomized controlled trials (RCTs). Patients who completed the RCTs were invited to enroll in this long‐term open‐label extension (OLE) trial, GWPCARE5 (NCT02224573). We present the final analysis of safety and efficacy outcomes from GWPCARE5.
Polysubstance Use Is Positively Associated with Gaming Disorder Symptom Severity: A Latent Class Analytical Study

Introduction: The link between gaming disorder (GD) and substance use amongst adolescents is not clear. Some studies reported positive associations, whereas others suggested that alcohol and illicit drug use are not related to GD severity. Objectives: The present study aimed to identify empirically based latent classes of alcohol and illicit drug use amongst adolescents and explore their associations with GD symptom severity and whether endorsement of specific criteria of GD is linked to the membership of latent classes of alcohol and illicit drug use. Methods: Data of the national sample of Hungarian adolescents from the Health Behaviour in School-aged Children survey (N = 2,768; females: 52.08%; mean age: 16.73 years) were analysed. Measures for frequency of alcohol and illicit drug use, gaming, GD symptom severity, and life satisfaction were included in the analyses. Results: Latent class analysis discriminated 4 subgroups of alcohol and illicit drug use: polysubstance users, high-risk alcohol users, moderate alcohol users, and infrequent substance users. Polysubstance users presented significantly higher levels of GD symptom severity and higher odds for endorsement of criteria of “giving up other activities” and “negative consequences. ” Conclusions: Positive associations were shown between higher GD severity and the polysubstance using class. The roles of criteria of “giving up other activities” and “negative consequences” were highlighted in more severe substance use patterns. However, GD severity and criteria did not differ as a function of the level of alcohol use. These findings may imply common roots of GD and illicit drug use in adolescents.
Meet your MAKR: the membrane‐associated kinase regulator protein family in the regulation of plant development

A small family composed of BRI1 KINASE INHIBITOR1 (BKI1) and MEMBRANE‐ASSOCIATED KINASE REGULATORS (MAKRs) has recently captured the attention of plant biologists, due to their involvement in developmental processes downstream of hormones and Receptor‐Like Kinases (RLK) signalling. BKI1/MAKRs are intrinsically disordered proteins (so‐called unstructured proteins) and as such lack specific domains. Instead, they are defined by the presence of two conserved linear motifs involved in the interaction with lipids and proteins, respectively. Here, we first relate the discovery of the MAKR gene family. Then, we review the individual function of characterized family members and discuss their shared and specific modes of action. Finally, we explore and summarize the structural, comparative and functional genomics data available on this gene family. Together, this review aims at building a comprehensive reference about BKI1/MAKR protein function in plants.
Carbohydrates to Prevent and Treat Obesity in a Murine Model of Diet-Induced Obesity

Introduction: The biggest risk factor for obesity and its associated comorbidities is a Western diet. This Western diet induces adipose tissue (AT) inflammation, which causes an AT dysfunction. Since AT is a vital endocrine organ, its dysfunction damages other organs, thus inducing a state of chronic inflammation and causing various comorbidities. Even though it is evident a Western diet, high in fat and carbohydrates, induces obesity and its complications, it is not known yet which macronutrient plays the most important role. Therefore, the aim of this study was to investigate the effect of macronutrient composition on obesity and to reverse the Western diet-induced metabolic risk via caloric restriction (CR) or a change of diet composition. Materials and Methods: Male, C57BL/6JRj mice were fed with a diet high in fat, sucrose, fructose, sucrose and fructose, starch, a Western diet, or a control diet for 15 weeks. To assess reversibility of the metabolic risk, mice were first made obese via 15 weeks of WD and then put on either a CR or switched to a sucrose-rich diet. Results: A sucrose-rich and high-starch diet induced less obesity and a better metabolic profile than a Western diet, evidenced by less hepatic steatosis, lower plasma cholesterol, and less insulin resistance. Furthermore, these diets induced less intra-abdominal AT inflammation than a Western diet, since mRNA levels of pro-inflammatory markers were lower and there was less macrophage infiltration. Expression of tight junction markers in colon tissue was higher in the sucrose-rich and high-starch group than the Western group, indicating a better intestinal integrity upon sucrose-rich and high-starch feeding. Additionally, CR induced weight loss and decreased both metabolic abnormalities and AT inflammation, regardless of macronutrient composition. However, effects were more pronounced upon CR with sucrose-rich or high-starch diet. Even without CR, switching obese mice to a sucrose-rich diet induced weight loss and decreased AT inflammation and metabolic aberrations. Discussion: A diet high in sucrose or starch induces less obesity and obesity-associated complications. Moreover, switching obese mice to a sucrose-rich diet elicits weight loss and decreases obesity-induced metabolic complications, highlighting the potential of carbohydrates to treat obesity.
Reflecting on Palliative Care Integration in Canada: A Qualitative Report

Studies have identified integrated interdisciplinary care as a hallmark of effective palliative care. Although models attempt to show how integration may function, there is little literature available that practically explores how integration is fostered and maintained. In this study we asked palliative care clinicians across Canada to comment on how services are integrated across the healthcare system. This is an analysis of qualitative data from a larger study, wherein clinicians provided written responses regarding their experiences. Content analysis was used to identify response categories. Clinicians (n = 14) included physicians, a nurse and a social worker from six provinces. They identified the benefits of formalized relationships and collaboration pathways with other services to streamline referral and consultation. Clinicians perceived a need for better training of residents and primary care physicians in the community and more acceptance, shared understanding, and referrals. Clinicians also described integrating well with oncology departments. Lastly, clinicians considered integration a complex process with departmental, provincial, and national involvement. The needs and strengths identified by the clinicians mirror the qualities of successfully integrated palliative care programs globally and highlight specific areas in policy, education, practice, and research that could benefit those in Canada.
A community-engaged approach to examining barriers and facilitators to accessing autism services in Korean immigrant families

This study adopted a community-engaged approach to explore Korean parents’ perceptions of barriers and facilitators to accessing autism services in British Columbia, Canada. Understanding the experiences of culturally and linguistically diverse families and their children may help facilitate the development of more inclusive, appropriate, and culturally sensitive services. Semi-structured interviews with 20 Korean parents of autistic children were analyzed using a thematic approach. Barriers and facilitators at the system, provider, and family/cultural level were identified. Barriers at the system level included delays and waitlists for services, and ineffective school policies to address child behavioral challenges. At the provider level, barriers included a lack of qualified professionals, negative attitudes, and lack of guidance navigating services. For family/cultural-related barriers, language and communication difficulties, out-of-pocket costs, and stigma impeded service access. Facilitators at the system level included family-centered care and prioritization of mental health supports. At the provider level, strengths included culturally competent and bilingual professionals. The family/cultural-related facilitators identified were informal support networks, characteristics of the parent, and connections to cultural community organizations. The findings emphasize the need to understand and consider diverse experiences, preferences, and values in the design and provision of autism services for families and their children. Lay abstract Perceptions and experiences of culturally and linguistically diverse groups in accessing autism services in Canada are extremely limited. Thus, this study partnered with a community member to explore Korean immigrant parents’ perceptions of barriers and facilitators to accessing autism services in British Columbia, Canada. Interviews were conducted with 20 Korean parents of autistic children. Barriers and facilitators at the system, provider, and family/cultural level were identified. Barriers at the system level included delays and waitlists for services, and ineffective school policies to address child behavioral challenges. At the provider level, barriers included a lack of qualified professionals, negative attitudes, and lack of guidance navigating services. For family/cultural-related barriers, these included language and communication difficulties, out-of-pocket costs, and stigma impeded service access. Facilitators at the system level included family-centered care and prioritization of mental health supports. At the provider level, strengths included culturally competent and bilingual professionals. The family/cultural-related facilitators identified were informal support networks, characteristics of the parent, and connections to cultural community organizations. The findings emphasize the need to understand and consider diverse experiences, preferences, and values in the design and provision of autism services for families and their children.
Measuring Catastrophic Costs Due to Tuberculosis in Myanmar

Background: This is the first survey to use the World Health Organization (WHO) methodology to document the magnitude and main drivers of tuberculosis (TB) patient costs in order to guide policies on cost mitigation and to produce a baseline measure for the percentage of TB-affected households experiencing catastrophic costs in Myanmar. Methods: A nationally representative cross-sectional survey was administered to 1000 TB patients in health facilities from December 2015 to February 2016, focusing on costs of TB treatment (direct and indirect), household income, and coping strategies. A total cost was estimated for each household by extrapolating reported costs and comparing them to household income. If the proportion of total costs exceeded 20% of the annual household income, a TB-affected household was deemed to have faced catastrophic costs. Results: 60% of TB-affected households faced catastrophic costs in Myanmar. On average, total costs were USD 759, and the largest proportion of this total was accounted for by patient time (USD 365), followed by food costs (USD 200), and medical expenses (USD 130). Low household wealth quintile and undergoing MDR-TB treatment were both significant predictors for households facing catastrophic costs. Conclusions: The high proportion of TB-affected households experiencing catastrophic costs suggests the need for TB-specific social protection programs in patient-centered healthcare. The survey findings have led the government and donors to increase support for MDR-TB patients. The significant proportion of total spending attributable to lost income and food or nutritional supplements suggests that income replacement programs and/or food packages may ameliorate the burdensome costs.
Prenatal Diagnosis of Fetal Lymphangioma: A Case Series

Fetal lymphangioma is an uncommon congenital malformation that is mainly comprised of the subcutaneous tissue of the neck. This malformation can develop in other areas like the thoracic and axillary regions, though rarely. We report 6 consecutive cases of lymphatic malformation in a fetal center in Dominican Republic. In our case series fetal chest lymphangiomas were present in 2 fetuses. In addition, 2 cases of axillary lymphangiomas also involved the thoracic region. Adequate management by a multidiciplinary team is necessary to provide a better approach to delivery.
N-glycosylation of immunoglobulin G predicts incident hypertension

Supplemental Digital Content is available in the text Objectives: Glycosylation of immunoglobulin G (IgG) is an important regulator of the immune system and has been implicated in prevalent hypertension. The aim of this study is to investigate whether the IgG glycome begins to change prior to hypertension diagnosis by analysing the IgG glycome composition in a large population-based female cohort with two independent replication samples. Methods: We included 989 unrelated cases with incident hypertension and 1628 controls from the TwinsUK cohort (mean follow-up time of 6.3 years) with IgG measured at baseline by ultra-performance liquid chromatography and longitudinal BP measurement available. We replicated our findings in 106 individuals from the 10 001 Dalmatians and 729 from KORA S4. Cox regression mixed models were applied to identify changes in glycan traits preincident hypertension, after adjusting for age, mean arterial pressure, BMI, family relatedness and multiple testing (FDR < 0.1). Significant IgG-incident hypertension associations were replicated in the two independent cohorts by leveraging Cox regression mixed models in the 10 001 Dalmatians and logistic regression models in the KORA cohort. Results: We identified and replicated four glycan traits, incidence of bisecting GlcNAc, GP4, GP9 and GP21, that are predictive of incident hypertension after adjusting for confoundes and multiple testing [hazard ratio (95% CI) ranging from 0.45 (0.24–0.84) for GP21 to 2.9 (1.5–5.68) for GP4]. We then linearly combined the four replicated glycans and found that the glycan score correlated with incident hypertension, SBP and DBP. Conclusion: Our results suggest that the IgG glycome changes prior to the development of hypertension.
Muscle‐derived exophers promote reproductive fitness

Organismal functionality and reproduction depend on metabolic rewiring and balanced energy resources. However, the crosstalk between organismal homeostasis and fecundity and the associated paracrine signaling mechanisms are still poorly understood. Using Caenorhabditis elegans, we discovered that large extracellular vesicles (known as exophers) previously found to remove damaged subcellular elements in neurons and cardiomyocytes are released by body wall muscles (BWM) to support embryonic growth. Exopher formation (exopheresis) by BWM is sex‐specific and a non‐cell autonomous process regulated by developing embryos in the uterus. Embryo‐derived factors induce the production of exophers that transport yolk proteins produced in the BWM and ultimately deliver them to newly formed oocytes. Consequently, offspring of mothers with a high number of muscle‐derived exophers grew faster. We propose that the primary role of muscular exopheresis is to stimulate reproductive capacity, thereby influencing the adaptation of worm populations to the current environmental conditions.
Expert review and recommendations for the management of acute, chronic, and neuropathic pain in Qatar.

BACKGROUND Pain management is an evolving area of expertise in Qatar. Gaps in knowledge, inadequate training for physicians and nurses, and the absence of policies/guidelines are the main barriers to effective pain management in Qatar. In addition, the use of certain pain medication, especially opioids, is highly regulated, limiting their availability in outpatient pain management. These factors are responsible for the undertreatment of pain in Qatar. This study aimed to standardize evidence-based local recommendations for pharmacological treatment of pain in Qatar. METHODS An expert panel of physicians from different disciplines, with experience in diagnosis and treatment of the three pain types (i.e., acute, chronic, and neuropathic), was convened for two face-to-face meetings in Doha, Qatar, on November 29, 2019, and on February 22, 2020, with subsequent virtual meetings. A literature search was performed on Medline and Google Scholar databases from inception till December 2019, and all relevant articles were selected. Based on these articles and repeated feedback from the authors, the final pain treatment protocols were developed. RESULTS Recommendations for the treatment of acute pain, based on pain severity, followed three approaches: acetaminophen/paracetamol or non-steroidal anti-inflammatory drugs (NSAIDs) for mild pain and moderate pain and referral to a pain specialist for severe pain. Acetaminophen/paracetamol or NSAIDs is recommended for chronic pain, and the use of opioids was strongly discouraged because of its long-term side effects. For neuropathic pain, tricyclic antidepressants or gabapentin or pregabalin or serotonin-norepinephrine reuptake inhibitors were recommended first-line agents. Non-responders must be referred to neurologists or a pain specialist. CONCLUSION The expert panel provides recommendations for the management of acute, chronic, and neuropathic pain based on international guidelines adapted to local practice and treatment availability in Qatar. More importantly, the panel has recommended taking extreme caution in the use of opioids for long-term management of chronic pain and to refer the patient to a pain specialist clinician as required.
Viridans Group Streptococci in Pediatric Leukemia and Stem Cell Transplant: Review of a Risk-stratified Guideline for Empiric Vancomycin in Febrile Neutropenia

Supplemental Digital Content is available in the text. Viridans group streptococci (VGS) are an important cause of sepsis in immunosuppressed children. We reviewed the effectiveness of risk-stratified addition of vancomycin to empiric febrile neutropenia therapy among 107 children with leukemia or undergoing an allogeneic transplant. Of 19 VGS bacteremia episodes, 78.9% were susceptible to risk-stratified antibiotics including 100% from high-risk patients. All blood cultures were flagged positive within 24 hours.