Miracle-dz/UniFAR-FTUs huggingface dataset:
WDR5 is a conserved regulator of protein synthesis gene expression

Abstract WDR5 is a highly-conserved nuclear protein that performs multiple scaffolding functions in the context of chromatin. WDR5 is also a promising target for pharmacological inhibition in cancer, with small molecule inhibitors of an arginine-binding pocket of WDR5 (the ‘WIN’ site) showing efficacy against a range of cancer cell lines in vitro. Efforts to understand WDR5, or establish the mechanism of action of WIN site inhibitors, however, are stymied by its many functions in the nucleus, and a lack of knowledge of the conserved gene networks—if any—that are under its control. Here, we have performed comparative genomic analyses to identify the conserved sites of WDR5 binding to chromatin, and the conserved genes regulated by WDR5, across a diverse panel of cancer cell lines. We show that a specific cohort of protein synthesis genes (PSGs) are invariantly bound by WDR5, demonstrate that the WIN site anchors WDR5 to chromatin at these sites, and establish that PSGs are bona fide, acute, and persistent targets of WIN site blockade. Together, these data reveal that WDR5 plays a predominant transcriptional role in biomass accumulation and provide further evidence that WIN site inhibitors act to repress gene networks linked to protein synthesis homeostasis.
Memory and preparedness in evaluative conditioning in a smell-taste paradigm. A registered report

ABSTRACT We investigate two questions, (1) the relevance of memory for evaluative conditioning (EC) effects based on smell-taste pairings, and (2) the potential preparedness of smell-taste combinations for yielding EC effects. The relevance of memory for EC effects is a subject of intense research. The majority of studies that investigate the memory-EC relation use visual stimuli and typically show no or relatively small EC effects without memory. For smell-taste combinations, only a few studies exist, with mixed results regarding the role of memory in EC. The idea that there might be a preparedness of smell and taste pairings comes from classical conditioning studies showing preparedness in food aversion and from research on joint processing of smells and tastes. In Experiment 1, we report a conceptual replication of previous studies with smell-taste and picture-taste pairings. In this experiment, we found no evidence for memory-independent EC overall. In a pre-registered Experiment 2, we used a design with smells, pictures, tastes, and sounds to test the role of memory more conclusively and test the preparedness hypothesis for smell-taste pairings. The results support the preparedness hypothesis for smell-taste pairings in EC. Furthermore, as in Experiment 1, we did not find evidence for memory-independent EC.
Value and Health Care Policy Ramifications of Rotator Cuff Repair

The societal burden of rotator cuff disease continues to increase with the aging of our population. Rotator cuff repairs have also become increasingly common over the last 2 decades. In our current cost conscious health care environment it is imperative to understand the value delivered to patients by various interventions. Value is most often equated with outcomes relative to the costs associated with care. To determine the value of different interventions, a thorough understanding of how to measure and interpret patient outcomes is crucial. In addition, calculating costs can be complex and physicians are often unaware of the costs related to their own decisions. Despite the complexities of measuring value, its benefits include heightened transparency in health care delivery, aligning stakeholders, and avoiding the trap of focussing solely on cost reductions, which may endanger effective treatment modalities.
Rehabilitation of companion animals following orthopaedic surgery

ABSTRACT Physical therapy and rehabilitation following orthopaedic surgery in companion animals have become more common and new advancements in this field have been made in recent years. Surgery alone may not return the animal to its previous physical activity or work-related tasks, whether due to concurrent soft tissue trauma, arthrogenic muscle inhibition or osteoarthritis. Rehabilitation therapies following surgery can restore function as well as strength, coordination and balance. Many simple techniques such as cryotherapy and passive range of motion exercises have been shown to improve outcomes following musculoskeletal procedures and may help restore function as well as reduce pain and facilitate healing. Some techniques are more useful during different stages in order to achieve optimum tissue healing and recovery of function. During the first 72 hours, rehabilitation should focus on reduction of inflammation and pain, maintaining joint nutrition and range of motion, and stimulating vascularisation and healing; and may include cryotherapy, passive range of motion exercises, massage and therapeutic exercises. Following the initial recovery period, the goals of rehabilitation also include restoring strength, balance and normal gait patterns, as well as recovery of function. During this period the focus of therapy may shift toward therapeutic exercises, aquatic therapy and increasing activity in the animal. Therapeutic modalities such as neuromuscular electrical stimulation, photobiomodulation (laser therapy), therapeutic ultrasound and extracorporeal shock wave therapy have been reported to reduce pain and inflammation, enhance healing and reduce recovery time in the early and late stages following orthopaedic surgery.
Anatomical study of the brachial plexus in human fetuses and its relation with neonatal upper limb paralysis

ABSTRACT Objective To study the anatomy of the brachial plexus in fetuses and to evaluate differences in morphology during evolution, or to find anatomical situations that can be identified as the cause of obstetric paralysis. Methods Nine fetuses (12 to 30 weeks of gestation) stored in formalin were used. The supraclavicular and infraclavicular parts of the brachial plexus were dissected. Results In its early course, the brachial plexus had a cord-like shape when it passed through the scalene hiatus. Origin of the phrenic nerve in the brachial plexus was observed in only one fetus. In the deep infraclavicular and retropectoralis minor spaces, the nerve fibers of the brachial plexus were distributed in the axilla and medial bicipital groove, where they formed the nerve endings. Conclusion The brachial plexus of human fetuses presents variations and relations with anatomical structures that must be considered during clinical and surgical procedures for neonatal paralysis of the upper limbs.
Polygenic Risk Scores Shed Light on the Relationship between Schizophrenia and Cognitive Functioning: Review and Meta-Analysis

Schizophrenia is a multifactorial disease associated with widespread cognitive impairment. Although cognitive deficits are one of the factors most strongly associated with functional impairment in schizophrenia (SZ), current treatment strategies hardly tackle these impairments. To develop more efficient treatment strategies in patients, a better understanding of their pathogenesis is needed. Recent progress in genetics, driven by large genome-wide association studies (GWAS) and the use of polygenic risk scores (PRS), has provided new insights about the genetic architecture of complex human traits, including cognition and SZ. Here, we review the recent findings examining the genetic links between SZ and cognitive functions in population-based samples as well as in participants with SZ. The performed meta-analysis showed a negative correlation between the polygenetic risk score of schizophrenia and global cognition (p < 0.001) when the samples rely on general and healthy participants, while no significant correlation was detected when the three studies devoted to schizophrenia patients were meta-analysed (p > 0.05). Our review and meta-analysis therefore argues against universal pleiotropy for schizophrenia alleles and cognition, since cognition in SZ patients would be underpinned by the same genetic factors than in the general population, and substantially independent of common variant liability to the disorder.
Prominent White Matter Involvement in Multiple System Atrophy of Cerebellar Type

Sporadic degenerative ataxia patients fall into 2 major groups: multiple system atrophy with predominant cerebellar ataxia (MSA‐C) and sporadic adult‐onset ataxia (SAOA). Both groups have cerebellar volume loss, but little is known about the differential involvement of gray and white matter in MSA‐C when compared with SAOA.
Risks of N95 Face Mask Use in Subjects With COPD

BACKGROUND: The N95 filtering facepiece respirator (FFR) is the most popular individual protective device to reduce exposure to particulate matter. However, concerns have been raised with regard to its use because it can increase respiratory resistance and dead space. Therefore, this study assessed the safety of N95 use in patients with COPD and air-flow limitation. METHODS: This prospective study was performed at a tertiary hospital and enrolled 97 subjects with COPD. The subjects were monitored for symptoms and physiologic variables during a 10-min rest period and 6-min walking test while wearing an N95. RESULTS: Of the 97 subjects, 7 with COPD did not wear the N95 for the entire test duration. This mask-failure group showed higher British modified Medical Research Council dyspnea scale scores and lower FEV1 percent of predicted values than did the successful mask use group. A modified Medical Research Council dyspnea scale score ≥ 3 (odds ratio 167, 95% CI 8.4 to >999.9; P = .008) or a FEV1 < 30% predicted (odds ratio 163, 95% CI 7.4 to >999.9; P = .001) was associated with a risk of failure to wear the N95. Breathing frequency, blood oxygen saturation, and exhaled carbon dioxide levels also showed significant differences before and after N95 use. CONCLUSIONS: This study demonstrated that subjects with COPD who had modified Medical Research Council dyspnea scale scores ≥ 3 or FEV1 < 30% predicted wear N95s only with care.
The mentalizing network and theory of mind mediate adjustment after childhood traumatic brain injury

Abstract Childhood traumatic brain injury (TBI) affects over 600 000 children per year in the United States. Following TBI, children are vulnerable to deficits in psychosocial adjustment and neurocognition, including social cognition, which persist long-term. They are also susceptible to direct and secondary damage to related brain networks. In this study, we examine whether brain morphometry of the mentalizing network (MN) and theory of mind (ToM; one component of social cognition) mediates the effects of TBI on adjustment. Children with severe TBI (n = 15, Mage = 10.32), complicated mild/moderate TBI (n = 30, Mage = 10.81) and orthopedic injury (OI; n = 42, Mage = 10.65) completed measures of ToM and executive function and underwent MRI; parents rated children’s psychosocial adjustment. Children with severe TBI demonstrated reduced right-hemisphere MN volume, and poorer ToM, vs children with OI. Ordinary least-squares path analysis indicated that right-hemisphere MN volume and ToM mediated the association between severe TBI and adjustment. Parallel analyses substituting the central executive network and executive function were not significant, suggesting some model specificity. Children at greatest risk of poor adjustment after TBI could be identified based in part on neuroimaging of social brain networks and assessment of social cognition and thereby more effectively allocate limited intervention resources.
Bacterial, Gut Microbiome-Modifying Therapies to Defend against Multidrug Resistant Organisms

Antibiotics have revolutionized human and animal healthcare, but their utility is reduced as bacteria evolve resistance mechanisms over time. Thankfully, there are novel antibiotics in the pipeline to overcome resistance, which are mentioned elsewhere in this special issue, but eventually bacteria are expected to evolve resistance to most new compounds as well. Multidrug resistant organisms (MDROs) that cause infections increase morbidity, mortality, and readmissions as compared with susceptible organisms. Consequently, many research and development pipelines are focused on non-antibiotic strategies, including fecal microbiota transplantation (FMT), probiotics and prebiotics, and a range of therapies in between. Studies reviewed here focus on efforts to directly treat or prevent MDRO infections or colonization. The studies were collected through clinicaltrials.gov, PubMed, and the International Conference on the Harmonisation Good Clinical Practice website (ichgcp.net). While the gold standard of clinical research is randomized controlled trials (RCTs), several pilot studies are included because the field is so young. Although a vast preclinical body of research has led to studies in humans, animal and in vitro studies are not within the scope of this review. This narrative review discusses microbiome-modifying therapies targeting MDROs in the gut and includes current results, ongoing clinical trials, companies with therapies in the pipeline specifically for MDROs, and commentary on clinical implementation and challenges.
Inflammation in Post-Traumatic Stress Disorder (PTSD): A Review of Potential Correlates of PTSD with a Neurological Perspective

Post-traumatic stress disorder (PTSD) is a chronic condition characterized by symptoms of physiological and psychosocial burden. While growing research demonstrated signs of inflammation in PTSD, specific biomarkers that may be representative of PTSD such as the detailed neural correlates underlying the inflammatory responses in relation to trauma exposure are seldom discussed. Here, we review recent studies that explored alterations in key inflammatory markers in PTSD, as well as neuroimaging-based studies that further investigated signs of inflammation within the brain in PTSD, as to provide a comprehensive summary of recent literature with a neurological perspective. A search was conducted on studies published from 2009 through 2019 in PubMed and Web of Science. Fifty original articles were selected. Major findings included elevated levels of serum proinflammatory cytokines in individuals with PTSD across various trauma types, as compared with those without PTSD. Furthermore, neuroimaging-based studies demonstrated that altered inflammatory markers are associated with structural and functional alterations in brain regions that are responsible for the regulation of stress and emotion, including the amygdala, hippocampus, and frontal cortex. Future studies that utilize both central and peripheral inflammatory markers are warranted to elucidate the underlying neurological pathway of the pathophysiology of PTSD.
Physiological, behavioral and subjective sadness reactivity in frontotemporal dementia subtypes

Abstract Frontotemporal dementia (FTD), a neurodegenerative disease broadly characterized by socioemotional impairments, includes three clinical subtypes: behavioral variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA) and non-fluent variant primary progressive aphasia (nfvPPA). Emerging evidence has shown emotional reactivity impairments in bvFTD and svPPA, whereas emotional reactivity in nfvPPA is far less studied. In 105 patients with FTD (49 bvFTD, 31 svPPA and 25 nfvPPA) and 27 healthy controls, we examined three aspects of emotional reactivity (physiology, facial behavior and subjective experience) in response to a sad film. In a subset of the sample, we also examined the neural correlates of diminished aspects of reactivity using voxel-based morphometry. Results indicated that all three subtypes of FTD showed diminished physiological responding in respiration rate and diastolic blood pressure; patients with bvFTD and svPPA also showed diminished subjective experience, and no subtypes showed diminished facial behavior. Moreover, there were differences among the clinical subtypes in brain regions where smaller volumes were associated with diminished sadness reactivity. These results show that emotion impairments extend to sadness reactivity in FTD and underscore the importance of considering different aspects of sadness reactivity in multiple clinical subtypes for characterizing emotional deficits and associated neurodegeneration in FTD.
Maternal education and language development at 2 years corrected age in children born very preterm: results from a European population-based cohort study

Background Socioeconomic factors influence language development in the general population, but the association remains poorly documented in children born very preterm (VPT). We assessed the impact of maternal education on language development in children born VPT and effect modification by perinatal risk. Methods Data were from the Effective Perinatal Intensive Care in Europe (EPICE) population-based cohort of children born <32 weeks’ gestational age (GA) in 2011/2012. Regions from six countries (Estonia, France, Germany, Italy, Sweden and UK) used a validated short form MacArthur Developmental Communicative Inventories Checklist to assess language at 2 years corrected age. Perinatal variables were collected from clinical records. We assessed expressive language delay (ELD), defined as (a) not combining words; and (b) expressive vocabulary <10th percentile of norms for age and sex. Perinatal risk (low, moderate and high) was determined using GA, small for GA and neonatal morbidities. We estimated adjusted risk ratios (aRR) of ELD by maternal education with inverse weighting to account for non-response bias. Results Of 2741 children, 24.6% were not combining words and 39.7% had a low expressive vocabulary. Low maternal education (lower secondary or less compared with a bachelor’s degree or more) increased risks of ELD: not combining words: aRR=1.52 (95% CI 1.36 to 1.69); low expressive vocabulary: aRR=1.25 (1.04 to 1.51). For children with low perinatal risk, the aRR were 1.88 (1.26 to 2.80) and 1.44 (1.06 to 1.95), respectively, compared with those with high perinatal risks: 1.36 (1.10 to 1.67) and 1.11 (0.97 to 1.27), respectively. Conclusion Low maternal education affects ELD for children born VPT, although the association appears attenuated among those with highest perinatal risk.
RNA Editing as a Therapeutic Approach for Retinal Gene Therapy Requiring Long Coding Sequences

RNA editing aims to treat genetic disease through altering gene expression at the transcript level. Pairing site-directed RNA-targeting mechanisms with engineered deaminase enzymes allows for the programmable correction of G>A and T>C mutations in RNA. This offers a promising therapeutic approach for a range of genetic diseases. For inherited retinal degenerations caused by point mutations in large genes not amenable to single-adeno-associated viral (AAV) gene therapy such as USH2A and ABCA4, correcting RNA offers an alternative to gene replacement. Genome editing of RNA rather than DNA may offer an improved safety profile, due to the transient and potentially reversible nature of edits made to RNA. This review considers the current site-directing RNA editing systems, and the potential to translate these to the clinic for the treatment of inherited retinal degeneration.
Sodium Chloride Induced Stress Responses of Antioxidative Activities in Leaves and Roots of Pistachio Rootstock

Salinity substantially affects plant growth and crop productivity worldwide. Plants adopt several biochemical mechanisms including regulation of antioxidant biosynthesis to protect themselves against the toxic effects induced by the stress. One-year-old pistachio rootstock exhibiting different degrees of salinity tolerance were subjected to sodium chloride induced stress to identify genetic diversity among cultivated pistachio rootstock for their antioxidant responses, and to determine the correlation of these enzymes to salinity stress. Leaves and roots were harvested following NaCl-induced stress. The results showed that a higher concentration of NaCl treatment induced oxidative stress in the leaf tissue and to a lesser extent in the roots. Both tissues showed an increase in ascorbate peroxidase, superoxide dismutase, catalase, glutathione reductase, peroxidase, and malondialdehyde. Responses of antioxidant enzymes were cultivar dependent, as well as temporal and dependent on the salinity level. Linear and quadratic regression model analysis revealed significant correlation of enzyme activities to salinity treatment in both tissues. The variation in salinity tolerance reflected their capabilities in orchestrating antioxidant enzymes at the roots and harmonized across the cell membranes of the leaves. This study provides a better understanding of root and leaf coordination in regulating the antioxidant enzymes to NaCl induced oxidative stress.
Effect of graft positioning on dissipated energy in knee osteochondral autologous transplantation—A biomechanical study

Focal cartilage defects can be treated by osteochondral autologous transplantation (OAT). High congruence of the graft with the surrounding cartilage structure is essential for a good clinical outcome, but can not always be achieved. We recently established a method to measure dissipated energy (DE) as a friction parameter in knee joints. We now investigated how autograft harvesting and implant positioning affect the DE during knee motion. Six sheep knee joints were cyclically motioned under 400 N axial load. During the cyclic motion, the flexion angle and the respective torque were recorded and the DE was calculated. Several experimental conditions were tested: first, the DE was measured after approach had been performed (“native”). Subsequently, a cylinder was removed from the medial femur condyles and a donor cylinder was inserted from an unloaded site in four different transplant positions: even, 1 mm deeper, 1 mm higher, and flush without cartilage (defect). No significant changes in friction were observed between the native knee and an even or deep OAT positioning. We, however, found a small but significant increase in DE between the “native” and “1 mm high” formations (ΔDE compared with native = 14 mJ/cycle; P = .004 after data normalization) and a large increase in defect situation (ΔDE compared with native = 119 mJ/cycle; P = .001). Considering the long‐term therapeutic aim that is pursued when performing OAT, elevated graft positioning should clearly be avoided. From a biomechanical point of view, donor site morbidity after cylinder harvest can be neglected.
Attitudes about and correlates of cannabis legalization policy among U.S. young adults

Abstract Objective Cannabis policies are rapidly evolving in the US. This study’s purpose was to examine relationships between cannabis harm perceptions, substance use, and demographic characteristics on attitudes toward cannabis policies. Participants Participants were 619 undergraduate students in a Mid-Atlantic state where cannabis use was illegal. Methods In 2016, participants completed a cross-sectional survey. Multinomial logistic regressions tested associations between attitudes toward cannabis policies (recreational cannabis use, use in private, or public) while controlling for harm perceptions, substance use, and demographics. Results The majority (64%) of participants supported recreational cannabis legalization, while 78% supported private and 29% supported public use. Perceiving cannabis as less harmful and current cannabis use were positively associated with supporting all three cannabis policies. Conclusions Results highlight diversity of young adults’ opinions regarding specific cannabis policies and underscore relationships between cannabis use behaviors, harm perceptions, and support for legalization that may inform policy making and prevention efforts.