Miracle-dz/UniFAR-FTUs huggingface dataset:
A novel MYT1L mutation in a patient with severe early‐onset obesity and intellectual disability

The genetic background of severe early‐onset obesity is still incompletely understood. Deletions at 2p25.3 associate with early‐onset obesity and variable intellectual disability. Myelin‐transcriptor‐factor‐1‐like (MYT1L) gene in this locus has been proposed a candidate gene for obesity. We report on a 13‐year‐old boy presenting with overweight already at 1 year of age (body mass index [BMI] Z‐score +2.3) and obesity at 2 years of age (BMI Z‐score +3.8). The patient had hyperphagia and delayed neurological, cognitive and motor development. He also had speech delay, strabismus, hyperactivity and intellectual disability. Brain MRI was normal. The parents and sister had normal BMI. Whole‐genome sequencing identified in the index patient a novel de novo frameshift deletion that introduces a premature termination of translation NM_015025. 2(MYT1L): c. 2215_2224delACGCGCTGCC, p.(Thr739Alafs*7) in MYT1L. The frameshift variant was confirmed by Sanger sequencing. Our finding supports the association of MYT1L mutations with early‐onset syndromic obesity. The identification of novel monogenic forms of childhood‐onset obesity will provide insights to the involved genetic and biologic pathways.
Effects of chlorogenic acid and caffeic acid on the quality of frozen‐thawed boar sperm

Chlorogenic acid (CGA) and caffeic acid (CA) are potent antioxidants that are mostly found in coffee beans. This study aimed to investigate the effects of CGA and CA supplementation during semen freezing on the quality of frozen-thawed boar spermatozoa. The antioxidants CGA and CA were added to a semen extender to achieve final concentrations of 50, 100, 200 and 400 µM. Supplementation of 100 µM CGA and CA yielded a significantly higher percentage of sperm viability (increased by 8%-10%) and plasma membrane integrity (increased by 4%-6%) than the control groups without the antioxidants at 0 and 3 hr after thawing (p < 0.05). At a concentration of 100 µM, CGA and CA also yielded beneficial effects on total and progressive sperm motility. Increases of CGA and CA concentrations to more than 200 µM did not enhance any sperm quality parameters. When the sperm penetrability and oocyte development by spermatozoa frozen with CGA and CA were evaluated, CGA and CA supplementations had no positive effects on the percentages of total fertilization, monospermic fertilization, cleavage and blastocyst formation. In conclusion, the supplementation of 100 µM CGA and CA during sperm freezing improved certain sperm parameters including motility, viability and plasma membrane integrity.
Resolution of inflammation is altered in chronic heart failure and entails a dysfunctional responsiveness of T lymphocytes

Chronic heart failure (CHF) is characterized by an ongoing nonresolving inflammatory status, where T lymphocytes seem critical. It has been recently recognized that transition from acute to chronic inflammation could be caused by defects in resolving inflammation, the resolution of which is mediated by a novel family of ω‐3‐derived specialized proresolving lipid mediators such as resolvins. We analyzed 27 elderly patients with CHF and 23 healthy age‐matched control subjects, and we reported significantly lower levels of D‐series resolvin (RvD)l in plasma of patients with CHF that were associated with a reduced ability of their leukocytes to produce this lipid via its biosynthetic enzyme 15‐lipoxygenase and that correlated with gas exchange dysfunction. Furthermore, when pretreating ex vivo peripheral blood mononuclear cells of patients with CHF with RvD1 or RvD2, we found that neither of them was able to modulate the immune response of CD8+ and CD4+ T cells in terms of proinflammatory cytokine production, namely TNF‐α, IFN‐γ, IL‐17, and IL‐2. Such impaired T‐cell responsiveness in patients with CHF was associated with a significant reduction in mRNA and protein expression of RvD1 receptor GPR32, suggesting a defective signaling in the proresolving pathway. We conclude that patients with CHF show alterations in producing proresolving mediator RvD1 and a failure of adaptive immune cells in responding to the anti‐inflammatory actions of RvDs that may contribute to the progression of chronic inflammation. Thus, the proresolution pathway might be a potential candidate to design better treatments for CHF aimed at reducing T cell‐mediated chronic inflammation. —Chiurchiù, V. , Leuti, A. , Saracini, S. , Fontana, D. , Finamore, P., Giua, R. , Padovini, L. , Incalzi, R. A. , Maccarrone, M. Resolution of inflammation is altered in chronic heart failure and entails a dysfunctional responsiveness of T lymphocytes. FASEB J. 33, 909–916 (2019). www.fasebj. org
Rigidity in Motor Behavior and Brain Functioning in Patients With Schizophrenia and High Levels of Apathy

The aim of this study was to investigate whether apathy in schizophrenia is associated with rigidity in behavior and brain functioning. To this end, we studied associations between variability in dynamic functional connectivity (DFC) in relevant functional brain networks, apathy, and variability in physical activity in schizophrenia. Thirty-one patients with schizophrenia, scoring high on apathy, were included and wore an actigraph. Activity variability was calculated on the activity counts using the root of the Mean Squared Successive Difference (MSSD). Furthermore, we calculated DFC on resting-state data as phase interactions between blood oxygen-level dependent (BOLD) signals of 270 brain regions per volume. Variability (MSSD) in DFC was calculated for 3 networks, including the default-mode network (DMN), frontoparietal network, and salience-reward network (SRN). Finally, we calculated correlations between these DFC estimates and apathy and activity variability. First, lower activity variability was associated with higher levels of apathy. Second, higher levels of apathy were associated with lower variability in DFC in the DMN and SRN. Third, higher activity variability was associated with higher variability in DFC in the SRN. In conclusion, patients with schizophrenia and more severe levels of apathy showed less variability in their physical activity and more rigid functional brain network behavior in the DMN and SRN. These networks have been shown relevant for self-reflection, mental simulation, and reward processing, processes that are pivotal for self-initiated goal-directed behavior. Functional rigidity of these networks may therefore contribute to reduced goal-directed behavior, which is characteristic for these patients.
Evaluation of a two-sample process for prevention of ABO mistransfusions in a high volume academic hospital

Background Acute haemolytic transfusion reactions due to ABO incompatible blood transfusion remain a leading cause of transfusion-associated morbidity and mortality in the USA. Erroneous patient identification and specimen labelling account for many errors that lead to ABO mistransfusions; these errors are largely preventable. Methods Our hospital requires a two-sample process of ABO/Rh typing prior to transfusion. Both samples must be drawn independently. To prevent simultaneous sample draw, our second sample tube has a unique pink top that is only available from the blood bank and can only be sent to the patient’s floor once the first sample arrives in the lab. We performed an audit of this process from 19 March to 30 July 2014 and 19 March to 30 July 2015. Results We reviewed type and crossmatch orders for 2702 new patients during the audit period and 824 patients (30.5%) required transfusion. All patients evaluated received compatible blood, and no mistransfusions were recorded using this method. Three per cent of testing was performed incorrectly, which safely defaulted to giving type O blood. Conclusions The two-sample protocol used by our institution can decrease the risk of mistransfusion. Our protocol was relatively inexpensive, safe, efficient and practical for adaptation by other hospitals.
Duration of corticosteroid use in chronic obstructive pulmonary disease exacerbations: improving prescribing practices on clinical teaching units with peer-to-peer teaching

Introduction The most recent Global Initiative for Chronic Obstructive Lung Disease consensus recommends a 5-day course of corticosteroid (CS) therapy for acute chronic obstructive pulmonary disease exacerbations (ACOPDE). As inappropriate use of CS therapy is associated with adverse events, we implemented a peer-to-peer education intervention to improve adherence to guidelines for patients with ACOPDE admitted to a medical clinical teaching unit at a tertiary care university centre. Methods Our study was a before–after design study with a concurrent control of a 15 min peer-to-peer educational intervention targeting medical residents at the beginning of a 4-week rotation for 12 consecutive months. Another medical teaching unit within the same university network, but at a different site, served as a concurrent control. The primary outcome was the proportion of patients who received appropriate duration of CS therapy (5 days) for ACOPDE during the intervention period as compared with the 12-month preintervention period at the intervention and control hospitals. Results Following the intervention, there was an increase in the proportion of patients receiving appropriate duration of CS therapy (34.2% to 51.3%, p=0.02) at the intervention hospital and no significant difference at the control hospital (22.8% to 34.1%, p=0.15). This effect was maintained at the intervention hospital 3 months postintervention period. Conclusion A short peer-to-peer educational intervention targeting medical residents on a clinical teaching unit improved adherence to appropriate duration of CS therapy for ACOPDE.
The bacterial microbiota in first-void urine from men with and without idiopathic urethritis

Background Non-gonococcal urethritis (NGU) is a common syndrome in men. NGU may have several causes, but many cases are caused by sexually transmitted infections that may also cause complications in their female partners. Chlamydia trachomatis and Mycoplasma genitalium are the most common causes of NGU, but in up to 35% of the cases, none of the known viral or bacterial causes are found. Traditionally, pathogens have been detected using various culture techniques that may not identify all species present in the urethra. To address this, we used culture-independent methods for analysis of the male urethral microbiota. Methods This case-control study analysed first void urine samples, collected at STD clinics in Stockholm, Sweden from men with idiopathic urethritis (IU), i.e. negative for Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Ureaplasma urealyticum, Trichomonas vaginalis, adenovirus, and herpes simplex virus type 1 and -2 together with samples from men without urethritis. Forty-six controls and 39 idiopathic urethritis patients were analysed. Results The microbiota was highly diverse: None of the 302 operational taxonomic units (OTUs) found in negative controls and IU patients were found in all of the samples or even in all of the samples in one group. More than 50% of the OTUs were only found in one or two of the total of 85 samples. Still the most dominant 1/6 of the genera constituted 79% of the sequences. Hierarchical clustering in a heatmap showed no specific clustering of patients or controls. A number of IU patient samples were dominated by a single genus previously related to urethritis (Gardnerella, Haemophilus, Ureaplasma). Conclusion The male urethra contain a very diverse composition of bacteria, even in healthy controls. NGU may be caused by a number of different bacteria but more studies including a higher number of samples are needed for elucidation of the role of each species.
Long-Term Depression Induced by Optogenetically Driven Nociceptive Inputs to Trigeminal Nucleus Caudalis or Headache Triggers

The peripheral trigeminovascular pathway mediates orofacial and craniofacial pain and projects centrally to the brainstem trigeminal nucleus caudalis (TNc). Sensitization of this pathway is involved in many pain conditions, but little is known about synaptic plasticity at its first central synapse. We have taken advantage of optogenetics to investigate plasticity selectively evoked at synapses of nociceptive primary afferents onto TNc neurons. Based on immunolabeling in the trigeminal ganglia, TRPV1-lineage neurons comprise primarily peptidergic and nonpeptidergic nociceptors. Optical stimulation of channelrhodopsin-expressing axons in the TRPV1/ChR2 mouse in TNc slices thus allowed us to activate a nociceptor-enriched subset of primary afferents. We recorded from lamina I/II neurons in acutely prepared transverse TNc slices, and alternately stimulated two independent afferent pathways, one with light-activated nociceptive afferents and the other with electrically-activated inputs. Low-frequency optical stimulation induced robust long-term depression (LTD) of optically-evoked EPSCs, but not of electrically-evoked EPSCs in the same neurons. Blocking NMDA receptors or nitric oxide synthase strongly attenuated LTD, whereas a cannabinoid receptor 1 antagonist had no effect. The neuropeptide PACAP-38 or the nitric oxide donors nitroglycerin or sodium nitroprusside are pharmacologic triggers of human headache. Bath application of any of these three compounds also persistently depressed optically-evoked EPSCs. Together, our data show that LTD of nociceptive afferent synapses on trigeminal nucleus neurons is elicited when the afferents are activated at frequencies consistent with the development of central sensitization of the trigeminovascular pathway. SIGNIFICANCE STATEMENT Animal models suggest that sensitization of trigeminovascular afferents plays a major role in craniofacial pain syndromes including primary headaches and trigeminal neuralgia, yet little is known about synaptic transmission and plasticity in the brainstem trigeminal nucleus caudalis (TNc). Here we used optogenetics to selectively drive a nociceptor-enriched population of trigeminal afferents while recording from superficial laminae neurons in the TNc. Low-frequency optical stimulation evoked robust long-term depression at TRPV1/ChR2 synapses. Moreover, application of three different headache trigger drugs also depressed TRPV1/ChR2 synapses. Synaptic depression at these primary afferent synapses may represent a newly identified mechanism contributing to central sensitization during headache.
Bioinspired dual-stiffness origami

An origami inspired by insect wings addresses the challenges of achieving both high load bearing and resilience in folding structures. Origami manufacturing has led to considerable advances in the field of foldable structures with innovative applications in robotics, aerospace, and metamaterials. However, existing origami are either load-bearing structures that are prone to tear and fail if overloaded or resilient soft structures with limited load capability. In this manuscript, we describe an origami structure that displays both high load bearing and high resilience characteristics. The structure, which is inspired by insect wings, consists of a prestretched elastomeric membrane, akin to the soft resilin joints of insect wings, sandwiched between rigid tiles, akin to the rigid cuticles of insect wings. The dual-stiffness properties of the proposed structure are validated by using the origami as an element of a quadcopter frame that can withstand aerodynamic forces within its flight envelope but softens during collisions to avoid permanent damage. In addition, we demonstrate an origami gripper that can be used for rigid grasping but softens to avoid overloading of the manipulated objects.
Is exon 8 the most critical or the only dispensable exon of the VCAN gene? Insights into VCAN variants and clinical spectrum of Wagner syndrome

Wagner syndrome and erosive vitreoretinopathy together constitute the phenotypic continuum of an autosomal dominant vitreoretinopathy, with clinical findings typically isolated to the eye. The disease is caused by pathogenic variants in the VCAN gene and all such variants reported to date are those that plausibly result in haploinsufficiency of exon 8 containing vcan transcripts. Here, we report the molecular findings and long‐term follow‐up of a 16‐year‐old female with a history of retinal detachments and pigmentary retinal changes. Next‐generation sequencing and microarray analysis of 141 genes established a diagnosis of Wagner syndrome in this individual, by detection of an 11.7 kilobase (kb) deletion encompassing exon 8 of VCAN. In light of the emerging functions and roles of versican protein in human disease, we discuss how variants within exon 8 of the VCAN gene can be compared to those in exon 2 of the COL2A1 gene that cause atypical Stickler syndrome and propose that variants in other regions of the gene can be expected to present with a more systemic disease. The distinctive facial features and atypical gastrointestinal symptoms observed in this long‐term follow‐up study support the possibility that individuals with VCAN‐related vitreoretinopathy may have extra‐ocular clinical features.
Syndecan-4 Modulates Epithelial Gut Barrier Function and Epithelial Regeneration in Experimental Colitis.

Background The transmembrane heparan sulfate proteoglycan Syndecan-4 (Sdc4) plays an important role in the regulation of various inflammatory disorders. However, the involvement of Sdc4 in intestinal inflammation remains unknown. Therefore, we assessed the impact of Sdc4 deficiency on experimental colitis and epithelial wound healing in vitro and in vivo. Methods Dextran sulfate sodium (DSS)-induced colitis was monitored in wild type and Sdc4-deficient (Sdc4-/-) mice by assessment of body weight, histology, inflammatory cellular infiltration, and colon length. Syndecan-4 expression was measured by immunohistochemistry, Western blot, and quantitative real-time PCR. Epithelial permeability was evaluated by Evans blue measurements, Western blot, and immunohistological analysis of tight junction protein expression. Impact of Sdc4 on epithelial wound healing was determined by scratch assay in vitro and by colonoscopy following mechanical wounding in vivo. Results In Sdc4-/- mice, colitis-like symptoms including severe weight loss, shortened colon length, histological damage, and invasion of macrophages and granulocytes were markedly aggravated compared with wild type (WT) animals. Moreover, colonic epithelial permeability in Sdc4-/- mice was enhanced, while tight junction protein expression decreased. Furthermore, Sdc4-/- colonic epithelial cells had lower cell proliferation and migration rates which presented in vivo as a prolonged intestinal wound healing phenotype. Strikingly, in WT animals, Sdc4 expression was reduced during colitis and was elevated during recovery. Conclusions The loss of Sdc4 aggravates the course of experimental colitis, potentially through impaired epithelial cell integrity and regeneration. In view of the development of current treatment approaches involving Sdc4 inhibition for inflammatory disorders like arthritis, particular caution should be taken in case of adverse gastrointestinal side-effects.
The Athletic Shoulder (ASH) test: reliability of a novel upper body isometric strength test in elite rugby players

Objectives Lower limb isometric tests are used to assess strength and strength asymmetries and monitor reductions in muscle force that may contribute to loss of performance and increase injury risk. Isometric tests in the upper body may be appropriate to monitor neuromuscular performance of the shoulder joint in sports involving contact and overhead actions. The aim of this study was to determine the reliability of a novel upper body isometric strength test. Methods Eighteen elite rugby players (age 22.4±4.6 years; body mass 95.5±13.4 kg) were tested on consecutive days. Maximal isometric contractions using both limbs against a force platform were assessed at three angles of abduction (180°, ‘I’; 135°, ‘Y’ and 90°, ‘T’), in a prone lying position. To evaluate interday reliability, intraclass coefficients (ICC) were calculated for mean net peak force (NPF) and highest NPF achieved in any trial (peak NPF). Intratrial variability was assessed using coefficient of variation (CV), and the standard error of measurement (SEM) was used to calculate minimal detectable change (MDC). Results Interday reliability for NPF was excellent in all test positions (ICC 0.94–0.98). The test demonstrated high absolute reliability values (SEM 4.8–10.8) and interday measurement error was below 10% in all test positions (CV 5.0–9.9%) except for the non-dominant arm I-position (CV 11.3%). Minimum detectable change was between 13.2 and 25.9 N. Conclusion The Athletic Shoulder test demonstrated excellent reliability for each test position supporting its use as a reliable tool to quantify the ability to produce and transfer force across the shoulder girdle.
Effects of situational variables on the physical activity profiles of elite soccer players in different score line states

The aim of this study were to investigate the effects of playing position, pitch location, team ability and opposition ability on the physical activity profiles of English premier league soccer players in difference score line states. A validated automatic tracking system (Venatrack Ltd.) was used to track players in real time (at 25 Hz) for total distance covered, high speed running distance and sprint distance. This is the first study to include every team from an entire season in the English premier league, resulting in 376 games, 570 players and 35 000 rows of data from the 2011‐12 season being analyzed using multi‐level modelling. Multi‐level regression revealed an inverted “u” shaped association between total distance covered and goal difference (GD), with greater distances covered when GD was zero and reduced distances when GD was either positive or negative. A similar “u” shaped association was found with high speed distance covered at home. In addition distance covered (both at home and away) were predicted by playing position. All activity profiles (with the exception of sprint distance at home) were predicted by pitch location and time scored. Lastly, distance away from home and high speed running at home were predicted by opposition ability. Score line appears to effect player activity profiles across a number of situational factors and thus should be considered by managers when preparing and selecting teams to maximize performance. The current study also highlighted the need for more sensitive score line definitions in which to consider score line effects.
Phase waves and trigger waves: emergent properties of oscillating and excitable networks in the gut

The gut is enmeshed by a number of cellular networks, but there is only a limited understanding of how these networks generate the complex patterns of activity that drive gut contractile functions. Here we review two fundamental types of cell behaviour, excitable and oscillating, and the patterns that networks of such cells generate, trigger waves and phase waves, respectively. We use both the language of biophysics and the theory of nonlinear dynamics to define these behaviours and understand how they generate patterns. Based on this we look for evidence of trigger and phase waves in the gut, including some of our recent work on the small intestine.