julilili42/papers huggingface dataset:
Simple models including energy and spike constraints reproduce complex activity patterns and metabolic disruptions
2020-12-21

In this work, we introduce new phenomenological neuronal models ( e LIF and mAdExp) that account for energy supply and demand in the cell as well as the inactivation of spike generation how these interact with subthreshold and spiking dynamics. Including these constraints, the new models reproduce a broad range of biologically-relevant behaviors that are identified to be crucial in many neurological disorders, but were not captured by commonly used phenomenological models. Because of their low dimensionality e LIF and mAdExp open the possibility of future large-scale simulations for more realistic studies of brain circuits involved in neuronal disorders. The new models enable both more accurate modeling and the possibility to study energy-associated disorders over the whole time-course of disease progression instead of only comparing the initially healthy status with the final diseased state. These models, therefore, provide new theoretical and computational methods to assess the opportunities of early diagnostics and the potential of energy-centered approaches to improve therapies.
Impact of Baseline Characteristics on the Effectiveness of Disorder-Specific Cognitive Behavioral Analysis System of Psychotherapy (CBASP) and Supportive Psychotherapy in Outpatient Treatment for Persistent Depressive Disorder
2020-12-21

Importance: In the treatment of persistent depressive disorder (PDD), disorder-specific Cognitive Behavioral Analysis System of Psychotherapy (CBASP) has been shown to be superior to Supportive Psychotherapy (SP) in outpatients. It remains to clear which subgroups of patients benefit equally and differentially from both psychotherapies. Objective: To identify those patient-level baseline characteristics that predict a comparable treatment effectiveness of CBASP and SP and those that moderate the differential effectiveness of CBASP compared to SP. Design, setting and participants: In this analysis of a 48-week multicenter randomized clinical trial comparing CBASP to SP in adult antidepressant-free outpatients with early-onset PDD, we evaluated baseline variables from the following domains as potential predictors and moderators of treatment effectiveness: socio-demography, clinical status, psychosocial and global functioning, life quality, interpersonal problems, childhood trauma, treatment history, preference for psychotherapy, and treatment expectancy. Interventions: A 48-week treatment program with 32 sessions of either CBASP or SP. Main outcomes and measures: Depression severity measured by the 24-item Hamilton Rating Scale for Depression (HRSD-24) at week 48. Results: From N = 268 randomized outpatients, N = 209 completed the 48-week treatment program. CBASP completers had significantly lower post-treatment HRSD-24 scores than SP completers (mean CBASP =13.96, sd CBASP = 9.56; mean SP = 16.69, sd SP = 9.87; p = 0.04). A poor response to both therapies was predicted by higher baseline levels of clinician-rated depression, elevated suicidality, comorbid anxiety, lower social functioning, higher social inhibition, moderate-to-severe early emotional or sexual abuse, no preference for psychotherapy, and the history of at least one previous inpatient treatment. Moderator analyses revealed that patients with higher baseline levels of self-rated depression, comorbidity of at least one Axis-I disorder, self-reported moderate-to-severe early emotional or physical neglect, or at least one previous antidepressant treatment, had a significantly lower post-treatment depression severity with CBASP compared to SP (all p &amp;lt; 0.05). Conclusions and relevance: A complex multifactorial interaction between severe symptoms of depression, suicidality, and traumatic childhood experiences characterized by abuse, social inhibition, and anxiety may represent the basis of non-response to psychotherapy in patients with early onset PDD. Specific psychotherapy with CBASP might, however, be more effective and recommendable for a variety of particularly burdened patients compared to SP.
Metabolite Triplet in Serum Improves the Diagnostic Accuracy of Prediabetes and Diabetes Screening
2020-12-21

Large-scale population screenings are not feasible by applying laborious oral glucose tolerance tests, but using fasting blood glucose (FPG) and glycated hemoglobin (HbA<sub>1c</sub>), a considerable number of diagnoses are missed. A novel marker is urgently needed to improve the diagnostic accuracy of broad-scale diabetes screening in easy-to-collect blood samples. In this study, by applying a novel knowledge-based, multistage discovery and validation strategy, we scaled down from 108 diabetes-associated metabolites to a diagnostic metabolite triplet (Met-T), namely hexose, 2-hydroxybutyric/2-hydroxyisobutyric acid, and phenylalanine. Met-T showed in two independent cohorts, each comprising healthy controls, prediabetic, and diabetic individuals, distinctly higher diagnostic sensitivities for diabetes screening than FPG alone (>79.6 vs <68%). Missed diagnoses decreased from >32% using fasting plasma glucose down to <20.4%. Combining Met-T and fasting plasma glucose further improved the diagnostic accuracy. Additionally, a positive association of Met-T with future diabetes risk was found (odds ratio: 1.41; <i>p</i> = 1.03 × 10<sup>-6</sup>). The results reveal that missed prediabetes and diabetes diagnoses can be markedly reduced by applying Met-T alone or in combination with FPG and it opens perspectives for higher diagnostic accuracy in broad-scale diabetes-screening approaches using easy to collect sample materials.
A context analysis of bobbing and fin‐flicking in a small marine benthic fish
2020-12-21

Abstract Most antipredator strategies increase survival of individuals by signaling to predators, by reducing the chances of being recognized as prey, or by bewildering a predator's perception. In fish, bobbing and fin‐flicking are commonly considered as pursuit‐deterrent behaviors that signal a predator that it has been detected and thus lost its surprise‐attack advantage. Yet, very few studies assessed whether such behavioral traits are restricted to the visual presence of a predator. In this study, we used the yellow black‐headed triplefin Tripterygion delaisi to investigate the association between these behaviors and the visual exposure to (a) a black scorpionfish predator ( Scorpaena porcus ), (b) a stone of a size similar to that of S. porcus , (c) a conspecific, and (d) a harmless heterospecific combtooth blenny ( Parablennius sanguinolentus ). We used a laboratory‐controlled experiment with freshly caught fish designed to test for differences in visual cues only. Distance kept by the focal fish to each stimulus and frequency of bobbing and fin‐flicking were recorded. Triplefins kept greater distance from the stimulus compartment when a scorpionfish predator was visible. Bobbing was more frequent in the visual presence of a scorpionfish, but also shown toward the other stimuli. However, fin flicks were equally abundant across all stimuli. Both behaviors decreased in frequency over time suggesting that triplefin become gradually comfortable in a nonchanging new environment. We discuss why bobbing and fin‐flicking are not exclusive pursuit‐deterrent behaviors in this species, and propose additional nonexclusive functions such as enhancing depth perception by parallax motion (bobbing) or signaling vigilance (fin‐flicking).
Response and oil degradation activities of a northeast Atlantic bacterial community to biogenic and synthetic surfactants
2020-12-21

Abstract Background Although synthetic dispersants are effective in dispersing crude oil, they can alter the natural microbial response to oil and potentially hinder its biodegradation. Biosurfactants, however, are naturally derived products that play a similar role to synthetic dispersants in oil spill response but are easily biodegradable and less toxic. This study investigated the microbial community dynamics, ecological drivers, functional diversity, and oil biodegradation potential of a northeast Atlantic marine microbial community to crude oil when exposed to rhamnolipid or synthetic dispersant Finasol OSR52. Results We found the microbial community composition and diversity were markedly different in the rhamnolipid-amended treatment compared to that with Finasol, with key aromatic hydrocarbon-degrading bacteria like Cycloclasticus being suppressed in the Finasol treatment but not in oil-only and rhamnolipid-amended treatments. Psychrophilic Colwellia and Oleispira dominated the community in both the rhamnolipid and Finasol OSR52 treatments initially but later community structure across treatments diverged significantly: Rhodobacteraceae and Vibrio dominated the Finasol-amended treatment and Colwellia, Oleispira , and later Cycloclasticus and Alcanivorax , dominated the rhamnolipid-amended treatment. Vibrio abundance increased substantially in treatments receiving Finasol, suggesting a potentially important role for these organisms in degrading dispersant components. In fact, Finasol was linked with a negative impact on alpha diversity. Deterministic environmental filtering played a dominant role in regulating the community assembly in all treatments but was strongest in the dispersant-amended treatments. Rhamnolipid-amended and oil-only treatments had the highest functional diversity, however, the overall oil biodegradation was greater in the Finasol treatment, but aromatic biodegradation was highest in the rhamnolipid treatment. Conclusion Overall, the natural marine microbial community in the northeast Atlantic responded differently to crude oil dispersed with either synthetic or biogenic surfactants over time, but oil degradation was more enhanced by the synthetic dispersant. Collectively, our results advance the understanding of how rhamnolipid biosurfactants affect the natural marine microbial community, supporting their potential application in oil spills.
Molecular Design of a “Two-in-One” Orthosteric-Allosteric Chimeric Mutant Selective EGFR Inhibitor
2020-12-21

Inhibitors developed to target the epidermal growth factor receptor (EGFR) are an effective therapy for patients with non-small cell lung cancer harbouring drug-sensitive activating mutations in the EGFR kinase domain. Drug resistance due to treatment-acquired mutations within the receptor itself has motivated development of successive generations of inhibitors that bind in the ATP-site, and third-generation agent osimertinib is now a first-line treatment for this disease. More recently, allosteric inhibitors have been developed to overcome the C797S mutation that confers resistance to osimertinib. In this study, we present the rational structure-guided design and synthesis of a mutant-selective EGFR inhibitor that spans the ATPand allosteric sites. The lead compound consists of a pyridinyl imidazole scaffold that binds irreversibly in the orthosteric site fused with a benzylisoindolinedione occupying the allosteric site. The compound potently inhibits enzymatic activity in L858R/T790M/C797S mutant EGFR (4.9 nM), with relative sparing of wild-type EGFR (47 nM). Additionally, this compound achieves cetuximab-independent, mutant-selective cellular efficacy on the L858R and L858R/T790M variants
Impaired adaptation of learning to contingency volatility in internalizing psychopathology
2020-12-22

Using a contingency volatility manipulation, we tested the hypothesis that difficulty adapting probabilistic decision-making to second-order uncertainty might reflect a core deficit that cuts across anxiety and depression and holds regardless of whether outcomes are aversive or involve reward gain or loss. We used bifactor modeling of internalizing symptoms to separate symptom variance common to both anxiety and depression from that unique to each. Across two experiments, we modeled performance on a probabilistic decision-making under volatility task using a hierarchical Bayesian framework. Elevated scores on the common internalizing factor, with high loadings across anxiety and depression items, were linked to impoverished adjustment of learning to volatility regardless of whether outcomes involved reward gain, electrical stimulation, or reward loss. In particular, high common factor scores were linked to dampened learning following better-than-expected outcomes in volatile environments. No such relationships were observed for anxiety- or depression-specific symptom factors.
Staphylococcus lugdunensis: a Skin Commensal with Invasive Pathogenic Potential
2020-12-22

Staphylococcus lugdunensis is a species of coagulase-negative staphylococcus (CoNS) that causes serious infections in humans akin to those of S. aureus . It was often misidentified as S. aureus , but this has been rectified by recent routine use of matrix-assisted laser desorption ionization–time of flight mass spectrometry (MALDI-TOF MS) in diagnostic laboratories. It encodes a diverse array of virulence factors for adhesion, cytotoxicity, and innate immune evasion, but these are less diverse than those encoded by S. aureus .
Dietary Carbohydrates and Fat Induce Distinct Surfactant Alterations in Mice
2020-12-22

Obesity and type 2 diabetes are nutrition-related conditions associated with lung function impairment and pulmonary diseases; however, the underlying pathomechanisms are incompletely understood. Pulmonary surfactant is essential for lung function, and surfactant synthesis by AT2 (alveolar epithelial type 2) cells relies on nutrient uptake. We hypothesized that dietary amounts of carbohydrates or fat affect surfactant homeostasis and composition. Feeding mice a starch-rich diet (StD), sucrose-rich diet (SuD), or fat-rich diet (FaD) for 30 weeks resulted in hypercholesterolemia and hyperinsulinemia compared with a fiber-rich control diet. In SuD and FaD groups, lung mechanic measurements revealed viscoelastic changes during inspiration, indicating surfactant alterations, and interfacial adsorption of isolated surfactant at the air-liquid interface was decreased under FaD. The composition of characteristic phospholipid species was modified, including a shift from dipalmitoyl-phosphatidylcholine (PC16:0/16:0) to palmitoyl-palmitoleoyl-phosphatidylcholine (PC16:0/16:1) in response to carbohydrates and decreased myristic acid-containing phosphatidylcholine species (PC14:0/14:0; PC16:0/14:0) on excess fat intake, as well as higher palmitoyl-oleoyl-phosphatidylglycerol (PG16:0/18:1) and palmitoyl-linoleoyl-phosphatidylglycerol (PG16:0/18:2) fractions in StD, SuD, and FaD groups than in the control diet. Moreover, mRNA expression levels of surfactant synthesis-related proteins within AT2 cells were altered. Under the StD regimen, AT2 cells showed prominent lipid accumulations and smaller lamellar bodies. Thus, in an established mouse model, distinct diet-related surfactant alterations were subtle, yet detectable, and may become challenging under conditions of reduced respiratory capacity. Dietary fat was the only macronutrient significantly affecting surfactant function. This warrants future studies examining alimentary effects on lung surfactant, with special regard to pulmonary complications in obesity and type 2 diabetes.
Comparative Proteomics of Marinobacter sp. TT1 Reveals Corexit Impacts on Hydrocarbon Metabolism, Chemotactic Motility, and Biofilm Formation
2020-12-22

The application of chemical dispersants during marine oil spills can affect the community composition and activity of marine microorganisms. Several studies have indicated that certain marine hydrocarbon-degrading bacteria, such as Marinobacter spp., can be inhibited by chemical dispersants, resulting in lower abundances and/or reduced biodegradation rates. However, a major knowledge gap exists regarding the mechanisms underlying these physiological effects. Here, we performed comparative proteomics of the Deepwater Horizon isolate Marinobacter sp. TT1 grown under different conditions. Strain TT1 received different carbon sources (pyruvate vs. n-hexadecane) with and without added dispersant (Corexit EC9500A). Additional treatments contained crude oil in the form of a water-accommodated fraction (WAF) or chemically-enhanced WAF (CEWAF; with Corexit). For the first time, we identified the proteins associated with alkane metabolism and alginate biosynthesis in strain TT1, report on its potential for aromatic hydrocarbon biodegradation and present a protein-based proposed metabolism of Corexit components as carbon substrates. Our findings revealed that Corexit exposure affects hydrocarbon metabolism, chemotactic motility, biofilm formation, and induces solvent tolerance mechanisms, like efflux pumps, in strain TT1. This study provides novel insights into dispersant impacts on microbial hydrocarbon degraders that should be taken into consideration for future oil spill response actions.
Case Report: Acute Spinal Cord Myelopathy in Patients With COVID-19
2020-12-22

COVID-19 is typically associated with fever and severe respiratory symptoms including dry cough and dyspnea. However, COVID-19 may also affect both central and peripheral nervous systems. To date, the incidence rate of spinal cord involvement in COVID-19 is not known and the pathogenesis is still not fully understood. We report here two female patients admitted to Assiut University Hospitals/Egypt during the period from first of July to August 10, 2020. Both presented with a positive SARS-CoV-2 polymerase chain reaction (PCR) nasopharyngeal swab, elevated serum d -dimer and ferritin levels, and bilateral ground glass appearance in a CT chest scan. The first was a 60-year-old female with acute onset of flaccid paraplegia 10 days after flu-like symptoms, in whom MRI revealed transverse myelitis. The second was a 21-year-old female with symptoms of acute quadriplegia, fever, headache, and anosmia in whom an MRI scan revealed long cervico-thoracic myelopathy. Anterior spinal artery occlusion and possibly transverse myelitis were considered as differential diagnosis of long segment myelopathy.
Case Report: Expanding the Genetic and Phenotypic Spectrum of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay
2020-12-22

Autosomal recessive spastic ataxia of Charlevoix–Saguenay (ARSACS) is a rare neurodegenerative disorder caused by biallelic mutations in the SACS gene. Once thought to be limited to Charlevoix–Saguenay region of Quebec, recent evidence has indicated that this disorder is present worldwide. It is classically characterized by the triad of ataxia, pyramidal involvement, and axonal-demyelinating sensorimotor neuropathy. However, diverse clinical features have been reported to be associated with this disorder. In this report, we present the first Iranian family affected by ARSACS with unique clinical features (mirror movements, hypokinesia/bradykinesia, and rigidity) harboring a novel deletion mutation in the SACS gene. Our findings expand the genetic and phenotypic spectrum of this disorder.
Predicting Math Student Success in the Initial Phase of College With Sparse Information Using Approaches From Statistical Learning
2020-12-22

In math teacher education, dropout research relies mostly on frameworks which carry out extensive variable collections leading to a lack of practical applicability. We investigate the completion of a first semester course as a dropout indicator and thereby provide not only good predictions, but also generate interpretable and practicable results together with easy-to-understand recommendations. As proof-of-concept, a sparse feature space together with machine learning methods is used for prediction of dropout, wherein the most predictive features have to be identified. Interpretability can be reached by introducing risk groups for the students. Implications for interventions are discussed.
High resolution X-ray spectroscopy of Supergiant HMXB 4U1700−37 during the compact object eclipse.
2020-12-22

Abstract We present an analysis of the first observation of the iconic High Mass X-ray Binary 4U 1700−37 with the Chandra High Energy Transmission Gratings during an X-ray eclipse. The goal of the observation was to study the structure/physical conditions in the clumpy stellar wind through high resolution spectroscopy. We find that: a) emission line brightness from K shell transitions, corresponding to near neutral species, directly correlates with continuum illumination. However, these lines do not greatly diminish during eclipse. This is readily explained if fluorescence Kα emission comes from the bulk of the wind. b) The highly ionised Fe xxv and Fe xxvi Lyα diminish during eclipse. Thus, they must be produced in the vicinity of the compact object where log ξ &amp;gt; 3. c) to describe the emission line spectrum, the sum of two self consistent photo ionisation models with low ionisation (log ξ ∼ −1) and high ionisation (log ξ ∼ 2.4) is required. From their emission measures, the clump-to-interclump density ratio can be estimated to be nc/ni ∼ 300. To fit the complex He-like Si xiii profile, the plasma requires a broadening with vbulk ∼ 840 km s−1. Reproducing the observed r ≈ f line fluxes requires the addition of a third collisionally ionised plasma. d) Emission lines widths appear unresolved at the hetg gratings resolution with exception of Silicon. There is no clear radial segregation between (quasi)neutral and ionised species, consistent with cold wind clumps interspersed in a hot rarefied interclump medium.
Cytopath: Simulation-based inference of differentiation trajectories from RNA velocity fields
2020-12-22

A bstract Trajectory inference from single-cell RNA sequencing data bears the potential to systematically reconstruct complex differentiation processes, however inferring trajectories that accurately model the biological characteristics of varied processes continues to be a challenge, notwithstanding the many available solutions. In general, trajectory and pseudotime inference methods have so far suffered from the ambiguity of static single-cell transcriptome snapshots lacking a concept of directionality and rate of transcriptional activity. We report Cytopath, a method for trajectory inference that takes advantage of transcriptional activity information from RNA velocity of single-cells to perform trajectory inference. Cytopath performs this task by defining a Markov chain model, simulating an ensemble of possible differentiation trajectories and constructs a consensus trajectory. We show that Cytopath can recapitulate the topological and molecular characteristics of the differentiation process under study. In our analysis we include differentiation trajectories with varying bifurcated, circular, convergent and mixed topology studied in single-snapshot as well as time-series single-cell RNA sequencing experiments. We demonstrate superior and enabling capability to reconstruct differentiation trajectories in comparison to state-of-the art trajectory inference approaches.
Fate trajectories of CD8+T cells in chronic LCMV infection
2020-12-22

A bstract In chronic infections CD8 + T cells acquire a state termed “exhaustion” which is characterized by impaired effector functions and expression of co-inhibitory receptors as response to continuous TCR stimulation. Recently, the pool of exhausted T cells has been shown to harbor multiple functionally distinct populations with memory-like and effector-like features, though differentiation and lineage relations between these are unclear. In this work we present a comprehensive scRNAseq time-series analysis from beginning of infection to established exhaustion in CD8 T cells. We apply lineage inference using informed cell transitions derived from RNA velocity to identify differential start and end states and connections between them. We identify a branch region early during chronic infection where pre-committed cells separate into an exhausted and a memory-like lineage and discovered molecular markers demarcating this branch event. Adoptive transfer experiments confirmed fate-commitment of cells only after this branch point. We additionally linked the progression along developmental lineages to antigenic TCR stimulation.