Miracle-dz/UniFAR-FTUs huggingface dataset:
A Novel Splice Site Mutation in IFNGR2 in Patients With Primary Immunodeficiency Exhibiting Susceptibility to Mycobacterial Diseases

Primary immunodeficiency (PID) refers to a group of heterogeneous genetic disorders with a weakened immune system. Mendelian susceptibility to mycobacterial disease (MSMD) is a subset of PID in which patients exhibit defects in intrinsic and innate immunity. It is a rare congenital disorder characterized by severe and recurrent infections caused by weakly virulent mycobacteria or other environmental mycobacteria. Any delay in definitive diagnosis poses a major concern due to the confounding nature of infections and immune deficiencies. Here, we report the clinical, immunological, and genetic characteristics of two siblings (infants) with recurrent infections. There was a history of death of two other siblings in the family after BCG vaccination. Whole exome sequencing of the two affected surviving infants along with their consanguineous parents identified a novel, homozygous single nucleotide splice acceptor site variant in intron 2 of the interferon gamma receptor 2 (IFNGR2) gene. Sanger sequencing of DNA obtained from blood and fibroblasts confirmed the variant. The patients underwent bone marrow transplantation from their father as a donor. RT-PCR and Sanger sequencing of the cDNA of patients from blood samples after transplantation showed the expression of both wild type and mutant transcript expression of IFNGR2. To assess partial or complete expression of IFNGR2 mutant transcripts, fibroblasts were cultured from skin biopsies. RT-PCR and Sanger sequencing of cDNA obtained from patient fibroblasts revealed complete expression of mutant allele and acquisition of a cryptic splice acceptor site in exon 3 that resulted in deletion of 9 nucleotides in exon 3. This led to an in-frame deletion of three amino acids p.(Thr70-Ser72) located in a fibronectin type III (FN3) domain in the extracellular region of IFNGR2. This illustrates individualized medicine enabled by next generation sequencing as identification of this mutation helped in the clinical diagnosis of MSMD in the infants as well as in choosing the most appropriate therapeutic option.
Perspectives of Healthcare Professionals on Meaningful Activities for Persons with Dementia in Transition from Home to a Nursing Home: An Explorative Study

Meaningful activities can enhance quality of life, a sense of connectedness, and personhood for persons with dementia. Healthcare professionals play an important role in maintaining meaningful activities, but little is currently known about the impact of the transition from home to nursing home on these activities. This study explored the experiences of professionals in four Dutch nursing homes, identifying facilitators and barriers to the maintenance of meaningful activities during the transition. A qualitative explorative design was used. Data were collected using focus groups and analyzed using thematic analysis. Twenty-two professionals participated in four focus groups, and three themes were identified: (1) a lack of awareness and attention for meaningful activities; (2) activities should be personalized and factors such as person characteristics, interests, the social and physical environment, and specific information such as roles, routines, activities, and personal issues play an important role in maintaining activities; (3) in the organization of care, a person-centered care vision, attitudes of professionals and interdisciplinary collaboration facilitate maintenance of meaningful activities. Healthcare professionals felt that meaningful activities are difficult to maintain and that improvements are needed. Our study provides suggestions on how to maintain meaningful activities for persons with dementia prior, during and after the transition.
A Minor Subpopulation of Mycobacteria Inherently Produces High Levels of Reactive Oxygen Species That Generate Antibiotic Resisters at High Frequency From Itself and Enhance Resister Generation From Its Major Kin Subpopulation

Antibiotic-exposed bacteria produce elevated levels of reactive oxygen species (ROS), to which either they succumb or get mutated genome-wide to generate antibiotic resisters. We recently showed that mycobacterial cultures contained two subpopulations, short-sized cells (SCs; ∼10%) and normal/long-sized cells (NCs; ∼90%). The SCs were significantly more antibiotic-susceptible than the NCs. It implied that the SCs might naturally be predisposed to generate significantly higher levels of ROS than the NCs. This in turn could make the SCs more susceptible to antibiotics or generate more resisters as compared to the NCs. Investigation into this possibility showed that the SCs in the actively growing mid-log phase culture naturally generated significantly high levels of superoxide, as compared to the equivalent NCs, due to the naturally high expression of a specific NADH oxidase in the SCs. This caused labile Fe2+ leaching from 4Fe-4S proteins and elevated H2O2 formation through superoxide dismutation. Thus, the SCs of both Mycobacterium smegmatis and Mycobacterium tuberculosis inherently contained significantly higher levels of H2O2 and labile Fe2+ than the NCs. This in turn produced significantly higher levels of hydroxyl radical through Fenton reaction, promoting enhanced antibiotic resister generation from the SCs than from the NCs. The SCs, when mixed back with the NCs, at their natural proportion in the actively growing mid-log phase culture, enhanced antibiotic resister generation from the NCs, to a level equivalent to that from the unfractionated whole culture. The enhanced antibiotic resister generation from the NCs in the reconstituted SCs-NCs natural mixture was found to be due to the high levels of H2O2 secreted by the SCs. Thus, the present work unveils and documents the metabolic designs of two mycobacterial subpopulations where one subpopulation produces high ROS levels, despite higher susceptibility, to generate significantly higher number of antibiotic resisters from itself and to enhance resister generation from its kin subpopulation. These findings show the existence of an inherent natural mechanism in both the non-pathogenic and pathogenic mycobacteria to generate antibiotic resisters. The presence of the SCs and the NCs in the pulmonary tuberculosis patients’ sputum, reported by us earlier, alludes to the clinical significance of the study.
A Robust and Universal Metaproteomics Workflow for Research Studies and Routine Diagnostics Within 24 h Using Phenol Extraction, FASP Digest, and the MetaProteomeAnalyzer

The investigation of microbial proteins by mass spectrometry (metaproteomics) is a key technology for simultaneously assessing the taxonomic composition and the functionality of microbial communities in medical, environmental, and biotechnological applications. We present an improved metaproteomics workflow using an updated sample preparation and a new version of the MetaProteomeAnalyzer software for data analysis. High resolution by multidimensional separation (GeLC, MudPIT) was sacrificed to aim at fast analysis of a broad range of different samples in less than 24 h. The improved workflow generated at least two times as many protein identifications than our previous workflow, and a drastic increase of taxonomic and functional annotations. Improvements of all aspects of the workflow, particularly the speed, are first steps toward potential routine clinical diagnostics (i.e., fecal samples) and analysis of technical and environmental samples. The MetaProteomeAnalyzer is provided to the scientific community as a central remote server solution at www.mpa. ovgu.de.
Association of Cortisol Levels With Neuropsychiatric Functions: A Mendelian Randomization Analysis

Aim: The conflicting evidence as to whether a real association exists between cortisol levels and depression lends support to adopting a Mendelian randomization approach to investigate whether cortisol levels have a causal effect with depression. Methods: Single nucleotide polymorphisms (SNPs) associated with serum morning plasma cortisol level and salivary cortisol level from CORNET consortium (12,597 participants) were proposed as instrumental variables. The primary outcome was depression, and the secondary outcomes were neuroticism and cognitive performance. Summary-level statistics were extracted from the Social Science Genetic Association Consortium including the United Kingdom Biobank cohort (105,739 subjects). Multiple analysis methods (inverse-variance weighted method, max likelihood method, weighted median estimator, model-based estimation, heterogeneity-penalized method, and MR-Egger regression) were applied to test the stability of the summary causal estimate. Results: Weighted median analysis estimated that the effect of serum morning cortisol on depression score was 0.027 per standard deviation increase of cortisol (95% CI, 0.000–0.054; p = 0.043). Other sensitivity analysis suggested similar results suggesting the result was robust. No evidence of pleiotropy (MR-Egger intercept, −0.002; p = 0.739) was observed. The effect of serum cortisol on neuroticism was 0.030 (95% CI, 0.008–0.052; p = 0.006) by weighted median estimator. None of the methods observed the effect of serum cortisol level on cognitive function. As for the effect of salivary cortisol level, no method obtained a p-value lower than 0.05 in any of the outcomes. Conclusion: Mendelian randomization analysis provided evidence that a genetic predisposition to higher serum morning cortisol level was associated with increased depression score.
The Nucleoprotein and Phosphoprotein of Measles Virus

Measles virus is a negative strand virus and the genomic and antigenomic RNA binds to the nucleoprotein (N), assembling into a helical nucleocapsid. The polymerase complex comprises two proteins, the Large protein (L), that both polymerizes RNA and caps the mRNA, and the phosphoprotein (P) that co-localizes with L on the nucleocapsid. This review presents recent results about N and P, in particular concerning their intrinsically disordered domains. N is a protein of 525 residues with a 120 amino acid disordered C-terminal domain, Ntail. The first 50 residues of Ntail extricate the disordered chain from the nucleocapsid, thereby loosening the otherwise rigid structure, and the C-terminus contains a linear motif that binds P. Recent results show how the 5′ end of the viral RNA binds to N within the nucleocapsid and also show that the bases at the 3′ end of the RNA are rather accessible to the viral polymerase. P is a tetramer and most of the protein is disordered; comprising 507 residues of which around 380 are disordered. The first 37 residues of P bind N, chaperoning against non-specific interaction with cellular RNA, while a second interaction site, around residue 200 also binds N. In addition, there is another interaction between C-terminal domain of P (XD) and Ntail. These results allow us to propose a new model of how the polymerase binds to the nucleocapsid and suggests a mechanism for initiation of transcription.
PACAP-PAC1 Receptor Activation Is Necessary for the Sympathetic Response to Acute Intermittent Hypoxia

Repetitive hypoxia is a key feature of obstructive sleep apnoea (OSA), a condition characterized by intermittent airways obstruction. Patients with OSA present with persistent increases in sympathetic activity and commonly develop hypertension. The objectives of this study were to determine if the persistent increases in sympathetic nerve activity, known to be induced by acute intermittent hypoxia (AIH), are mediated through activation of the pituitary adenylate cyclase activating polypeptide (PACAP) signaling system. Here, we show that the excitatory neuropeptide PACAP, acting in the spinal cord, is important for generating the sympathetic response seen following AIH. Using PACAP receptor knockout mice, and pharmacological agents in Sprague Dawley rats, we measured blood pressure, heart rate, pH, PaCO2, and splanchnic sympathetic nerve activity, under anaesthesia, to demonstrate that the sympathetic response to AIH is mediated via the PAC1 receptor, in a cAMP-dependent manner. We also report that both intermittent microinjection of glutamate into the rostroventrolateral medulla (RVLM) and intermittent infusion of a sub-threshold dose of PACAP into the subarachnoid space can mimic the sympathetic response to AIH. All the sympathetic responses are independent of blood pressure, pH or PaCO2 changes. Our results show that in AIH, PACAP signaling in the spinal cord helps drive persistent increases in sympathetic nerve activity. This mechanism may be a precursor to the development of hypertension in conditions of chronic intermittent hypoxia, such as OSA.
Spatial Continuity Effect vs. Spatial Contiguity Failure. Revising the Effects of Spatial Proximity Between Related and Unrelated Representations

The split-attention effect refers to learning with related representations in multimedia. Spatial proximity and integration of these representations are crucial for learning processes. The influence of varying amounts of proximity between related and unrelated information has not yet been specified. In two experiments (N1 = 98; N2 = 85), spatial proximity between a pictorial presentation and text labels was manipulated (high vs. medium vs. low). Additionally, in experiment 1, a control group with separated picture and text presentation was implemented. The results revealed a significant effect of spatial proximity on learning performance. In contrast to previous studies, the medium condition leads to the highest transfer, and in experiment 2, the highest retention score. These results are interpreted considering cognitive load and instructional efficiency. Findings indicate that transfer efficiency is optimal at a medium distance between representations in experiment 1. Implications regarding the spatial contiguity principle and the spatial contiguity failure are discussed.
Why Do Leaders Express Humility and How Does This Matter: A Rational Choice Perspective

The utility of leader humility expressing behavior has been examined by several studies across multiple levels. However, our knowledge about why leaders express humility continues to be sparse. Drawing on rational choice theory, this paper proposes a model examining whether followers’ capability triggers leader’s humility expressing behavior and how followers’ interpretations of it influence its effectiveness. Results from 278 leader-follower dyads from a time-lagged research design showed that followers’ capability as perceived by the leader is positively related to leader-expressed humility and, in turn, this behavior would conditionally enhance follower trust, that is, followers will trust the humble leader less when they attribute leader’s expressed humility more to serving impression management motives. Several theoretical and practical implications of this observation are discussed in this study.
Comparison of Sample Preparation Methods for Multielements Analysis of Olive Oil by ICP-MS

Elemental analysis of olive oils by Inductively Coupled Plasma Mass Spectrometry (ICP-MS) is challenging because of the high organic load in olive oil samples and the low analyte concentrations. However, conflicting operating procedures in the preparation of oils prior to analysis by ICP-MS have been reported to overcome these difficulties. This study compared three methods of inorganic elements’ extraction from olive oils: The two commonly used microwave-assisted, acid digestion, and liquid–liquid, ultrasound-assisted extraction methods; and an optimized method: The combined microwave digestion-evaporation. Overall, microwave digestion-based methods did not compare opportunely, and ultrasound-assisted extraction was found to provide the best accord between simplicity of use, detection limits and precision improvement. The detection limits were in the range of 0.3–160 µg·kg-1, 0.012–190 µg·kg−1 and 0.00061–1.5 µg·kg−1, while repeatabilities were in the range of 5–21%, 5.4–99% and 5.1–40% for the microwave digestion, the combined digestion-evaporation and the ultrasound assisted extraction, respectively. The ultrasound-assisted extraction is therefore recommended as a preparation method for olive oils prior to analysis by ICP-MS. The broader range of elements that can be accurately detected is expected to help increase the discriminatory power and performance of geographical traceability models.
Sarcopenia and sarcopenic obesity as prognostic predictors in hospitalized elderly patients with acute myocardial infarction

ABSTRACT Objective: To investigate the potential value of sarcopenia and sarcopenic obesity as prognostic predictors in hospitalized elderly patients with acute myocardial infarction. Methods: A cross-sectional study based on data collected from elderly patients with acute myocardial infarction, admitted to a public hospital located in the Northeastern region of Brazil, from April to July 2015. The diagnosis of sarcopenia was based on muscle mass, muscle strength and physical performance measurements. Cardiovascular risk and prognostic markers, such as troponin and creatine kynase MB isoenzyme values, acute myocardial infarction classification according to ST segment elevation, and thrombolysis in myocardial infarction score were used. Results: The sample comprised 99 patients with mean age of 71.6 (±7.4) years. Prevalence of sarcopenia and sarcopenic obesity was 64.6% and 35.4%, respectively. Sarcopenia was more prevalent among males (p=0.017) aged >80 years (p=0.008). Thrombolysis in myocardial infarction was the only marker of cardiovascular risk significantly associated with sarcopenia (p=0.002). Conclusion: Prevalence of sarcopenia was high and associated with thrombolysis in myocardial infarction risk score. Sarcopenic obesity affected approximately one-third of patients and was not associated with any of the prognostic predictors.
Regularization of the Spatial Inverse Positioning Problem of Revolute Joint Manipulators

Inverse kinematics is a central problem in robotics, and its solution is burdened with kinematic singularities, i.e. the task Jacobian of the problem is singular. A subproblem of the general inverse kinematics problem, the inverse positioning problem is considered for spatial manipulators consisting of revolute joints, and a regularization method is proposed that results in a regular task Jacobian in singular configurations as well, provided that the manipulator’s geometry makes movement in singular directions possible. The conditions of regularizability are investigated, and bounds on the singular values of the regularized task Jacobian are given that can be used to create stable closed-loop inverse kinematics algorithms. The proposed method is demonstrated on the inverse positioning problem of an elbow manipulator and compared to the Damped Least Squares and the Levenberg-Marquardt methods, and it is shown that only the proposed method can leave the singular configuration in the singular direction.
Effects of Metabolic Syndrome on Cognitive Performance of Adults During Exercise

The metabolic syndrome (MS) has been associated with poor performances in multiple cognitive domains, as processing speed, visuo-spatial abilities, and executive functioning. Exercise is a critical factor for MS people’s vulnerability to cognitive dysfunction, because this may be beneficial to reduce cognitive impairment, but limited physical activity and impaired cerebral blood flow in response to exercise have been reported by individuals suffering from MS. Using an attentional interference test, the Bivalent Shape Task (BST), and metaboreflex, we analyzed cognitive performance and cerebral oxygenation (COX) in 13 MS people (five women), and 14 normal age-matched control (CTL, six women). Five different sessions were administered to all participants, each lasting 12 min: control exercise recovery (CER), post-exercise muscle ischemia (PEMI) to activate the metaboreflex, CER + BST, PEMI + BST, and BST alone. During each session, cognitive performance was assessed by means of response times and response accuracy with which participants make the decision and COX was evaluated by near infrared spectroscopy with sensors applied in the forehead. Compared to CTL, MS group performed significantly worse in all sessions (F = 4.18; p = 0.05; ES = 0.13): their poorest performance was observed in the BST alone session. Moreover, when BST was added to PEMI, individuals of the CTL group significantly increased their COX compared to baseline (103.46 ± 3.14%), whereas this capacity was impaired in MS people (102.37 ± 2.46%). It was concluded that: (1) MS affects cognitive performance; (2) people with MS were able to enhance COX during exercise, but they impair their COX when an attentional interference task was added.
Clinicians’ views of using cortical auditory evoked potentials (CAEP) in the permanent childhood hearing impairment patient pathway

Abstract Objective: To obtain clinicians’ views on the use of cortical auditory evoked potentials (CAEP) in the clinical pathway. Design: A questionnaire aimed at clinicians who use the HEARLab system with the Aided Cortical Assessment (ACA) Module. Results compared for Australians (where HEARLab produced) to other countries. Sample: The questionnaire was completed by 49 clinicians; 33 from Australia and 13 clinicians outside of Australia and 3 clinicians, destination unknown. Results: The findings of this research demonstrated that clinicians using CAEPs found them valuable for clinical practice. CAEPs were used to verify or modify hearing aid fittings and were used for counselling parents to reinforce the need for hearing aids. With the use of speech token as the stimulus clinicians had more relevant information to increase confidence in decision-making on paediatric hearing management. Conclusions: The main benefit from the use of CAEPs (using speech token stimuli) was for infant hearing aid fitting programmes, to facilitate earlier decisions relating to hearing aid fitting, for fine-tuning the aids and as an additional measure for cochlear implant referrals.
Environmental pollution is associated with increased risk of psychiatric disorders in the US and Denmark

The search for the genetic factors underlying complex neuropsychiatric disorders has proceeded apace in the past decade. Despite some advances in identifying genetic variants associated with psychiatric disorders, most variants have small individual contributions to risk. By contrast, disease risk increase appears to be less subtle for disease-predisposing environmental insults. In this study, we sought to identify associations between environmental pollution and risk of neuropsychiatric disorders. We present exploratory analyses of 2 independent, very large datasets: 151 million unique individuals, represented in a United States insurance claims dataset, and 1.4 million unique individuals documented in Danish national treatment registers. Environmental Protection Agency (EPA) county-level environmental quality indices (EQIs) in the US and individual-level exposure to air pollution in Denmark were used to assess the association between pollution exposure and the risk of neuropsychiatric disorders. These results show that air pollution is significantly associated with increased risk of psychiatric disorders. We hypothesize that pollutants affect the human brain via neuroinflammatory pathways that have also been shown to cause depression-like phenotypes in animal studies.