julilili42/papers huggingface dataset:
Indepth characterization of a cohort of individuals with missense and loss-of-function variants disruptingFOXP2
2022-06-06

Abstract Background Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder; childhood apraxia of speech (CAS), yet few cases have been reported, limiting knowledge of the condition. Methods Here we phenotyped 29 individuals from 18 families with pathogenic FOXP2 -only variants (13 loss-of-function, 5 missense variants; 14 males; aged 2 years to 62 years). Health and development (cognitive, motor, social domains) was examined, including speech and language outcomes with the first cross-linguistic analysis of English and German. Results Speech disorders were prevalent (24/26, 92%) and CAS was most common (23/26, 89%), with similar speech presentations across English and German. Speech was still impaired in adulthood and some speech sounds (e.g. ‘th’, ‘r’, ‘ch’, ‘j’) were never acquired. Language impairments (22/26, 85%) ranged from mild to severe. Comorbidities included feeding difficulties in infancy (10/27, 37%), fine (14/27, 52%) and gross (14/27, 52%) motor impairment, anxiety (6/28, 21%), depression (7/28, 25%), and sleep disturbance (11/15, 44%). Physical features were common (23/28, 82%) but with no consistent pattern. Cognition ranged from average to mildly impaired, and was incongruent with language ability; for example, seven participants with severe language disorder had average non-verbal cognition. Conclusions Although we identify increased prevalence of conditions like anxiety, depression and sleep disturbance, we confirm that the consequences of FOXP2 dysfunction remain relatively specific to speech disorder, as compared to other recently identified monogenic conditions associated with CAS. Thus, our findings reinforce that FOXP2 provides a valuable entrypoint for examining the neurobiological bases of speech disorder. What is already known on this topic Heterozygous disruptions of FOXP2 were the first identified molecular cause for severe speech disorder; childhood apraxia of speech (CAS), yet few cases have been reported, limiting knowledge of the condition. What this study adds Here we provide the most comprehensive characterisation of individuals with pathogenic FOXP2 variants, almost doubling the number of published families to date. We provide the first cross-linguistic analysis of speech and language across German and English. We show that the phenotype for pathogenic FOXP2 variants remains relatively specific to speech disorder, compared to phenotypes associated with other monogenic conditions involving CAS. How this study might affect research, practice or policy This study guides identification of cases with a FOXP2 -related disorder for a clinical genetic diagnosis, will improve prognostic counselling and lead to better targeted clinical management.
The emerging frontier of plant immunity's core hubs
2022-06-07

The ever‐growing world population, increasingly frequent extreme weather events and conditions, emergence of novel devastating crop pathogens and the social strive for quality food products represent a huge challenge for current and future agricultural production systems. To address these challenges and find realistic solutions, it is becoming more important by the day to understand the complex interactions between plants and the environment, mainly the associated organisms, but in particular pathogens. In the past several years, research in the fields of plant pathology and plant–microbe interactions has enabled tremendous progress in understanding how certain receptor‐based plant innate immune systems function to successfully prevent infections and diseases. In this review, we highlight and discuss some of these new ground‐breaking discoveries and point out strategies of how pathogens counteract the function of important core convergence hubs of the plant immune system. For practical reasons, we specifically place emphasis on potential applications that can be detracted by such discoveries and what challenges the future of agriculture has to face, but also how these challenges could be tackled.
From $t$-SNE to UMAP with contrastive learning
2022-06-07

Neighbor embedding methods -SNE and UMAP are the de facto standard for visualizing high-dimensional datasets. Motivated from entirely different viewpoints, their loss functions appear to be unrelated. In practice, they yield strongly differing embeddings and can suggest conflicting interpretations of the same data. The fundamental reasons for this and, more generally, the exact relationship between -SNE and UMAP have remained unclear. In this work, we uncover their conceptual connection via a new insight into contrastive learning methods. Noise-contrastive estimation can be used to optimize -SNE, while UMAP relies on negative sampling, another contrastive method. We find the precise relationship between these two contrastive methods and provide a mathematical characterization of the distortion introduced by negative sampling. Visually, this distortion results in UMAP generating more compact embeddings with tighter clusters compared to -SNE. We exploit this new conceptual connection to propose and implement a generalization of negative sampling, allowing us to interpolate between (and even extrapolate beyond) -SNE and UMAP and their respective embeddings. Moving along this spectrum of embeddings leads to a trade-off between discrete / local and continuous / global structures, mitigating the risk of over-interpreting ostensible features of any single embedding. We provide a PyTorch implementation.
GFPT1-Associated Congenital Myasthenic Syndrome Mimicking a Glycogen Storage Disease – Diagnostic Pitfalls in Myopathology Solved by Next-Generation-Sequencing
2022-06-07

GFPT1-related congenital myasthenic syndrome (CMS) is characterized by progressive limb girdle weakness, and less prominent involvement of facial, bulbar, or respiratory muscles. While tubular aggregates in muscle biopsy are considered highly indicative in GFPT1-associated CMS, excessive glycogen storage has not been described. Here, we report on three affected siblings with limb-girdle myasthenia due to biallelic pathogenic variants in GFPT1: the previously reported missense variant c.41G &gt; A (p.Arg14Gln) and the novel truncating variant c.1265_1268del (p.Phe422TrpfsTer26). Patients showed progressive proximal atrophic muscular weakness with respiratory involvement, and a lethal disease course in adulthood. In the diagnostic workup at that time, muscle biopsy suggested a glycogen storage disease. Initially, Pompe disease was suspected. However, enzymatic activity of acid alpha-glucosidase was normal, and gene panel analysis including 38 genes associated with limb-girdle weakness (GAA included) remained unevocative. Hence, a non-specified glycogen storage myopathy was diagnosed. A decade later, the diagnosis of GFPT1-related CMS was established by genome sequencing. Myopathological reexamination showed pronounced glycogen accumulations, that were exclusively found in denervated muscle fibers. Only single fibers showed very small tubular aggregates, identified in evaluation of serial sections. This family demonstrates how diagnostic pitfalls can be addressed by an integrative approach including broad genetic analysis and re-evaluation of clinical as well as myopathological findings.
Using circles games to investigate the referential use of negation
2022-06-07

Studies on the spontaneous production of negation suggest that it can be modulated by pragmatic principles of successful communication such as informativity and relevance. The present study investigates whether negation production is additionally modulated by a more general principle of effort minimisation. In a series of circles games, subjects were presented with pairs of circles and asked to complete a sentence that would allow a listener to identify one of the two circles. Negation was only produced when an affirmative description for the circle at issue was harder, i.e. there was no simple intuitive way to describe the circle's pattern. The length of the concurrent descriptions did not strictly influence the production of negation. The results suggest that the use of negation becomes more frequent as the effort to produce it decreases with respect to a concurrent affirmation, even at the cost of greater informativity of affirmation.
The TonB dependent uptake of pyrroloquinoline-quinone (PQQ) and secretion of gluconate by Escherichia coli K-12
2022-06-07

Summary Glucose is taken up by Escherichia coli through the phosphotransferase system (PTS) as the preferred carbon source. PTS mutants grow with glucose as a carbon source only in the presence of pyrroloquinoline quinone (PQQ), which is needed as a redox cofactor for the glucose dehydrogenase Gcd. The membrane-anchored Gcd enzyme oxidizes glucose to gluconolactone in the periplasm. For this reaction to occur, external supply of PQQ is required as E. coli is unable to produce PQQ de novo . Growth experiments show that PqqU (YncD) is the TonB-ExbBD dependent transporter for PQQ through the outer membrane. PQQ protected the cells from the PqqU dependent phage IsaakIselin (Bas10) by competition for the receptor protein. As a high affinity uptake system PqqU allows E. coli to activate Gcd even at surrounding PQQ concentrations of about 1 nmol/l. At about 30 fold higher PQQ concentrations the activation of Gcd gets PqqU independent. Due to its small size Pqq may also pass the outer membrane through porins. The PQQ dependent production of gluconate has been demonstrated in many plant growth promoting bacteria that solubilise phosphate minerals in the soil by secreting this acid. Under Pi limiting conditions also E. coli induces the glucose dehydrogenase and secretes gluconate, even in absence of PTS, that is, even when the bacterium is unable to grow on glucose without PQQ.
Inflammasome activation and an involvement of Caspase-1 in a bacterial clearance during S. aureus infection.
2022-06-07

BactInflam IJL focuses on the bacterial components involved in some inflammatory diseases. In particular, in two of them: chronic inflammatory bowel disease (IBD) and mastitis, affecting human health and animal health, respectively.
Influence of Oil Polarity and Cosurfactants on the Foamability of Mono- and Diacylphosphatidylcholine Stabilized Emulsions
2022-06-07

Foam formulations are safe and effective therapy options for the treatment of chronic skin conditions that require the application of a topical formulation to delicate skin areas, such as scalp psoriasis or seborrheic dermatitis. This study focused on the development of foamable emulsions based on aqueous phospholipid blends. The effects of cosurfactants (nonionic Lauryglucoside (LG); zwitterionic Lauramidopropyl betaine (LAPB)), as well as of oil phases of different polarities, namely paraffin oil (PO), medium-chain triglycerides (MCT) and castor oil (CO), were investigated. The foaming experiments showed that both the type of cosurfactant, as well as the type of oil phase, affects the quality of the resulting foam. Emulsions that were based on a combination of hydrogenated lysophosphatidylcholine (hLPC) and a non-hydrogenated phospholipid, as well as LG as a cosurfactant and MCT as an oil phase, yielded the most satisfactory results. Furthermore, profile analysis tensiometry (PAT), polarization microscopy and laser diffraction analysis were used to characterize the developed formulations. These experiments suggest that the employed phospholipids predominantly stabilize the emulsions, while the cosurfactants are mainly responsible for the formation and stabilization of the foams. However, it appears that both sets of excipients are needed in order to acquire stable emulsions with satisfactory foaming properties.
Neurodegeneration and Neuroinflammation in Parkinson’s Disease: a Self-Sustained Loop
2022-06-08

Abstract Purpose of Review Neuroinflammation plays a significant role in Parkinson’s disease (PD) etiology along with mitochondrial dysfunction and impaired proteostasis. In this context, mechanisms related to immune response can act as modifiers at different steps of the neurodegenerative process and justify the growing interest in anti-inflammatory agents as potential disease-modifying treatments in PD. The discovery of inherited gene mutations in PD has allowed researchers to develop cellular and animal models to study the mechanisms of the underlying biology, but the original cause of neuroinflammation in PD is still debated to date. Recent Findings Cell autonomous alterations in neuronal cells, including mitochondrial damage and protein aggregation, could play a role, but recent findings also highlighted the importance of intercellular communication at both local and systemic level. This has given rise to debate about the role of non-neuronal cells in PD and reignited intense research into the gut-brain axis and other non-neuronal interactions in the development of the disease. Whatever the original trigger of neuroinflammation in PD, what appears quite clear is that the aberrant activation of glial cells and other components of the immune system creates a vicious circle in which neurodegeneration and neuroinflammation nourish each other. Summary In this review, we will provide an up-to-date summary of the main cellular alterations underlying neuroinflammation in PD, including those induced by environmental factors (e.g. the gut microbiome) and those related to the genetic background of affected patients. Starting from the lesson provided by familial forms of PD, we will discuss pathophysiological mechanisms linked to inflammation that could also play a role in idiopathic forms. Finally, we will comment on the potential clinical translatability of immunobiomarkers identified in PD patient cohorts and provide an update on current therapeutic strategies aimed at overcoming or preventing inflammation in PD.
18F-Fluorodeoxyglucose Positron Emission Tomography of Head and Neck Cancer: Location and HPV Specific Parameters for Potential Treatment Individualization
2022-06-08

Purpose 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is utilized for staging and treatment planning of head and neck squamous cell carcinomas (HNSCC). Some older publications on the prognostic relevance showed inconclusive results, most probably due to small study sizes. This study evaluates the prognostic and potentially predictive value of FDG-PET in a large multi-center analysis. Methods Original analysis of individual FDG-PET and patient data from 16 international centers (8 institutional datasets, 8 public repositories) with 1104 patients. All patients received curative intent radiotherapy/chemoradiation (CRT) and pre-treatment FDG-PET imaging. Primary tumors were semi-automatically delineated for calculation of SUV max , SUV mean , metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Cox regression analyses were performed for event-free survival (EFS), overall survival (OS), loco-regional control (LRC) and freedom from distant metastases (FFDM). Results FDG-PET parameters were associated with patient outcome in the whole cohort regarding clinical endpoints (EFS, OS, LRC, FFDM), in uni- and multivariate Cox regression analyses. Several previously published cut-off values were successfully validated. Subgroup analyses identified tumor- and human papillomavirus (HPV) specific parameters. In HPV positive oropharynx cancer (OPC) SUV max was well suited to identify patients with excellent LRC for organ preservation. Patients with SUV max of 14 or less were unlikely to develop loco-regional recurrence after definitive CRT. In contrast FDG PET parameters deliver only limited prognostic information in laryngeal cancer. Conclusion FDG-PET parameters bear considerable prognostic value in HNSCC and potential predictive value in subgroups of patients, especially regarding treatment de-intensification and organ-preservation. The potential predictive value needs further validation in appropriate control groups. Further research on advanced imaging approaches including radiomics or artificial intelligence methods should implement the identified cut-off values as benchmark routine imaging parameters.
Large-stepsize integrators for charged-particle dynamics over multiple time scales
2022-06-08

Abstract The Boris algorithm, a closely related variational integrator and a newly proposed filtered variational integrator are studied when they are used to numerically integrate the equations of motion of a charged particle in a mildly non-uniform strong magnetic field, taking step sizes that are much larger than the period of the Larmor rotations. For the Boris algorithm and the standard (unfiltered) variational integrator, satisfactory behaviour is only obtained when the component of the initial velocity orthogonal to the magnetic field is filtered out. The particle motion shows varying behaviour over multiple time scales: fast gyrorotation, guiding centre motion, slow perpendicular drift, near-conservation of the magnetic moment over very long times and conservation of energy for all times. Using modulated Fourier expansions of the exact and numerical solutions, it is analysed to which extent this behaviour is reproduced by the three numerical integrators used with large step sizes that do not resolve the fast gyrorotations.
Gravitoturbulent dynamo in global simulations of gaseous disks
2022-06-08

The turbulence driven by gravitational instabilities (GIs) can amplify magnetic fields in massive gaseous disks. This GI dynamo may appear in young circumstellar disks, whose weak ionization challenges other amplification routes, as well as in active galactic nuclei. Although regarded as a large-scale dynamo, only local simulations have so far described its kinematic regime. We study the GI dynamo in global magnetohydrodynamic (MHD) models of accretion disks, focusing on its kinematic phase. We perform resistive MHD simulations with the Pluto code for different radiative cooling times and electrical resistivities. A weak magnetic field seeds the dynamo, and we adopt mean-field and heuristic models to capture its essence. We recover the same induction process leading to magnetic field amplification as previously identified in local simulations. The dynamo is, however, global in nature, connecting distant annuli of the disk via a large-scale dynamo mode of a fixed growth rate. This large-scale amplification can be described by a mean-field model that does not rely on conventional alpha-Omega effects. When varying the disk parameters we find an optimal resistivity that facilitates magnetic amplification, whose magnetic Reynolds number, Rm < 10, is substantially smaller than in local simulations. Unlike local simulations, we find an optimal cooling rate and the existence of global oscillating dynamo modes. The nonlinear saturation of the dynamo puts the disk in a strongly magnetized turbulent state on the margins of the effective range of GI. In our simulations, the accretion power eventually exceeds the threshold required by local thermal balance against cooling, leaving the long-term nonlinear outcome of the GI dynamo uncertain.
The impact of enzalutamide on quality of life in men with metastatic hormone‐sensitive prostate cancer based on prior therapy, risk, and symptom subgroups
2022-06-08

Abstract Background Enzalutamide plus androgen deprivation therapy (ADT) improved radiographic progression‐free survival versus ADT alone in patients with metastatic hormone‐sensitive prostate cancer (mHSPC) in ARCHES (NCT02677896). While health‐related quality of life (HRQoL) was generally maintained in the intent‐to‐treat population, we further analyzed patient‐reported outcomes (PROs) in defined subgroups. Methods ARCHES was a randomized, double‐blind, placebo‐controlled, phase 3 study. Patients with mHSPC received enzalutamide (160 mg/day) plus ADT ( n = 574) or placebo plus ADT ( n = 576). Questionnaires, including the Functional Assessment of Cancer Therapy−Prostate, Brief Pain Inventory−Short Form, and EuroQol 5‐Dimension, 5‐Level (EQ‐5D‐5L), were completed at baseline, Week 13, and every 12 weeks until disease progression. PRO endpoints were time to first confirmed clinically meaningful deterioration (TTFCD) in HRQoL or pain. Subgroups included prognostic risk, pain/HRQoL, prior docetaxel, and local therapy (radical prostatectomy [RP] and/or radiotherapy [RT]). Results There were several between‐treatment differences in TTFCD for pain and functioning/HRQoL PROs. Enzalutamide plus ADT delayed TTFCD for worst pain in the prior RT group (not reached vs. 14.06 months; hazard ratio [HR]: 0.56 [95% confidence interval: 0.34−0.94]) and pain interference in low‐baseline‐HRQoL group (19.32 vs. 11.20 months; HR: 0.64 [0.44−0.94]) versus placebo plus ADT. In prior/no prior RP, prior RT, prior local therapy, no prior docetaxel, mild baseline pain, and low‐risk subgroups, TTFCD was delayed for the EQ‐5D‐5L visual analog scale. Conclusion Enzalutamide plus ADT provides clinical benefits in defined patient subgroups versus ADT alone, while maintaining lack of pain and high HRQoL, with delayed deterioration in several HRQoL measures.
Beware of gastric tube in esophagectomy after gastric radiotherapy: A case report
2022-06-08

This case report may represent the start for further investigation to know if it is reasonable to refrain from esophagogastrostomy in patients with a long interval between gastric radiotherapy and surgery.
The interaction between anti-PF4 antibodies and anticoagulants in vaccine-induced thrombotic thrombocytopenia
2022-06-09

Abstract Life-threatening thrombotic events at unusual sites have been reported after vector-based vaccinations against severe acute respiratory syndrome coronavirus 2. This phenomenon is now termed vaccine-induced immune thrombotic thrombocytopenia (VITT). The pathophysiology of VITT is similar to that of heparin-induced thrombocytopenia (HIT) and is associated with platelet-activating antibodies (Abs) against platelet factor 4 (PF4). Therefore, current guidelines suggest nonheparin anticoagulants to treat VITT patients. In this study, we investigated the interactions of heparin, danaparoid, fondaparinux, and argatroban with VITT–Ab/PF4 complexes using an ex vivo model for thrombus formation as well as in vitro assays to analyze Ab binding and platelet activation. We found that immunoglobulin Gs (IgGs) from VITT patients induce increased adherent platelets/thrombus formation in comparison with IgGs from healthy controls. In this ex vivo flow-based model, the procoagulant activity of VITT IgGs was effectively inhibited with danaparoid and argatroban but also by heparin. Interestingly, heparin and danaparoid not only inhibited IgG binding to PF4 but were also able to effectively dissociate the preformed PF4/IgG complexes. Fondaparinux reduced the in vitro generation of procoagulant platelets and thrombus formation; however, it did not affect platelet aggregation. In contrast, argatroban showed no effect on procoagulant platelets and aggregation but significantly inhibited VITT-mediated thrombus formation. Taken together, our data indicate that negatively charged anticoagulants can disrupt VITT–Ab/PF4 interactions, which might serve as an approach to reduce Ab-mediated complications in VITT. Our results should be confirmed, however, in a clinical setting before a recommendation regarding the selection of anticoagulants in VITT patients could be made.