Miracle-dz/UniFAR-FTUs huggingface dataset:
RNA thermoswitches modulate Staphylococcus aureus adaptation to ambient temperatures

Abstract Thermoregulation of virulence genes in bacterial pathogens is essential for environment-to-host transition. However, the mechanisms governing cold adaptation when outside the host remain poorly understood. Here, we found that the production of cold shock proteins CspB and CspC from Staphylococcus aureus is controlled by two paralogous RNA thermoswitches. Through in silico prediction, enzymatic probing and site-directed mutagenesis, we demonstrated that cspB and cspC 5′UTRs adopt alternative RNA structures that shift from one another upon temperature shifts. The open (O) conformation that facilitates mRNA translation is favoured at ambient temperatures (22°C). Conversely, the alternative locked (L) conformation, where the ribosome binding site (RBS) is sequestered in a double-stranded RNA structure, is folded at host-related temperatures (37°C). These structural rearrangements depend on a long RNA hairpin found in the O conformation that sequesters the anti-RBS sequence. Notably, the remaining S. aureus CSP, CspA, may interact with a UUUGUUU motif located in the loop of this long hairpin and favour the folding of the L conformation. This folding represses CspB and CspC production at 37°C. Simultaneous deletion of the cspB/cspC genes or their RNA thermoswitches significantly decreases S. aureus growth rate at ambient temperatures, highlighting the importance of CspB/CspC thermoregulation when S. aureus transitions from the host to the environment.
Guinea Pig Cytomegalovirus Protective T Cell Antigen GP83 Is a Functional pp65 Homolog for Innate Immune Evasion and Pentamer-Dependent Virus Tropism

Congenital CMV (cCMV) is a leading cause of cognitive impairment and deafness in newborns, and a vaccine is a high priority. The guinea pig is the only small animal model for cCMV but requires guinea pig cytomegalovirus (GPCMV). ABSTRACT The guinea pig is the only small animal model for congenital cytomegalovirus (CMV) but requires species-specific guinea pig cytomegalovirus (GPCMV). Tegument protein GP83 is the presumed homolog of HCMV pp65, but gene duplication in the UL82-UL84 homolog locus in various animal CMVs made it unclear if GP83 was a functional homolog. A GP83 null deletion mutant GPCMV (GP83dPC+) generated in the backdrop of glycoprotein pentamer complex (PC)-positive virus, required for nonfibroblast infection, had normal growth kinetics on fibroblasts but was highly impaired on epithelial and trophoblast cells. GP83dPC+ virus was highly sensitive to type I interferon (IFN-I), suggesting that GP83 had an innate immune evasion function. GP83 interacted with cellular DNA sensors guinea pig IFI16 and cGAS, indicating a role in the cGAS/STING pathway. Ectopically expressed GP83 in trophoblast cells restored GP83dPC+ virus growth. Additionally, mutant virus growth was restored in epithelial cells by expression of bovine viral diarrhea virus (BVDV) Npro protein targeting IRF3 as part of the cGAS/STING pathway, or alternatively, by expression of the fibroblast cell receptor platelet-derived growth factor receptor alpha (PDGFRA). HCMV pp65 is a T cell target antigen, and a recombinant adenovirus encoding GP83 was evaluated as a vaccine. In GPCMV challenge studies, vaccinated animals had various levels of protection against wild-type virus, with a protective response against the 22122 prototype strain but little protection against a novel clinical strain of GPCMV (TAMYC), despite 100% identity in GP83 protein sequences. Overall, GP83 is a functional pp65 homolog with novel importance for epithelial cell infection, but a GP83 T cell response provides limited vaccine efficacy. IMPORTANCE Congenital CMV (cCMV) is a leading cause of cognitive impairment and deafness in newborns, and a vaccine is a high priority. The guinea pig is the only small animal model for cCMV but requires guinea pig cytomegalovirus (GPCMV). The translational impact of GPCMV research is potentially reduced if the virus does not encode functional HCMV homolog proteins. This study demonstrates that tegument protein GP83 (pp65 homolog) is involved in innate immune evasion and highly important for infection of nonfibroblast cells via the viral glycoprotein pentamer complex (PC)-dependent endocytic entry pathway. The PC pathway is highly significant for virus dissemination and disease in the host, including cCMV. A GP83 candidate adenovirus (Ad) vaccine strategy in animals induced a cell-mediated response but failed to provide cross-strain protection against a novel clinical strain of GPCMV. Results suggest that the pp65 antigen provides very limited efficacy as a stand-alone vaccine, especially in cross-strain protection.
Comparative study between two 2D-Shear Waves Elastography techniques for the non-invasive assessment of liver fibrosis in patients with chronic hepatitis C virus (HCV) infection.

AIMS We aimed to compare the diagnostic performance of two 2D-Shear Wave Elastography (2D-SWE) techniques for the non-invasive assessment of liver fibrosis in patients with chronic hepatitis C virus (HCV) infection using Transient Elas-tography (TE) as reference. MATERIAL AND METHODS We enrolled 208 consecutive patients with chronic HCV infection, in which liver stiffness (LS) was evaluated in the same session using two 2D-SWE techniques: 2D-SWE.GE and 2D-SWE.SSI using TE as the method of reference. LS measurements were considered failures when no value was obtained after 10 attempts. RESULTS Valid LSMs were obtained in 95.6% (199/208) of cases by 2D-SWE.GE, 92.7% (193/208) of cases by 2D-SWE.SSI, and in 94.7% (197/208) of cases by TE (p>0.05). The mean LS values by 2D-SWE.GE were significantly lower than those obtained by 2D-SWE.SSI: 10.3±3.8 kPa vs. 15±10.4 kPa (p<0.0001). 2D-SWE.GE LSMs correlated better with TE than 2D-SWE.SSI (r=0.75, p<0.0001 vs. r=0.57, p<0.0001, z test p=0.0012). Linear regression analysis showed a moderate correlation between LSMs obtained by 2D-SWE.GE and 2D-SWE.SSI (r=0.63, R2=0.4, P<0.0001). Pairwise comparison of receiver operating characteristics curves (ROC) found no significant differences between 2D-SWE.GE and 2D-SWE.SSI in identifying F≥2 fibrosis (0.97 vs. 0.96, P = 0.5650), F≥3 (0.97 vs. 0.95, P = 0.2935), or F=4 (0.97 vs. 0.96, p = 0.6914). CONCLUSIONS Both 2D-SWE techniques had good feasibility for the noninvasive assessment of liver fibrosis. LS values obtained by 2D-SWE.GE were significantly lower than those obtained by 2D-SWE.SSI. No significant differences were found between both methods in staging liver fibrosis in patients with chronic HCV.
User Engagement and Clinical Impact of the Manage My Pain App in Patients With Chronic Pain: A Real-World, Multi-site Trial

Background Chronic pain imposes a large burden on individuals and society. A patient-centric digital chronic pain management app called Manage My Pain (MMP) can be used to enhance communication between providers and patients and promote self-management. Objective The purpose of this study was to evaluate the real-world engagement of patients in urban and rural settings in Ontario, Canada with the MMP app alongside their standard of care and assess the impact of its usage on clinical outcomes of pain and related mental health. Methods A total of 246 participants with chronic pain at a rural and 2 urban pain clinics were recruited into this prospective, open-label, exploratory study that compared the use of MMP, a digital health app for pain that incorporates validated questionnaires and provides patients with summarized reports of their progress in combination with standard care (app group), against data entered on paper-based questionnaires (nonapp group). Participants completed validated questionnaires on anxiety, depression, pain catastrophizing, satisfaction, and daily opioid consumption up to 4.5 months after the initial visit (short-term follow-up) and between 4.5 and 7 months after the initial visit (long-term follow-up). Engagement and clinical outcomes were compared between participants in the two groups. Results A total of 73.6% (181/246) of the participants agreed to use the app, with 63.4% (111/175) of them using it for at least one month. Individuals who used the app rated lower anxiety (reduction in Generalized Anxiety Disorder 7-item questionnaire score by 2.10 points, 95% CI –3.96 to –0.24) at short-term follow-up and had a greater reduction in pain catastrophizing (reduction in Pain Catastrophizing Scale score by 5.23 points, 95% CI –9.55 to –0.91) at long-term follow-up relative to patients with pain who did not engage with the MMP app. Conclusions The use of MMP by patients with chronic pain is associated with engagement and improvements in self-reported anxiety and pain catastrophizing. Further research is required to understand factors that impact continued engagement and clinical outcomes in patients with chronic pain. Trial Registration ClinicalTrials.gov NCT04762329; https://clinicaltrials.gov/ct2/show/NCT04762329
Traumatic Brain Injury and Incidence Risk of Sleep Disorders in Nearly 200,000 US Veterans

Objective To test the hypothesis that veterans with traumatic brain injury (TBI) have an increased subsequent risk of sleep disorders, we studied the longitudinal association between TBI and incident sleep disorders in nearly 200,000 veterans. Methods We performed a cohort study of all patients diagnosed with a TBI in the Veterans Health Administration system from October 1, 2001, to September 30, 2015, who were age-matched 1:1 to veterans without TBI. Veterans with prevalent sleep disorders at baseline were excluded. Development of sleep disorders was defined as any inpatient or outpatient diagnosis of sleep apnea, hypersomnia, insomnia, or sleep-related movement disorders based on ICD-9 codes after the first TBI diagnosis or the random selection date for those without TBI. We restricted the analysis to those with at least 1 year of follow-up. We used Cox proportional hazards models to examine the association between TBI and subsequent risk of sleep disorders. Results The study included 98,709 veterans with TBI and 98,709 age-matched veterans without TBI (age 49 ± 20 years). After an average follow-up of 5 (1–14) years, 23,127 (19.6%) veterans developed sleep disorders. After adjustment for demographics, education, income, and medical and psychiatric conditions, those who had TBI compared to those without TBI were 41% more likely to develop any sleep disorders (hazard ratio 1.41 [95% confidence interval 1.37–1.44]), including sleep apnea (1.28 [1.24–1.32]), insomnia (1.50 [1.45–1.55]), hypersomnia (1.50 [1.39–1.61]), and sleep-related movement disorders (1.33 [1.16–1.52]). The association was stronger for mild TBIs, did not differ appreciably by presence of posttraumatic stress disorder, and remained after a 2-year time lag. Conclusion In 197,418 veterans without sleep disorders, those with diagnosed TBI had an increased risk of incident sleep disorders over 14 years. Improved prevention and long-term management strategies for sleep are needed for veterans with TBI.
Relação entre o alumínio extraível com KCl e oxalato de amônio e a mineralogia da fração argila, em solos ácidos brasileiros

Em solos acidos de ambiente mais tropical com esmectitas, assim como em solos altamente tamponados de ambiente subtropical, contendo esmectita com hidroxi-Al entrecamadas (EHE) e, ou, vermiculita com hidroxi-Al entrecamadas (VHE), os teores de Al-KCl podem ser excepcionalmente altos; entretanto, em alguns casos nao se manifestam efeitos fitotoxicos do elemento nas culturas. O Al "trocavel" e tradicionalmente quantificado no extrato da solucao de KCl 1 mol L-1 (Al-KCl), mas nem sempre esse elemento provem unicamente de formas trocaveis. Este trabalho objetivou investigar relacoes entre o Al extraido com solucao de KCl e de oxalato de amonio com a mineralogia da fracao argila. A quantificacao do Al nos extratos de KCl e oxalato de amonio foi feita, respectivamente, por titulacao com NaOH 0,02 mol L-1 padronizado e por espectrofotometria de absorcao atomica. Foram utilizadas amostras de dois horizontes (A e B) de 12 perfis de solo de cinco estados brasileiros (AC, PE, BA, RS e SC), com diferentes caracteristicas mineralogicas, todos com teores de Al-KCl superior a 4 cmolc kg-1 no horizonte B. Dois perfis de SC (Rancho Queimado e Curitibanos), com niveis mais baixos de Al-KCl, foram incluidos para comparacao. Os altos teores de Al-KCl evidenciaram-se relacionados com a mineralogia dos solos estudados. Nos solos acidos com mais esmectitas, drenagem moderada ou imperfeita e oscilacao do lencol freatico houve evidencias morfologicas, confirmadas pelas analises mineralogicas, de que no clima atual ocorre um processo de destruicao de argilas, liberando Al que precipita como compostos amorfos. A alta concentracao salina da solucao de KCl dissolve parcialmente tais compostos, superestimando as formas trocaveis desse elemento, principalmente nos horizontes subsuperficiais. Nos solos acidos do ambiente subtropical, os teores de Al-KCl tambem foram altos, embora com valores mais baixos do que nos com predominio de esmectitas. Parte do Al-KCl nesses solos parece provir da dissolucao de compostos orgânicos e de Al presente em entrecamadas de argilominerais 2:1. Os resultados demonstraram que o KCl 1 mol L-1 nao foi adequado para estimar o Al "trocavel" na maioria dos solos estudados.
Defective lysosomal storage in Fabry disease modifies mitochondrial structure, metabolism and turnover in renal epithelial cells

Fabry disease (FD) is an X‐linked lysosomal storage disorder. Deficiency of the lysosomal enzyme alpha‐galactosidase (GLA) leads to accumulation of potentially toxic globotriaosylceramide (Gb3) on a multisystem level. Cardiac and cerebrovascular abnormalities as well as progressive renal failure are severe, life‐threatening long‐term complications. The complete pathophysiology of chronic kidney disease (CKD) in FD and the role of tubular involvement for its progression are unclear. We established human renal tubular epithelial cell lines from the urine of male FD patients and male controls. The renal tubular system is rich in mitochondria and involved in transport processes at high‐energy costs. Our studies revealed fragmented mitochondria with disrupted cristae structure in FD patient cells. Oxidative stress levels were elevated and oxidative phosphorylation was upregulated in FD pointing at enhanced energetic needs. Mitochondrial homeostasis and energy metabolism revealed major changes as evidenced by differences in mitochondrial number, energy production and fuel consumption. The changes were accompanied by activation of the autophagy machinery in FD. Sirtuin1, an important sensor of (renal) metabolic stress and modifier of different defense pathways, was highly expressed in FD. Our data show that lysosomal FD impairs mitochondrial function and results in severe disturbance of mitochondrial energy metabolism in renal cells. This insight on a tissue‐specific level points to new therapeutic targets which might enhance treatment efficacy.
Feasibility of Remote Occupational Therapy Services via Telemedicine in a Breast Cancer Recovery Program.

IMPORTANCE Access to perioperative breast surgery occupational therapy services remains limited in remote areas. OBJECTIVE To assess the feasibility and acceptance of occupational therapy services using a "hub-and-spoke" telemedicine model. DESIGN Prospective study using videoconferencing to connect the occupational therapist, located at the hub site, with the patient, located at the spoke site. SETTING National Cancer Institute Comprehensive Cancer Center (hub site) and affiliated community cancer center (spoke site). The sites are 75 mi apart. PARTICIPANTS Female breast cancer patients (N = 26) scheduled for breast surgery were asked to participate in telemedicine occupation therapy sessions. Patients lived in a geographically remote region and travelled a mean of 16 miles (range = 3-85) to the hub site. The majority (56%) of the patients had public insurance. INTERVENTION Perioperative occupational therapy sessions completed through videoconferencing. OUTCOMES AND MEASURES Outcome measures were participation in and completion rate for the sessions, number of sessions required to return to baseline, and time interval from surgery to return to baseline function. Patient satisfaction was assessed with a questionnaire. RESULTS Of the patients who enrolled in the study, 18 completed all postoperative sessions in which functional assessments, exercises, and education were provided. Patients regained baseline function within a mean of 42.4 days after surgery and after an average of three sessions. Patients reported high satisfaction with the sessions. CONCLUSIONS AND RELEVANCE Videoconference telemedicine in breast perioperative rehabilitation is feasible, effective, and acceptable to patients. This study adds to the emerging use of telemedicine for rehabilitative services. WHAT THIS ARTICLE ADDS This study, by demonstrating the acceptability, practicality, and efficacy of breast perioperative occupational therapy services offered through a videoconferencing platform, supports continued research to evaluate the value of telemedicine. Issues with access to medical care may be mitigated through creative use of technology.
Obesity Can Contribute to Severe Persistent Allergic Rhinitis in Children through Leptin and Interleukin-1β

Background: Obesity/overweight is associated with a higher risk of allergic rhinitis (AR) in children. Objective: This study aimed at exploring the mechanisms by which obesity affects the severity of AR through leptin and interleukin (IL)-1β were investigated. Methods: In all, 210 subjects with AR and 82 subjects without AR were included in this study. The levels of leptin and inflammatory biomarkers were measured in the serum to investigate the correlation with the severity of AR. Additionally, we analyzed whether changes in BMI regulate the severity of AR through serial follow-up of obese children. Results: IL-1β, which is a biomarker of active inflammation in AR, was significantly higher in individuals with AR than in those without and higher in subjects in the obesity group than in those in the normal weight group. A regression analysis showed that the leptin level was associated with increased IL-1β expression in children with AR. In the multivariate analysis, only parental AR (9.2-fold increase in risk), elevated leptin (11.3-fold increase in risk), and high expression of IL-1β (5.8-fold increase in risk) emerged as significant risk factors of moderate to severe persistent allergic rhinitis. We also found that children with an increase or decrease in BMI showed changes in IL-1β and AR symptoms, which these changes were dependent on leptin and BMI. Conclusions: These results suggest that obesity is an important risk factor for the exacerbation of symptoms and leptin can exacerbate inflammation as well as severe and persistent symptoms through IL-1β in AR.
Upfront admixing antibodies and EGFR inhibitors preempts sequential treatments in lung cancer models

Some antibacterial therapies entail sequential treatments with different antibiotics, but whether this approach is optimal for anti‐cancer tyrosine kinase inhibitors (TKIs) remains open. EGFR mutations identify lung cancer patients who can derive benefit from TKIs, but most patients develop resistance to the first‐, second‐, and third‐generation drugs. To explore alternatives to such whack‐a‐mole strategies, we simulated in patient‐derived xenograft models the situation of patients receiving first‐line TKIs. Monotherapies comprising approved first‐line TKIs were compared to combinations with antibodies specific to EGFR and HER2. We observed uniform and strong superiority of all drug combinations over the respective monotherapies. Prolonged treatments, high TKI dose, and specificity were essential for drug–drug cooperation. Blocking pathways essential for mitosis (e.g., FOXM1), along with downregulation of resistance‐conferring receptors (e.g., AXL), might underlie drug cooperation. Thus, upfront treatments using combinations of TKIs and antibodies can prevent emergence of resistance and hence might replace the widely applied sequential treatments utilizing next‐generation TKIs.
Brains that Fire Together Wire Together: Interbrain Plasticity Underlies Learning in Social Interactions

Social interactions are powerful determinants of learning. Yet the field of neuroplasticity is deeply rooted in probing changes occurring in synapses, brain structures, and networks within an individual brain. Here I synthesize disparate findings on network neuroplasticity and mechanisms of social interactions to propose a new approach for understanding interaction-based learning that focuses on the dynamics of interbrain coupling. I argue that the facilitation effect of social interactions on learning may be explained by interbrain plasticity, defined here as the short- and long-term experience-dependent changes in interbrain coupling. The interbrain plasticity approach may radically change our understanding of how we learn in social interactions.
Indeterminate Pulmonary Nodules in Osteosarcoma Are Associated With Increased Risk of Pulmonary Metastasis

Osteosarcoma is the most common primary malignant bone tumor in children. In addition to pulmonary metastasis, computed tomography frequently detects indeterminate pulmonary nodules (IPN). We conducted this study to determine the clinical significance of IPN in terms of progression to pulmonary metastasis and its impact on survival. It was a retrospective cohort study of pediatric nonmetastatic osteosarcoma patients treated from January 2005 to December 2018. Baseline computed tomography scans were reviewed for the presence of IPN (defined as a single nodule of <10 mm or ≥3 nodules of <5 mm). Subsequent scans were reviewed for the development of pulmonary metastasis. Of 155 patients, 31.6% (n=49) had IPN at baseline. A total of 43% (n=21) of those with IPN subsequently progressed to pulmonary metastasis compared with only 26% (n=28) of those without IPN (P<0.001) with a relative risk of 1.6 (1.03 to 2.5) in the IPN group. Patients with ≥3 IPN at baseline were at significantly greater risk of pulmonary metastasis as compared with <3 IPN (P=0.013). Overall and event-free survival in patients with and without IPN was 58% and 35%, and 72% and 46%, respectively. Our results suggest that patients with IPN may be at greater risk for progressing to pulmonary metastasis.
Natural Convection in Horizontal Concentric Cylindrical Annuli

The problem of steady, laminar natural convection between horizontal concentric circular cylinders was attacked numerically via detailed difference equation approximations for the differential equations of conservation. No terms were eliminated by boundary layer arguments. The problem was solved with machine language on an IBM 650 digital computer for several diameter ratios and several Grashof numbers at a Prandtl number of 0.714. Computed results agree well with experiments reported in the literature. In the appropriate limiting case, the computed results also accord with an analytical derivation for creeping flow.