julilili42/papers huggingface dataset:
Pharmacotherapy for behavioural manifestations in frontotemporal dementia: An expert consensus from the European Reference Network for Rare Neurological Diseases (ERN‐RND)
2024-10-24

Abstract Background and Purpose Frontotemporal dementia (FTD) is a neurodegenerative disorder characterized by pervasive personality and behavioural disturbances with severe impact on patients and caregivers. In current clinical practice, treatment is based on nonpharmacological and pharmacological approaches. Unfortunately, trial‐based evidence supporting symptomatic pharmacological treatment for the behavioural disturbances in FTD is scarce despite the significant burden this poses on the patients and caregivers. Method The study examined drug management decisions for several behavioural disturbances in patients with FTD by 21 experts across European expert centres affiliated with the European Reference Network for Rare Neurological Diseases (ERN‐RND). Results The study revealed the highest consensus on drug treatments for physical and verbal aggression, impulsivity and obsessive delusions. Antipsychotics (primarily quetiapine) were recommended for behaviours posing safety risks to both patients and caregivers (aggression, self‐injury and self‐harm) and nightly unrest. Selective serotonin reuptake inhibitors were recommended for perseverative somatic complaints, rigidity of thought, hyperphagia, loss of empathy and for impulsivity. Trazodone was specifically recommended for motor unrest, mirtazapine for nightly unrest, and bupropion and methylphenidate for apathy. Additionally, bupropion was strongly advised against in 10 out of the 14 behavioural symptoms, emphasizing a clear recommendation against its use in the majority of cases. Conclusions The survey data can provide expert guidance that is helpful for healthcare professionals involved in the treatment of behavioural symptoms. Additionally, they offer insights that may inform prioritization and design of therapeutic studies, particularly for existing drugs targeting behavioural disturbances in FTD.
Infants infer and predict coherent event interactions: Modeling cognitive development
2024-10-24

Mental representations of the environment in infants are sparse and grow richer during their development. Anticipatory eye fixation studies show that infants aged around 7 months start to predict the goal of an observed action, e.g., an object targeted by a reaching hand. Interestingly, goal-predictive gaze shifts occur at an earlier age when the hand subsequently manipulates an object and later when an action is performed by an inanimate actor, e.g., a mechanical claw. We introduce CAPRI 2 (Cognitive Action PRediction and Inference in Infants), a computational model that explains this development from a functional, algorithmic perspective. It is based on the theory that infants learn object files and events as they develop a physical reasoning system. In particular, CAPRI 2 learns a generative event-predictive model, which it uses to both interpret sensory information and infer goal-directed behavior. When observing object interactions, CAPRI 2 (i) interprets the unfolding interactions in terms of event-segmented dynamics, (ii) maximizes the coherence of its event interpretations, updating its internal estimates and (iii) chooses gaze behavior to minimize expected uncertainty. As a result, CAPRI 2 mimics the developmental pathway of infants’ goal-predictive gaze behavior. Our modeling work suggests that the involved event-predictive representations, longer-term generative model learning, and shorter-term retrospective and active inference principles constitute fundamental building blocks for the effective development of goal-predictive capacities.
Dissection of signaling pathways regulating TrkB-dependent gephyrin clustering
2024-10-24

Introduction The TrkB receptor is known for its role in regulating excitatory neuronal plasticity. However, accumulating evidence over the past decade has highlighted the involvement of TrkB in regulating inhibitory synapse stability and plasticity, particularly through regulation of the inhibitory scaffold protein gephyrin, although with contradicting results. Methods In this study, we extended on these findings by overexpressing rat TrkB mutants deficient in either Shc-or PLCγ-dependent signaling, as well as a kinase-dead mutant, to dissect the contributions of specific TrkB-dependent signaling pathways to gephyrin clustering. Results Our results demonstrate that TrkB signaling is required for gephyrin clustering on the perisomatic area of granule cells in the dentate gyrus in vivo . To further investigate, we expressed TrkB wild-type and mutants in hippocampal neurons in vitro . Discussion Under basal conditions, TrkB-Shc signaling was important for the reduction of gephyrin cluster size, while TrkB-PLCγ signaling accounts for gephyrin clustering specifically at synaptic sites. Concomitant, impaired PLCγ signaling was associated with disinhibition of transduced neurons. Moreover, chemically induced inhibitory long-term potentiation (chem iLTP) depended on TrkB signaling and the activation of both Shc and PLCγ pathways. Conclusion Our findings suggest a complex, pathway-specific regulation of TrkB-dependent gephyrin clustering, both under basal conditions and during chem iLTP.
Diversity of Neurotransmitter Producing Human Skin Commensals
2024-10-24

Recent findings indicate that human microbiota can excrete trace amines, dopamine, and serotonin. These neurotransmitters (NTs) can either affect classical neurotransmitter signaling or directly trigger trace amine-associated receptors (TAARs), with still unclear consequences for host physiology. Compared to gut microbiota, less information is available on the role of skin microbiota in NT production. To explore this, 1909 skin isolates, mainly from the genera Staphylococcus, Bacillus, and Corynebacterium, were tested for NT production. Only 6.7% of the isolates were capable of producing NTs, all of which belonged to the Staphylococcus genus. Based on substrate specificity, we identified two distinct profiles among the NT producers. One group primarily produced tryptamine (TRY) and phenylethylamine (PEA), while the other mainly produced tyramine (TYM) and dopamine (Dopa). These differing production profiles could be attributed to the activity of two distinct aromatic amino acid decarboxylase enzymes, SadA and TDC, responsible for generating the TRY/PEA and TYM/Dopa product spectra, respectively. SadA and TDC orthologues differ in structure and size; SadA has approximately 475 amino acids, whereas the TDC-type consists of about 620 amino acids. The genomic localization of the respective genes also varies: tdc genes are typically found in small, conserved gene clusters, while sadA genes are not. Heterologous expression of sadA and tdc in Escherichia coli yielded the same product spectrum as the parent strains. The possible effects of skin microbiota-derived NTs on neuroreceptor signaling in the human host remain to be investigated.
Inferential-connexive mixed logics
2024-10-24

Abstract In this article, we present a new type of connexive-like logics. We call them inferential-connexive mixed logics, as they satisfy inferential versions of the main four connexive principles: AT, AT’, BT and BT’. We focus first on some Strong-Kleene type of mixed and inferentially connexive logics that cannot be interpreted as truth-preserving, but that can receive other interpretations in terms to falsity-preservation and related features. We introduce afterwards the notion of inferential-connexive Boolean logic, and present some logics that fall in this ballpark. We also explain the relation between inferentially-connexive Boolean logics and some inferentially-connexive Strong-Kleene logics, and show how they can also be interpreted in epistemic (or attitudinal)-related terms.
Evaluation of the Tobacco Heating System (THS) During Closed Lower Limb Fracture Healing in Trauma Smokers’ Patients
2024-10-24

BACKGROUND: Since 1976, it's been recognized that increased cigarette consumption correlates with decreased bone density, hindering fracture healing and leading to prolonged hospitalization. Although prior research has shown the relatively less harmful effects of electronic nicotine delivery systems (ENDS) on bone cells in lab settings and animal models, clinical evidence regarding their impact on fracture healing remains scarce. This study aims to investigate whether switching to a tobacco heating system (THS) post-orthopedic surgery improves outcomes for smoking patients during tibia or femur fracture healing over a 6-month period. METHODS: The study is a prospective, open-label, non-parallel, single-center trial involving 150 patients from a Level 1 Trauma center, Germany, diagnosed and treated for closed tibia, closed femur shaft, or closed distal femur fractures (according to AO/OTA: 41A2-41C3, 42A-C, 43A-C, 32A-C, 33A2-3, 33B-C). Participants will be categorized into three groups based on smoking behavior: smokers (no intervention), THS (participants switching from cigarettes to THS), and ex-smokers (participants abstaining from cigarettes or ENDS during the study). Clinical, radiological, and laboratory data will be collected during preoperative and postoperative assessments at 6, 12, 18, and 24 weeks. The primary outcome will be the serum concentration of N-terminal propeptide procollagen type 1, a bone formation marker. Secondary outcomes include bone metabolism, healing, immunological, blood count, and clinical parameters. Approval for the study protocol and consent declarations was obtained from the ethics committee of the medical faculty of Eberhard Karls University (724/2022BO1). DISCUSSION: The study results will provide evidence that switching to THS previous orthopedic intervention improves clinical outcomes during closed tibia or femur fracture healing in smokers’ patients due to reduced bone resorption rate consequent to the diminished activity of cigarette smoke-activated osteoclast.
The impact of viral respiratory infection on surgical outcome of cavopulmonary shunt
2024-10-24

Abstract Undetected respiratory infections may adversely affect the intrapulmonary resistance after Stage 2 or Stage 3 Fontan palliation. A few studies describe a higher risk for viral pneumonia during respiratory virus season, but none of them have focused on the effect of symptomatic viral pneumonia on in-hospital clinical course after bidirectional Glenn shunt. We analysed 77 patients who underwent bidirectional Glenn shunt surgery. Six patients were detected with pneumonia and proof of viral ribonucleic acid in tracheal mucus in the very early postoperative time. We compared them retrospectively to the remaining 71 patients regarding preoperative inflammatory signs, mortality, paediatric ICU length of stay, and ventilation time. The infection rate was not seasonal dependent. Ventilation time was significantly elongated in the pneumonia group (558 h ± 634 vs. 8.7 h ± 1.9; p &lt; 0.0001) and so was the paediatric ICU length of stay (29 days ± 26 vs. 3 days±1; p = 0.007). Significantly more patients in the pneumonia group required extracorporeal cardiac life support postoperatively. The mortality was significantly increased in patients with pneumonia. Even subclinical viral pneumonia may cause ventilation-to-perfusion mismatch by raising intrapulmonary resistance. Recorded parameters of postoperative paediatric ICU therapy showed a significant impact of a viral pneumonia on patients after bidirectional Glenn shunt. The respiratory syncytial virus vaccination does not protect these patients from infection with other respiratory viruses. The focus should be put on preoperative diagnosis of pulmonary infections in the vulnerable group of patients with univentricular hearts.
Functional PET/MRI reveals active inhibition of neuronal activity during optogenetic activation of the nigrostriatal pathway
2024-10-25

The dopaminergic system is a central component of the brain’s neurobiological framework, governing motor control and reward responses and playing an essential role in various brain disorders. Within this complex network, the nigrostriatal pathway represents a critical circuit for dopamine neurotransmission from the substantia nigra to the striatum. However, stand-alone functional magnetic resonance imaging is unable to study the intricate interplay between brain activation and its molecular underpinnings. In our study, the use of a functional [fluorine-18]2-fluor-2-deoxy- d -glucose positron emission tomography approach, simultaneously with blood oxygen level–dependent functional magnetic resonance imaging, provided an important insight that demonstrates an active suppression of the nigrostriatal activity during optogenetic stimulation. This result increases our understanding of the molecular mechanisms of brain function and provides an important perspective on how dopamine influences hemodynamic responses in the brain.
Continuous Blood Pressure Indices During the First 72 Hours and Functional Outcome in Patients with Spontaneous Intracerebral Hemorrhage
2024-10-25

Abstract Background Management of intracerebral hemorrhage (ICH) is challenged by limited therapeutic options and a complex relationship between blood pressure (BP) dynamics, especially BP variability (BPV) and ICH outcome. Methods In an exploratory analysis of prospectively collected data on consecutive patients with nontraumatic ICH between 2015 and 2020, continuous BP accessed via an arterial line extracted from the Intellispace Critical Care and Anesthesia information system (Philips Healthcare) was analyzed over the first 72 h post admission. Arterial lines were used as part of standard clinical practice in the intensive care, ensuring high fidelity and real-time data essential for acute care settings. BPV was assessed through successive variation (SV), standard deviation (SD), and coefficient of variation using all available BP measurements. Multivariate regression models were applied to evaluate the association between BPV indices and functional outcome at 3 months. Results Among 261 patients (mean age 69.6 ± 15.2 years, 47.9% female, median National Institutes of Health Stroke Scale [NIHSS] score 6 [interquartile range 2–12]) analyzed, lower systolic BP upon admission (&lt; 140 mm Hg) and lower systolic BPV were significantly associated with favorable outcome, whereas higher diastolic BPV correlated with improved outcomes. In the multivariate analysis, diastolic BPV (SD, SV) within the first 72 h post admission emerged as an independent predictor of good functional outcome (modified Rankin Scale score &lt; 3; odds ratio 1.123, 95% confidence interval CI 1.008–1.184, p = 0.035), whereas systolic BPV (SD) showed a negative association. Patients with better outcomes also exhibited distinct clinical characteristics, including younger age, lower median NIHSS scores, and less prevalence of anticoagulation therapy upon admission. Conclusions This study shows the prognostic value of BPV in the acute phase of ICH. Lower systolic BPV (SD) and higher diastolic BPV (SD, SV) were associated with better functional outcomes, challenging traditional BP management strategies. These findings might help to tailor a personalized BP management in ICH.
Heterogeneity of Endothelial Cells Impacts the Functionality of Human Pancreatic In Vitro Models
2024-10-25

Endothelial cells (ECs) play a crucial role in maintaining tissue homeostasis and functionality. Depending on their tissue of origin, ECs can be highly heterogeneous regarding their morphology, gene and protein expression, functionality, and signaling pathways. Understanding the interaction between organ-specific ECs and their surrounding tissue is therefore critical when investigating tissue homeostasis, disease development, and progression. <i>In vitro</i> models often lack organ-specific ECs, potentially limiting the translatability and validity of the obtained results. The goal of this study was to assess the differences between commonly used EC sources in tissue engineering applications, including human umbilical vein ECs (HUVECs), human dermal microvascular ECs (hdmvECs), and human foreskin microvascular ECs (hfmvECs), and organ-specific human pancreatic microvascular ECs (hpmvECs), and test their impact on functionality within an <i>in vitro</i> pancreas test system used for diabetes research. Utilizing high-resolution Raman microspectroscopy and Raman imaging in combination with established protein and gene expression analyses and exposure to defined physical signals within microfluidic cultures, we identified that ECs exhibit significant differences in their biochemical composition, relevant protein expression, angiogenic potential, and response to the application of mechanical shear stress. Proof-of-concept results showed that the coculture of isolated human islets of Langerhans with hpmvECs significantly increased the functionality when compared with control islets and islets cocultured with HUVECs. Our study demonstrates that the choice of EC type significantly impacts the experimental results, which needs to be considered when implementing ECs into <i>in vitro</i> models.
Strategic use of English quantifiers in the reporting of quantitative information
2024-10-25

This study investigates how quantifiers are used strategically to serve differ-ent argumentative goals. We report two experiments on how English speak-ers describe the results of school exams when being instructed to frame theirdescriptions either as a good or bad outcome. Experiment 1 shows thatparticipants have clear preferences for specific quantifier combinations inthis task. Experiment 2 shows that, in situations where producing descrip-tions that meet one’s argumentative goals is difficult (i.e. framing very badoutcomes positively), participants tend to use quantifiers that are informa-tionally weaker than other salient alternatives. Experiment 2 also shows thatpeople have a bias to frame outcomes positively, even when the task asksthem to frame them negatively. Put together, these results shed light on thequestion of how language users strategically explore different linguisticstrategies to communicate quantity in pragmatically favorable ways, includ-ing how quantifiers are used vis-`a-vis other lexical expressions of quantity.
Targeting the Plasmodium falciparum IspE Enzyme
2024-10-25

The enzyme IspE in <i>Plasmodium falciparum</i> is considered an attractive drug target, as it is essential for parasite survival and is absent in the human proteome. Yet it still has not been addressed by a small-molecule inhibitor. In this study, we conducted a high-throughput screening campaign against the <i>Pf</i>IspE enzyme. Our approach toward a <i>Pf</i>IspE inhibitor comprises <i>in vitro</i> screening, structure-activity relationship studies, examining the docking position using an AlphaFold model, and finally target verification through probe binding and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis. The newly synthesized probe containing a diazirine and an alkyne moiety (<b>23</b>) allowed us to demonstrate its binding to IspE in the presence of a lysate of human cells (HEK293 cells) and to get evidence that both probe <b>23</b> and the best inhibitor of the series (<b>19</b>) compete for the same IspE binding site.
Dysfunction of the episodic memory network in the Alzheimer’s disease cascade
2024-10-26

Abstract Alzheimer’s disease (AD) is a major cause of dementia and cognitive decline. Here we assessed how episodic memory circuit dysfunction, a hallmark of AD, is related to the longitudinal cascade of AD biomarkers, neurodegeneration and cognition using data from the DZNE Longitudinal Cognitive Impairment and Dementia study. This data set is unique by including over 1000 longitudinal functional magnetic resonance imaging (fMRI) measurements during episodic memory encoding. We leveraged a disease progression model (DPM) to obtain AD progression scores. Voxel-wise analyses revealed widespread loss of deactivation (hyperactivation) and activation (hypoactivation) with increasing disease stage. Hyperactivation trajectories were nonlinear and visually preceded trajectories of cognition. Overall, hyperactivation was independently associated with co-occurrence of amyloid- and tau-positivity and neurodegeneration, suggesting synaptic dysfunction and neurodegeneration as two independent drives of cognitive decline. Our results therefore provide evidence for a critical time window in which pharmacological treatments targeting the synapse may improve cognition.
Randomized crossover trial on motor and non-motor outcome of directional deep brain stimulation in Parkinson’s disease
2024-10-26

Abstract Deep brain stimulation (DBS) with electric field steering may avoid areas responsible for side effects. This prospective randomized cross-over trial compared omnidirectional (OS) and directional (DS) subthalamic DBS in 19 patients. Electromyographically measured rigidity was the primary outcome. Motor and non-motor scores were secondary outcomes. There were no significant differences between OS and DS. In the acute setting, both conditions improved motor scores compared to no stimulation. Motor symptoms improved after 3 weeks of OS relative to acute measurements, whereas they worsened under DS. The more ventral the active contact, and the less the motor improvement sweet spot was stimulated, the greater the benefit of DS over OS for executive function. Accurate OS of the dorsal subthalamic nucleus ensures motor and non-motor improvements. While DS can mitigate executive decline stemming from off-target stimulation, it may lead to worse motor outcomes. Larger, long-term studies are needed to confirm these findings. (Registration: subthalamic steering for therapy optimization in Parkinson’s Disease ClinicalTrials.gov: NCT03548506, 2018-06-06).
Biotic interactions shape infection outcomes inArabidopsis
2024-10-26

Abstract The plant microbiome protects plants from stresses, including pathogen attacks. However, identifying microbes that provide plant protection remains challenging in complex microbial communities. In this study, we analysed samples from natural A. thaliana populations, including both plants infected with the pathogenic oomycete Albugo laibachii and uninfected plants, over six years. Using machine learning classification models, we achieved high accuracy in distinguishing infected and uninfected plants based on microbiome abundance. We identified 80 key taxa associated with health and disease. Among the health-associated microbes (HCom), we selected bacteria, fungi, and cercozoa that effectively reduced pathogen presence in co-inoculation assays. In comparison, disease-associated microbes (DCom) were less effective in conferring protection. Our findings highlight the complexity of plant-microbe interactions and advance our understanding of microbial roles in plant disease ecology. By integrating ecological insights with machine learning, we take a significant step towards designing robust microbial consortia that enhance plant resilience against pathogens.