Miracle-dz/UniFAR-FTUs huggingface dataset:
Universal stabilization of the influenza hemagglutinin by structure-based redesign of the pH switch regions

Significance Influenza hemagglutinin (HA) is a prototypical class I fusion protein and a major component of current flu vaccines. HA is a metastable glycoprotein and undergoes conformational changes to the so-called postfusion state. Stabilization of the prefusion conformations of fusion proteins has proven to be a key success factor for the induction of efficacious immune response and stabilization has become a grand challenge in structural vaccinology. The study shows that three stabilizing mutations in two important pH-sensitive switch regions involved in the early refolding process impede refolding of the prefusion HA. Based on the substitutions of these highly conserved and buried HA residues a generally applicable stabilization strategy for all subtypes of group 1 and 2 influenza A HA was developed. For an efficacious vaccine immunogen, influenza hemagglutinin (HA) needs to maintain a stable quaternary structure, which is contrary to the inherently dynamic and metastable nature of class I fusion proteins. In this study, we stabilized HA with three substitutions within its pH-sensitive regions where the refolding starts. An X-ray structure reveals how these substitutions stabilize the intersubunit β-sheet in the base and form an interprotomeric aliphatic layer across the stem while the native prefusion HA fold is retained. The identification of the stabilizing substitutions increases our understanding of how the pH sensitivity is structurally accomplished in HA and possibly other pH-sensitive class I fusion proteins. Our stabilization approach in combination with the occasional back mutation of rare amino acids to consensus results in well-expressing stable trimeric HAs. This repair and stabilization approach, which proves broadly applicable to all tested influenza A HAs of group 1 and 2, will improve the developability of influenza vaccines based on different types of platforms and formats and can potentially improve efficacy.
The Effect of Neck Assistive Device Considering Mckenzie Type Subjects with Forward Head Posture

PURPOSE: The aim of this study was to determine the effect of device considering Mckenzie type for the subjects with forward head posture (FHP). METHODS: The subjects were 35 patients with FHP (mean age was years; mean height; , mean weight; , mean NDI(Neck Disability Index; , mean FHP; ). We measured the posture with the Body style S-8.0(LU Commerce, South Korea) to evaluate the FHP. We collected the surface EMG(Myosystem 1400, Noraxon, USA) data to quantify changes in normalized activation levels of muscles in SternoCleidoMastoid muscle(SCM), Scalenus Anterior(SA), Trapezius upper fiber(TU) and Splenius Cervicis(SC), during the subjects were instructed to glide their head into a "chin-in" position for a retraction without and with device. RESULTS: The condition with device significantly decreased the %RVC of SA(), SCM() and TU() compared to the condition without device(SA;, SCM;, Trapezius;). But the %RVC of capitis() with device was increased(). There was significant difference in the %RVC between SCM and Trapezius muscle in two conditions. CONCLUSION: New device for FHP reduces the EMG activities of the TU, SCM and SA muscle. We have to develop the function of feedback to facilitate the motion in the future.
Formal Health and Social Services That Directly and Indirectly Benefit Stroke Caregivers: A Scoping Review of Access and Use

Stroke can be a life altering event that necessitates considerable amounts of formal and informal care. The impacts of stroke often persist over time requiring ongoing support for stroke survivors. Family members provide the majority of care and experience many life changes as a result of their caregiving role including social, financial, employment and health impacts. Formal supports such as counselling, respite, and health promotion initiatives that directly benefit caregivers or benefit them indirectly through supporting the stroke survivor, are well-placed to help caregivers manage their caregiving role. However, to date little is known about formal service use by stroke caregivers and the factors that influence their service use. This scoping review provides a critique and synthesis of what is known about stroke caregivers’ access and use of formal services intended to support them. Findings suggest that while services are available, caregivers’ ability to use them are impacted by both facilitators and barriers. Facilitators included: sex, age, and having a higher household income (depending on services used). Barriers included: high cost, poor service quality and deficient knowledge/communication regarding service availability. This review highlights a significant gap in our knowledge of caregivers’ experience in accessing and using formal services.
Coupled changes in pH, temperature, and dissolved oxygen impact the physiology and ecology of herbivorous kelp forest grazers

Understanding species’ responses to upwelling may be especially important in light of ongoing environmental change. Upwelling frequency and intensity are expected to increase in the future, while ocean acidification and deoxygenation are expected to decrease the pH and dissolved oxygen (DO) of upwelled waters. However, the acute effects of a single upwelling event and the integrated effects of multiple upwelling events on marine organisms are poorly understood. Here, we use in situ measurements of pH, temperature, and DO to characterize the covariance of environmental conditions within upwelling‐dominated kelp forest ecosystems. We then test the effects of acute (0–3 days) and chronic (1–3 months) upwelling on the performance of two species of kelp forest grazers, the echinoderm, Mesocentrotus franciscanus, and the gastropod, Promartynia pulligo. We exposed organisms to static conditions in a regression design to determine the shape of the relationship between upwelling and performance and provide insights into the potential effects in a variable environment. We found that respiration, grazing, growth, and net calcification decline linearly with increasing upwelling intensity for M. francicanus over both acute and chronic timescales. Promartynia pulligo exhibited decreased respiration, grazing, and net calcification with increased upwelling intensity after chronic exposure, but we did not detect an effect over acute timescales or on growth after chronic exposure. Given the highly correlated nature of pH, temperature, and DO in the California Current, our results suggest the relationship between upwelling intensity and growth in the 3‐month trial could potentially be used to estimate growth integrated over long‐term dynamic oceanographic conditions for M. franciscanus. Together, these results indicate current exposure to upwelling may reduce species performance and predicted future increases in upwelling frequency and intensity could affect ecosystem function by modifying the ecological roles of key species.
Emerging therapeutic targets for epilepsy: preclinical insights

ABSTRACT Introduction Around 30% of patients with epilepsy suffer from drug-resistant seizures. Drug-resistant seizures may have significant consequences such as sudden death in epilepsy, injuries, memory disturbances, and childhood learning and developmental problems. Available antiepileptic drugs (AEDs) work via numerous mechanisms – mainly through inhibition of voltage-operated Na+ and/or Ca2+ channels, excitation of K+ channels, enhancement of GABA-mediated inhibition and/or blockade of glutamate-produced excitation. However, the discovery and development of novel brain targets may improve the future pharmacological management of epilepsy and hence is of pivotal importance. Areas covered This article examines novel drug targets such as brain multidrug efflux transporters and inflammatory pathways; it progresses to discuss possible strategies for the management of drug-resistant seizures. Reduction of the consequences of blood brain barrier dysfunction and enhancement of anti-oxidative defense are discussed. Expert Opinion Novel drug targets comprise brain multidrug efflux transporters, TGF-β, Nrf2-ARE or m-TOR signaling and inflammatory pathways. Gene therapy and antagomirs seem the most promising targets. Epileptic foci may be significantly suppressed by viral-vector-mediated gene transfer, leading to an increased in situ concentration of inhibitory factors (for instance, galanin). Also, antagomirs offer a promising possibility of seizure inhibition by silencing micro-RNAs involved in epileptogenesis and possibly in seizure generation.
Higher SBP in female patients with mitochondrial disease

Background: Previous research suggests that hypertension is more prevalent among patients with mitochondrial diseases. Blood pressure (BP) is linearly related to increased cardiovascular risk, and this relationship is strongest for SBP; nevertheless, studies on SBP and DBP in mitochondrial diseases have not yet been performed. Method: In a retrospective case–control study design, BP in mitochondrial disease patients was compared with BP in a population cohort. Secondly, using multiple linear regression, we examined blood pressure differences in various genetic mitochondrial diseases. Lastly, we explored additional predictors of BP in a subgroup with the m.3243A > G variant. Results: Two hundred and eighty-six genetically confirmed mitochondrial disease patients were included. One hundred and eighty of these patients carried the m.3243A>G mitochondrial DNA variant. SBP was 9 mmHg higher in female mitochondrial disease patients than in the general female population (95% CI: 4.4–13.3 mmHg, P < 0.001), whereas male patients had similar BP compared with controls. BP was not significantly different in patients with m.8344A>G and m.8363G>A, a mtDNA deletion or a nuclear mutation compared with m.3243A>G patients. Higher SBP was a predictor for left ventricular hypertrophy in the m.3243A>G subgroup (P = 0.04). Conclusion: Novel aspects of the role of mitochondrial dysfunction in blood pressure regulation are exposed in this study. Compared with the general population, female mitochondrial disease patients have a higher SBP. Left ventricular hypertrophy is more prevalent in patients with higher SBP. Clinicians should be aware of this to prevent hypertensive complications in mitochondrial disease patients.
Hypertension screening, awareness, treatment, and control: a study of their prevalence and associated factors in a nationally representative sample from Nepal

ABSTRACT Background The growing burden of hypertension is emerging as one of the major healthcare challenges in low- and middle-income countries (LMICs), such as Nepal. Given that they are struggling to deliver adequate health services, some LMICs have significant gaps in the cascade of hypertension care (including screening, awareness, treatment, and control). This results in uncontrolled hypertension, placing a high burden on both patients and healthcare providers. Objective The objective of this study was to quantify the gaps in hypertension screening, awareness, treatment, and control in the Nepalese population. Methods We used the data from a pooled sample of 9682 participants collected through two consecutive STEPwise approach to Surveillance (STEPS) surveys conducted in Nepal in 2013 and 2019. A multistage cluster sampling method was applied in the surveys, to select nationally representative samples of 15- to 69-year-old Nepalese individuals. Prevalence ratios were calculated using multivariable Poisson regression. Results Among the hypertensive participants, the prevalence of hypertension screening was 65.9% (95% CI: 62.2, 69.5), the prevalence of hypertension awareness was 20% (95% CI: 18.1, 22.1), the prevalence of hypertension treatment was 10.3% (95% CI: 8.8, 12.0), and the prevalence of hypertension control was 3.8% (95% CI: 2.9, 4.9). The unmet need of hypertension treatment and control was highest amongst the poorest individuals, the participants from Lumbini and Sudurpaschim provinces, those who received treatment in public hospitals, the uninsured, and those under the age of 30 years. Conclusions The gaps in the cascade of hypertension care in Nepal are large. These gaps are particularly pronounced among the poor, persons living in Lumbini and Sudurpaschim provinces, those who sought treatment in public hospitals, those who did not have health insurance, and young people. National- and local-level public health interventions are needed to improve hypertension screening, awareness, treatment, and control in Nepal.
Investigating Bilateral Cochlear Implant Users' Localization of Amplitude- and Time-Panned Stimuli Produced Over a Limited Loudspeaker Arrangement.

OBJECTIVE The objective of this study was to investigate the localization ability of bilateral cochlear implant (BiCI) users for virtual sound sources produced over a limited loudspeaker arrangement. DESIGN Ten BiCI users and 10 normal-hearing subjects participated in listening tests in which amplitude- and time-panned virtual sound sources were produced over a limited loudspeaker setup with varying azimuth angles. Three stimuli were utilized: speech, bandpassed pink noise between 20 Hz and 1 kHz, and bandpassed pink noise between 1 kHz and 8 kHz. The data were collected via a two-alternative forced-choice procedure and used to calculate the minimum audible angle (MAA) of each subject, which was subsequently compared to the results of previous studies in which real sound sources were employed. RESULT The median MAAs of the amplitude-panned speech, low-frequency pink noise, and high-frequency pink noise stimuli for the BiCI group were calculated to be 20°, 38°, and 12°, respectively. For the time-panned stimuli, the MAAs of the BiCI group for all three stimuli were calculated to be close to the upper limit of the listening test. CONCLUSIONS The computed MAAs of the BiCI group for amplitude-panned speech were marginally larger than BiCI users' previously reported MAAs for real sound sources, whereas their computed MAAs for the time-panned stimuli were significantly larger. Subsequent statistical analysis indicated a statistically significant difference in the performances of the BiCI group in localizing the amplitude-panned sources and the time-panned sources. It follows that time-panning over limited loudspeaker arrangements may not be a useful clinical tool, whereas amplitude-panning utilizing such a setup may be further explored as such. Additionally, a comparison with the patient demographics indicated correlations between the results and the patients' age at time of diagnoses and the time passed between date of diagnosis and their implant surgeries.
Cannabis and cannabinoids: pharmacology and therapeutic potential.

INTRODUCTION Cannabis (also known as marijuana) is the most frequently used psychoactive substance in the world. The role of cannabis in medicine is rapidly evolving, and advances in the understanding of its pharmacology have led to numerous proposed uses of these drugs. STATE OF THE ART Cannabis contains Δ9-tetrahydrocannabinol and cannabidiol as the primary constituents responsible for pharmacological activity. It is now known that there are at least two types of cannabinoid receptors. CB1 receptors are found mainly in the CNS, and their primary role is to inhibit the release of neurotransmitters. CB2 receptors' leading role is to modulate cytokine release and immune cell migration. Colocalisation of cannabinoid receptors with other types of nervous system receptors allows them to interact with many other transmitters such as dopamine, noradrenaline, acetylcholine, gamma-aminobutyric acid, serotonin, and glutamic and aspartic acids. CLINICAL IMPLICATIONS The rapidly expanding understanding regarding cannabinoids led to initial attempts to treat selected diseases with cannabinoid receptor agonists and antagonists. The most promising of these was the potential possibility of treating diseases for which current therapy is unsatisfactory, such as neurological diseases including multiple sclerosis, spastic muscular tension, extrapyramidal system diseases, neurodegenerative diseases and cerebral ischaemia. Attempts to treat psychiatric diseases (e.g. psychoses, neuroses, mood disorders, and alcohol dependence syndrome) with cannabinoids are much less advanced. FUTURE DIRECTIONS Cannabis and cannabinoids can be widely used to treat several diseases or alleviate symptoms, but their efficacy for specific indications is not always apparent. Further exploration is needed to understand whether the enhanced sensitivity to the cognitive effects of Δ9-THC depends on brain cannabinoid receptor dysfunction, and how these changes contribute to the cognitive deterioration and core pathophysiology symptoms associated with schizophrenia or other neurological and somatoform disorders.
Model‐free robust adaptive integral sliding mode impedance control of knee–ankle–toe active transfemoral prosthesis

Wearing appropriate active prosthesis is the guarantee of daily life for amputees. Normally the controller of the traditional active transfemoral prosthesis is designed based on the mathematical model. The modelling error and the external interference will reduce the control accuracy of the system and make the prosthesis unable to operate in the desired trajectory.
Using Pet Therapy to Decrease Patients’ Anxiety on Two Diverse Inpatient Units

Background: The physical benefits for patients who spend time with a therapy dog have been reported, including decreased anxiety. Pet therapy has decreased anxiety in various hospitalized patient populations. The human–animal bond is the foundation for the positive interaction therapy dogs create. Aims: This study’s purpose was to explore the use of pet therapy as an intervention to decrease patients’ anxiety levels on two diverse inpatient units: Behavioral Health (BHU) and Pediatrics (PEDS). Methods: This was a quantitative study using a convenience sample, with systematic assignment to the experimental and control group. The State Anxiety Scale (SAS), a 6-item, Likert-type Short Form version of the State-Trait Anxiety Inventory, was used with adults and children; a Pediatric Emoji Method was constructed to assist children with the SAS. After consent, both groups completed the SAS pretest. Intervention patients then spent up to 15 minutes with a therapy dog and handler. The SAS posttest was completed 1 hour later by the experimental and control group. Descriptive and inferential statistics were used, including an independent samples t test, paired-sample t test, Wilcoxon signed rank tests, and Spearman correlation coefficients. Results: Findings revealed that the therapy dog visitations had a positive effect on lowering anxiety supporting the hypothesis. Both the PEDS and BHU participants experienced a significant decrease in their anxiety level following the dog visits. Conclusion: Patients on the BHU and PEDS units benefitted from their visit with a therapy dog by experiencing a decrease in their anxiety level.
Temporomandibular joint shape in anthropoid primates varies widely and is patterned by size and phylogeny

The temporomandibular joint is the direct interface between the mandible and the cranium and is critical for transmitting joint reaction forces and determining mandibular range of motion. As a consequence, understanding variation in the morphology of this joint and how it relates to other aspects of craniofacial form is important for better understanding masticatory function. Here, we present a detailed three‐dimensional (3D) geometric morphometric analysis of the cranial component of this joint, the glenoid fossa, across a sample of 17 anthropoid primates, and we evaluate covariation between the glenoid and the cranium and mandible. We find high levels of intraspecific variation in glenoid shape that is likely linked to sexual dimorphism and joint remodeling, and we identify differences in mean glenoid shape across taxonomic groups and in relation to size. Analyses of covariation reveal strong relationships between glenoid shape and a variety of aspects of cranial and mandibular form. Our findings suggest that intraspecific variation in glenoid shape in primates could further be reflective of high levels of functional flexibility in the masticatory apparatus, as has also been suggested for primate jaw kinematics and muscle activation patterns. Conversely, interspecific differences likely reflect larger scale differences between species in body size and/or masticatory function. Results of the covariation analyses dovetail with those examining covariation in the cranium of canids and may be indicative of larger patterns across mammals.
A scoping review of outpatient interventions to support the reduction of prescription opioid medication for chronic non cancer pain

Abstract Background Prescription opioid use is a global health issue. Previous systematic reviews have not identified that any specific intervention supports prescription opioid reduction effectively. In keeping with the nature of a scoping review, this review details an overview of the existing literature on this topic, with quality of evidence being discussed rather than formally analysed. Aim This review aimed to examine and describe outpatient interventions that support the reduction of prescription opioid medication for chronic non cancer pain. Eligibility criteria Abstracts were reviewed against the inclusion criteria of outpatient clinical interventions, for the purpose of prescription opioid dose reduction, offered to adults with CNCP. Sources of evidence Following a structured review approach an electronic database search, of Medline, Embase, Cochrane, Cinahl, and Proquest and grey literature was undertaken. Search results were screened by title for relevance. Charting methods Two reviewers adhering to the PRISMA‐ScR checklist charted and assessed studies for quality using Critical Appraisal Skills Programme checklist assessment tools. Extracted data were collated and synthesised for presentation as a tabular and narrative review. Results From the initial search of 5089 papers, 19 underwent full‐text review and quality appraisal. A variety of interventions were described to support reduction in prescription opioid use, however only one study of at least fair quality was able to demonstrate a demonstrated a statistically significant benefit in reducing measured opioid dose compared with a control group. Interventions were implemented in both specialist pain services and in primary care with multidisciplinary and interdisciplinary clinician care. Barriers and facilitators were observed in both settings. Conclusion and implications for clinical practice Further rigorous research needs to be conducted to conclusively answer the question of what outpatient interventions support opioid reduction in chronic non cancer pain. This scoping review is the first step of inquiry in the development of a nursing intervention to support reduction of prescription opioids.