Genome sequencing and comprehensive rare-variant analysis of 465 families with neurodevelopmental disorders.

Despite significant progress in unraveling the genetic causes of neurodevelopmental disorders (NDDs), a substantial proportion of individuals with NDDs remain without a genetic diagnosis after microarray and/or exome sequencing. Here, we aimed to assess the power of short-read genome sequencing (GS), complemented with long-read GS, to identify causal variants in participants with NDD from the National Institute for Health and Care Research (NIHR) BioResource project. Short-read GS was conducted on 692 individuals (489 affected and 203 unaffected relatives) from 465 families. Additionally, long-read GS was performed on five affected individuals who had structural variants (SVs) in technically challenging regions, had complex SVs, or required distal variant phasing. Causal variants were identified in 36% of affected individuals (177/489), and a further 23% (112/489) had a variant of uncertain significance after multiple rounds of re-analysis. Among all reported variants, 88% (333/380) were coding nuclear SNVs or insertions and deletions (indels), and the remainder were SVs, non-coding variants, and mitochondrial variants. Furthermore, long-read GS facilitated the resolution of challenging SVs and invalidated variants of difficult interpretation from short-read GS. This study demonstrates the value of short-read GS, complemented with long-read GS, in investigating the genetic causes of NDDs. GS provides a comprehensive and unbiased method of identifying all types of variants throughout the nuclear and mitochondrial genomes in individuals with NDD.

Transcranial magnetic stimulation to frontal but not occipital cortex disrupts endogenous attention.

Covert endogenous (voluntary) attention improves visual performance. Human neuroimaging studies suggest that the putative human homolog of macaque frontal eye fields (FEF+) is critical for this improvement, whereas early visual areas are not. Yet, correlational MRI methods do not manipulate brain function. We investigated whether rFEF+ or V1/V2 plays a causal role in endogenous attention. We used transcranial magnetic stimulation (TMS) to alter activity in the visual cortex or rFEF+ when observers performed an orientation discrimination task while attention was manipulated. On every trial, they received double-pulse TMS at a predetermined site (stimulated region) around V1/V2 or rFEF+. Two cortically magnified gratings were presented, one in the stimulated region (contralateral to the stimulated area) and another in the symmetric (ipsilateral) nonstimulated region. Grating contrast was varied to measure contrast response functions (CRFs) for all attention and stimulation combinations. In experiment 1, the CRFs were similar at the stimulated and nonstimulated regions, indicating that early visual areas do not modulate endogenous attention during stimulus presentation. In contrast, occipital TMS eliminates exogenous (involuntary) attention effects on performance [A. Fernández, M. Carrasco,Curr. Biol. 30, 4078-4084 (2020)]. In experiment 2, rFEF+ stimulation decreased the overall attentional effect; neither benefits at the attended location nor costs at the unattended location were significant. The frequency and directionality of microsaccades mimicked this pattern: Whereas occipital stimulation did not affect microsaccades, rFEF+ stimulation caused a higher microsaccade rate directed toward the stimulated hemifield. These results provide causal evidence of the role of this frontal region for endogenous attention.

Featural Representation and Internal Noise Underlie the Eccentricity Effect in Contrast Sensitivity.

Human visual performance for basic visual dimensions (e.g., contrast sensitivity and acuity) peaks at the fovea and decreases with eccentricity. The eccentricity effect is related to the larger visual cortical surface area corresponding to the fovea, but it is unknown if differential feature tuning contributes to this eccentricity effect. Here, we investigated two system-level computations underlying the eccentricity effect: featural representation (tuning) and internal noise. Observers (both sexes) detected a Gabor embedded in filtered white noise which appeared at the fovea or one of four perifoveal locations. We used psychophysical reverse correlation to estimate the weights assigned by the visual system to a range of orientations and spatial frequencies (SFs) in noisy stimuli, which are conventionally interpreted as perceptual sensitivity to the corresponding features. We found higher sensitivity to task-relevant orientations and SFs at the fovea than that at the perifovea, and no difference in selectivity for either orientation or SF. Concurrently, we measured response consistency using a double-pass method, which allowed us to infer the level of internal noise by implementing a noisy observer model. We found lower internal noise at the fovea than that at the perifovea. Finally, individual variability in contrast sensitivity correlated with sensitivity to and selectivity for task-relevant features as well as with internal noise. Moreover, the behavioral eccentricity effect mainly reflects the foveal advantage in orientation sensitivity compared with other computations. These findings suggest that the eccentricity effect stems from a better representation of task-relevant features and lower internal noise at the fovea than that at the perifovea.

L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study.

GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes.

Inhibition of adenylyl cyclase 8 prevents the upregulation of Orai1 channel, which improves cardiac function after myocardial infarction.

The upregulation of Orai1 and subsequent store-operated Ca2+ entry (SOCE) has been associated with adverse cardiac remodeling and heart failure (HF). However, the mechanism underlying Orai1 upregulation and its role in myocardial infarction remains unclear. Our study investigated the role of Orai1 in activating adenylyl cyclase 8 (AC8) and cyclic AMP (cAMP) response element-binding protein (CREB), as well as its contribution to cardiac dysfunction induced by ischemia and reperfusion (I/R). We found that I/R evoked an increase in the expression of Orai1 and AC8 in rats' hearts, resulting in a substantial rise in diastolic Ca2+ concentration ([Ca2+]i), and reduced ventricular contractions. The expression of Orai1 and AC8 was also increased in ventricular biopsies of post-ischemic HF patients. Mechanistically, we demonstrate that I/R activation of Orai1 stimulated AC8, which produced cAMP and phosphorylated CREB. Subsequently, p-CREB activated the ORAI1 promoter, resulting in Orai1 upregulation and SOCE exacerbation. Intramyocardial administration of AAV9 carrying AC8 short hairpin RNA decreased the expression of AC8, Orai1 and CREB, which restored diastolic [Ca2+]i and improved cardiac contraction. Therefore, our data suggests that the axis composed by Orai1/AC8/CREB plays a critical role in I/R-induced cardiac dysfunction, representing a potential new therapeutic target to limit the progression of the disease toward HF.

The bottlenose dolphin (Tursiops truncatus): a novel model for studying healthy arterial aging.

Endothelial function declines with aging and independently predicts future cardiovascular disease (CVD) events. Diving also impairs endothelial function in humans. Yet, dolphins, being long-lived mammals adapted to diving, undergo repetitive cycles of tissue hypoxia-reoxygenation and disturbed shear stress without manifesting any apparent detrimental effects, as CVD is essentially nonexistent in these animals. Thus, dolphins may be a unique model of healthy arterial aging and may provide insights into strategies for clinical medicine. Emerging evidence shows that the circulating milieu (bioactive factors in the blood) is at least partially responsible for transducing reductions in age-related endothelial function. To assess whether dolphins have preserved endothelial function with aging because of a protected circulating milieu, we tested if the serum (pool of the circulating milieu) of bottlenose dolphins (Tursiops truncatus) induces the same arterial aging phenotype as the serum of age-equivalent humans. We incubated conduit arteries from young and old mice with dolphin and human serum and measured endothelial function ex vivo via endothelium-dependent dilation to acetylcholine. Although young arteries incubated with serum from midlife/older adult human serum had lower endothelial function, those incubated with dolphin serum consistently maintained high endothelial function regardless of the age of the donor. Thus, studying the arterial health of dolphins could lead to potential novel therapeutic strategies to improve age-related endothelial dysfunction in humans.NEW & NOTEWORTHY We demonstrate that, unlike serum of midlife/older adult humans, age-matched dolphin serum elicits higher endothelial function ex vivo in young mouse carotid arteries, suggesting that the circulating milieu of bottlenose dolphins may be geroprotective. We propose that dolphins are a novel model to investigate potential novel therapeutic strategies to mitigate age-related endothelial dysfunction in humans.

The impact of acute kidney damage in the community.

BACKGROUND AND HYPOTHESIS: Assess incidence of Acute Kidney Diseas and Disorders (AKD) and Acute Kidney Injury (AKI) episodes and impact on progression of renal dysfunction and risk of all-cause mortality in the community. METHODS: Community of 1 863 731 aged > 23 years with at least two serum creatinine measurements. eGFR was calculated using CKD-EPI formula. CKD, AKD and AKI were defined according to the harmonized KDIGO criteria (Lameire 2021). The sCr values and RIFLE scale was used to classify episodes. Progression of renal dysfunction and mortality were evaluated. RESULTS: 56 850 episodes of AKD in 47 972 patients in 4.8 years were identified. AKD incidence of AKD was 3.51 and 12.56/1000 patients/year in non-CKD and CKD, respectively. One AKD episode was observed in 87.3% patients, two in 9.3% and three or more in 3.4%. A second episode was less common in patients without CKD (10.3%) compared to those with CKD (18.4%). Among patients without CKD a total of 43.8% progressed to CKD, and those with previous CKD 63.1% had eGFR decline of > 50%. The risk of progression to CKD was higher in women, older, overweight-obesity and heart failure, as was the risk of eGFR decline > 50% in CKD patients, although the number of AKD episodes was also a risk factor. AKI episodes were observed in 5646 patients with or without CKD. Of these, 12.7% progressed to CKD and of those with pre-existing CKD, 43.2% had an eGFR decline of > 20%. In the toal population mortality within 3 months of detection of AKD episode occurred in 7% patients, and was even higher in patients with AKI, 30.1%. CONCLUSION: Acute elevations in serum creatinine in the community may pose a health risk and contribute to the development of CKD. Identification of therapeutic targets and provision of appropriate follow-up for those who survive an episode is warranted.

Overactive bladder negatively affects erectile function and promotes premature ejaculation: findings from large representative population-level study.

PURPOSE: The effect of overactive bladder (OAB) on sexual health has been evaluated extensively for women but much less for men. Therefore, the aim of this study was to evaluate the relationship between OAB and men's sexual activity and the effect of OAB on erectile dysfunction (ED) and premature ejaculation (PE) in a large representative cohort of men at the population level. METHODS: This study was based on computer-assisted web interviews that used validated questionnaires. The most recent census and the sample size estimation calculations were employed to produce a population-representative pool. RESULTS: The study included 3001 men, representative of the population in terms of age and place of residence. The frequency of sexual intercourse was higher for respondents without OAB symptoms compared with persons who had OAB (p = 0.001), but there was no association between OAB symptoms and number of sexual partners (p = 0.754). Regression models did not confirm the effect of OAB on sexual activity (odds ratio 0.993, CI 0.974-1.013, p = 0.511). Both ED and PE were more prevalent in respondents with OAB symptoms compared with persons who lacked those symptoms (p < 0.001). Importantly, the effect of OAB on ED or PE was independent of age, comorbidities, and lifestyle habits (regression coefficients of 0.13 and 0.158 for ED and PE, respectively). CONCLUSION: Overactive bladder did not significantly affect men's sexual activity, but it significantly correlated with ED and PE. Our results suggest a need in daily clinical practice to screen for OAB symptoms for persons who report ED or PE.

Survey of severe acute respiratory syndrome coronavirus 2 in captive and free-ranging wildlife from Spain.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), considered a zoonotic agent of wildlife origin, can infect various animal species, including wildlife in free-range and captive environments. Detecting susceptible species and potential reservoirs is crucial for preventing the transmission, spread, genetic evolution, and further emergence of viral variants that are major threats to global health. This study aimed to detect exposure or acute infection by SARS-CoV-2 in 420 animals from 40 different wildlife species, including terrestrial and aquatic mammals, from different regions of Spain during the 2020-2023 coronavirus disease 19 (COVID-19) pandemic. In total, 8/137 animals were positive for SARS-CoV-2 antibodies against the receptor binding domain and/or viral nucleoprotein according to independent ELISAs. However, only one ELISA-positive sample of a captive bottlenose dolphin (Tursiops truncatus) tested positive for SARS-CoV-2 neutralizing antibodies with a low titre (SNT50 38.15) according to a virus neutralization test. Cetaceans are expected to have a high risk of infection with SARS-CoV-2 according to early predictive studies due to the similarity of their angiotensin converting enzyme 2 cell receptor to that of humans. Moreover, of 283 animals analysed for SARS-CoV-2 RNA using RT-qPCR, none tested positive. Our results reinforce the importance of considering cetaceans at risk for SARS-CoV-2 infection and support taking preventive biosecurity measures when interacting with them, especially in the presence of individuals with suspected or confirmed COVID-19. Although most animals in this study tested negative for acute infection or viral exposure, ongoing surveillance of wildlife species and potentially susceptible animals is important to prevent future spillover events and detect potential novel reservoirs.

Age and sex differences in pharmaceutical contamination in a keystone scavenger.

Pharmaceutical contaminants have a recognized negative impact on wildlife health. However, there are still many knowledge gaps on the factors influencing exposure and metabolic processing of compound mixtures as a function of season and individual characteristics such as age and sex. We evaluated age and sex differences in a set of seventeen compounds, including eleven antibiotics, five NSAIDs and caffeine, evaluated by HPLC-MS-TOF analysis in griffon vultures (Gyps fulvus) from central Spain. Pharmaceutical cocktails (up to 10 compounds simultaneously) were found in all individuals. Lincomycin was detected in all individuals, and fluoroquinolones were found at high frequencies, while NSAIDs were at low frequencies and concentrations, including flumixin meglumine, which can be lethal to vultures. A higher total number of compounds and sum of concentrations, as well as prevalence and concentration of several of the pharmaceuticals tested was found in females than in males for both nestlings and adults. This is the first study to present evidence of sex differences in the pharmacokinetics of dietary drug contaminants in a vulture species. Chronic exposure to "medications" in entire populations can potentially have sub-lethal health effects that affect fitness differently according to age and sex, with demographic implications for population viability. Specifically, if females have higher mortality after fledging due to high pharmaceutical contamination, this should be considered when modelling the population dynamic of this species for conservation purposes.

Tooth loss during supportive periodontal care: A prospective study.

AIM: To assess periodontal stability and the association between tooth- and patient-related factors and tooth loss during supportive periodontal care (SPC). MATERIALS AND METHODS: A prospective observational study was carried out on previously treated periodontitis patients followed up for 5 years in SPC. The risk profile (low, moderate, high) of each patient based on periodontal risk assessment (PRA) scoring at baseline was evaluated, and tooth loss rates were analysed. RESULTS: Two hundred patients were included in the study, and 143 had 5-year follow-up data available for analysis. The overall annual tooth loss per patient was 0.07 ± 0.14 teeth/patient/year. Older age, smoking, staging and grading were associated with increased tooth loss rates. Most patients whose teeth were extracted belonged to the PRA high-risk group. Both PRA and a tooth prognosis system used at baseline showed high negative predictive value but low positive predictive value for tooth loss during SPC. CONCLUSIONS: Overall, the tooth loss rate of periodontitis patients in this prospective cohort study under SPC in private practice was low. Both tooth-based and patient-based prognostic systems can identify high-risk cases, but their positive predictive value should be improved.

Expanding the phenotypic spectrum of TRAPPC11-related muscular dystrophy: 25 Roma individuals carrying a founder variant.

BACKGROUND: Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders. TRAPPC11-related LGMD is an autosomal-recessive condition characterised by muscle weakness and intellectual disability. METHODS: A clinical and histopathological characterisation of 25 Roma individuals with LGMD R18 caused by the homozygous TRAPPC11 c.1287+5G>A variant is reported. Functional effects of the variant on mitochondrial function were investigated. RESULTS: The c.1287+5G>A variant leads to a phenotype characterised by early onset muscle weakness, movement disorder, intellectual disability and elevated serum creatine kinase, which is similar to other series. As novel clinical findings, we found that microcephaly is almost universal and that infections in the first years of life seem to act as triggers for a psychomotor regression and onset of seizures in several individuals with TRAPPC11 variants, who showed pseudometabolic crises triggered by infections. Our functional studies expanded the role of TRAPPC11 deficiency in mitochondrial function, as a decreased mitochondrial ATP production capacity and alterations in the mitochondrial network architecture were detected. CONCLUSION: We provide a comprehensive phenotypic characterisation of the pathogenic variant TRAPPC11 c.1287+5G>A, which is founder in the Roma population. Our observations indicate that some typical features of golgipathies, such as microcephaly and clinical decompensation associated with infections, are prevalent in individuals with LGMD R18.

Understanding consumer food choices & promotion of healthy and sustainable Mediterranean diet and lifestyle in children and adolescents through behavioural change actions: the DELICIOUS project.

Over the last decades, the abandonment of traditional dietary patterns, such as the Mediterranean diet, represents an important threat for human health and environmental safeguard. The DELICIOUS project aims to promote healthy lifestyles among children and adolescents by implementing activities and tools to increase the adherence to the Mediterranean Diet with an attention to the environmental impacts of the diet. This study protocol describes the DELICIOUS project as a single-arm, uncontrolled behavioural intervention providing formal and non-formal education activities, development of new snacks and recipe reformulation, web/mobile app development, and physical activities to school children and adolescents in five European countries. The project aims to increase awareness of the nutritional benefits and the sustainability aspects of the Mediterranean Diet and to promote consumers' empowerment through an online platform for sustainable and healthy meal planning in the school canteen.

Mandibular bone mass density in a medieval population and its relationship with stable isotopes δ13C and δ15N.

The aim of this study was to compare the level of bone mass in digital orthopantomograms in two populations (medieval and current) using two radiomorphometric indexes, and to correlate the mandibular bone mass value, in the medieval mandible population, with stable isotope data δ13C and δ15N. An observational, cross-sectional, and analytical study on mandibles from two diachronic groups, 15 mandibles from the medieval settlement of La Torrecilla (Granada, Spain) and 15 mandibles from current patients at the Faculty of Dentistry of the University of Granada (Spain), matched by age and sex was conducted. The bone mass density was determined using the Mandibular Cortical Width Index (MCW) and the Mandibular Panoramic Index (PMI) in digital panoramic radiographs. In the medieval group, the values of bone mass density were correlated with those of two stable isotopes (δ13C and δ15N). The mean value of MCW in mm in the medieval group was 3.96 ± 0.60 (mean ± standard deviation) and in the current group was 4.02 ± 1.01. The PMI was 0.33 ± 0.06 and 0.35 ± 0.08 in the medieval and current groups respectively, with similar results in both groups (p = 0.820 and p = 0.575). A negative correlation was found between both morphometric indices and the δ15N isotope (rs = 0.56, p = 0.030 and rs = 0.61, p = 0.016, respectively). The bone mass density in mandibles belonging to the two compared populations, determined by two quantitative radiomorphometric indices, is similar. Within the medieval population, there is an inverse correlation between the δ15N value and bone mass density.

Correlation between Inflammasomes and Microbiota in Peri-Implantitis.

The activation of inflammasomes is thought to induce the inflammatory process around dental implants. No information is available on the correlation between microbiota and inflammasomes in clinical samples from patients suffering peri-implantitis. For this cross-sectional study, 30 biofilm samples were obtained from 19 patients undergoing surgical treatment for peri-implantitis because of the presence of bleeding on probing, probing depth higher than 6 mm, and radiographic bone loss higher than 3 mm. Then, soft tissue samples from around the implant were also collected. The relative abundance of bacteria and alpha-diversity indexes were calculated after analyzing the 16S rRNA gene using next-generation sequencing. The soft-tissue samples were processed for evaluation of the inflammasomes NLRP3 and AIM2 as well as caspase-1 and IL-1ß. The relative abundance (mean (SD)) of specific species indicated that the most abundant species were Porphyromonas gingivalis (10.95 (14.17)%), Fusobacterium vincentii (10.93 (13.18)%), Porphyromonas endodontalis (5.89 (7.23)%), Prevotella oris (3.88 (4.94)%), Treponema denticola (2.91 (3.19)%), and Tannerella forsythia (2.84 (4.15)%). Several correlations were found between the species and the immunohistochemical detection of the inflammasomes NLRP3 and AIM2 as well as caspase-1 and IL-1ß, both in the epithelium and the lamina propria. A network analysis found an important cluster of variables formed by NLRP3 in the lamina propria and AIM2, caspase-1, and IL-1ß in the lamina propria and the epithelium with Prevotella dentalis, Prevotella tannerae, Tannerella forsythia, or Selenomonas timonae. Thus, it could be concluded that inflammasomes NLRP3 and AIM2 and their downstream effectors caspase-1 and interleukin-1ß can be significantly associated with specific bacteria.

Time Course of Recovery From Different Velocity Loss Thresholds and Set Configurations During Full-Squat Training.

ABSTRACT: Cornejo-Daza, PJ, Villalba-Fernández, A, González-Badillo, JJ, and Pareja-Blanco, F. Time course of recovery from different velocity loss thresholds and set configurations during full-squat training. J Strength Cond Res 38(2): 221-227, 2024-The aims of the research were to examine the effects of (a) velocity loss (VL) thresholds and (b) set configuration, traditional or cluster, on time-course recovery. A randomized cross-over research design was conducted, in which 15 resistance-trained men performed 4 protocols consisting of 3 sets of 70% 1RM in full squat (SQ), differing in the VL incurred during the set assessed with a linear velocity transducer: (a) 20% (70-20), (b) 30% (70-30), (c) 40% (70-40), and in the set configuration (d) 20% of VL using a cluster methodology (70-CLU). Movement velocity against the load that elicited a 1 m·s -1 velocity at baseline measurements (V1-load) in SQ, countermovement jump (CMJ) height, and sprint time in 20 m (T20) were assessed at baseline (Pre) and postintervention (Post, 6 hour-Post, 24 hour-Post, and 48 hour-Post). The 70-20 protocol resulted in fewer total repetitions than the other protocols ( p = 0.001), whereas 70-CLU, 70-30, and 70-40 completed similar total repetitions. The 70-30 protocol significantly worsened T20 at 6 hours-Post, CMJ at 48 hours-Post, and V1-load at 6 hours-Post ( p < 0.05). The 70-40 protocol significantly impaired T20 at 6 hours-Post, and CMJ and V1-load at 24 hours-Post ( p < 0.05). No significant performance reductions were observed for 70-20 and 70-CLU at 6 hours-Post, 24 hours-Post, and 48 hours-Post. Protocols with higher VL resulted in more pronounced fatigue and a slower rate of recovery. Cluster sets (70-CLU) resulted in higher volume than protocols with a similar level of fatigue (70-20) and a quicker recovery than protocols with a similar volume (70-30 and 70-40).

Modeling Peptide-Protein Interactions by a Logo-Based Method: Application in Peptide-HLA Binding Predictions.

Peptide-protein interactions form a cornerstone in molecular biology, governing cellular signaling, structure, and enzymatic activities in living organisms. Improving computational models and experimental techniques to describe and predict these interactions remains an ongoing area of research. Here, we present a computational method for peptide-protein interactions' description and prediction based on leveraged amino acid frequencies within specific binding cores. Utilizing normalized frequencies, we construct quantitative matrices (QMs), termed 'logo models' derived from sequence logos. The method was developed to predict peptide binding to HLA-DQ2.5 and HLA-DQ8.1 proteins associated with susceptibility to celiac disease. The models were validated by more than 17,000 peptides demonstrating their efficacy in discriminating between binding and non-binding peptides. The logo method could be applied to diverse peptide-protein interactions, offering a versatile tool for predictive analysis in molecular binding studies.

Differential efficacy with epidural blood and fibrin patches for the treatment of post-dural puncture headache.

BACKGROUND: Accidental dural puncture (ADP) is the most frequent major complication when performing an epidural procedure in obstetrics. Consequently, loss of pressure in the cerebrospinal fluid (CSF) leads to the development of post-dural puncture headache (PDPH), which occurs in 16%-86% of cases. To date, the efficacy of epidural fibrin patches (EFP) has not been evaluated in a controlled clinical trial, nor in comparative studies with epidural blood patches (EBP). METHODS: The objective of the present study was to compare the efficacy of EFP with respect to EBP for the treatment of refractory accidental PDPH. This prospective, randomized, open-label, parallel, comparative study included 70 puerperal women who received an EBP or EFP (35 in each group) after failure of the conventional analgesic treatment for accidental PDPH in a hospital. RESULTS: A higher percentage of women with EFP than EBP achieved complete PDPH relief after 2 (97.1% vs. 54.3%) and 12 h (100.0% vs. 65.7%) of the patch injection. The percentage of patients who needed rescue analgesia was significantly lower with EFP after 2 (2.9% vs. 48.6%) and 12 h (0.0% vs. 37.1%). After 24 h, PDPH was resolved in all women who received EFP. The recurrence of PDPH was reported in one woman from the EBP group (2.9%), who subsequently required a second patch. The mean length of hospital stay was significantly lower with EFP (3.9 days) than EBP (5.9 days). Regarding satisfaction, the mean value (Likert scale) was significantly higher with EFP (4.7 vs. 3.0). CONCLUSIONS: EFP provided better outcomes than EBP for the treatment of obstetric PDPH in terms of efficacy, safety, and patient satisfaction.

A Simple and Sequential Strategy for the Introduction of Complexity and Hierarchy in Hydrogen-Bonded Organic Framework (HOF) Crystals for Environmental Applications.

Hydrogen-bonded organic frameworks (HOFs) are a new class of crystalline porous organic molecular materials (POMMs) with great potential for a diverse range of applications. HOFs face common challenges to POMMs, and in general to purely organic crystals, that is, the difficulty of integrating complexity in crystals. Herein, we propose a simple and sequential strategy for the formation of HOFs with hierarchical superstructures. The strategy is based on controlling the assembly conditions, avoiding the use of any surface functionalization or template, which allows to obtain hierarchical crystalline porous superstructures in an easy manner. As proof of concept, we obtained the first example of core-shell (HOF-on-HOF) crystals and HOFs with hierarchical superstructures having superhydrophobicity and trapping abilities for the capture of persistent water contaminants such as oils and microplastics. We expect that this strategy could serve as inspiration for the construction of more intricate multiscale structures that could greatly expand the library of HOF materials.

Differential Effects of Endogenous and Exogenous Attention on Sensory Tuning.

Covert spatial attention (without concurrent eye movements) improves performance in many visual tasks (e.g., orientation discrimination and visual search). However, both covert attention systems-endogenous (voluntary) and exogenous (involuntary)-exhibit differential effects on performance in tasks mediated by spatial and temporal resolution suggesting an underlying mechanistic difference. We investigated whether these differences manifest in sensory tuning by assessing whether and how endogenous and exogenous attention differentially alter the representation of two basic visual dimensions-orientation and spatial frequency (SF). The same human observers detected a grating embedded in noise in two separate experiments (with endogenous or exogenous attention cues). Reverse correlation was used to infer the underlying neural representation from behavioral responses, and we linked our results to established neural computations via a normalization model of attention. Both endogenous and exogenous attention similarly improved performance at the attended location by enhancing the gain of all orientations without changing tuning width. In the SF dimension, endogenous attention enhanced the gain of SFs above and below the target SF, whereas exogenous attention only enhanced those above. Additionally, exogenous attention shifted peak sensitivity to SFs above the target SF, whereas endogenous attention did not. Both covert attention systems modulated sensory tuning via the same computation (gain changes). However, there were differences in the strength of the gain. Compared with endogenous attention, exogenous attention had a stronger orientation gain enhancement but a weaker overall SF gain enhancement. These differences in sensory tuning may underlie differential effects of endogenous and exogenous attention on performance.SIGNIFICANCE STATEMENT Covert spatial attention is a fundamental aspect of cognition and perception that allows us to selectively process and prioritize incoming visual information at a given location. There are two types: endogenous (voluntary) and exogenous (involuntary). Both typically improve visual perception, but there are instances where endogenous improves perception but exogenous hinders perception. Whether and how such differences extend to sensory representations is unknown. Here we show that both endogenous and exogenous attention mediate perception via the same neural computation-gain changes-but the strength of the orientation gain and the range of enhanced spatial frequencies depends on the type of attention being deployed. These findings reveal that both attention systems differentially reshape the tuning of features coded in striate cortex.