julilili42/papers huggingface dataset:
Author Response: mitoBKCa is functionally expressed in murine and human breast cancer cells and potentially contributes to metabolic reprogramming
2024-04-08

Alterations in the function of K+ channels such as the voltage- and Ca2+ activated K+ channel of large conductance (BKCa) reportedly promote breast cancer (BC) development and progression. Underlying molecular mechanisms remain, however, elusive. Here, we provide electrophysiological evidence for a BKCa splice variant localized to the inner mitochondrial membrane of murine and human BC cells (mitoBKCa). Through a combination of genetic knockdown and knockout along with cell permeable BKCa channel blocker, we show that mitoBKCa modulates overall cellular and mitochondrial energy production and mediates the metabolic rewiring referred to as the "Warburg effect", thereby promoting BC cell proliferation in the presence and absence of oxygen. Additionally, we detect mitoBKCa and BKCa transcripts in low or high abundance, respectively, in clinical BC specimens. Together, our results emphasize, that targeting mitoBKCa could represent a treatment strategy for selected BC patients in future.
mitoBKCa is functionally expressed in murine and human breast cancer cells and potentially contributes to metabolic reprogramming
2024-04-08

Summary Alterations in the function of K+ channels such as the voltage- and Ca2+ activated K+ channel of large conductance (BKCa) reportedly promote breast cancer (BC) development and progression. Underlying molecular mechanisms remain, however, elusive. Here, we provide electrophysiological evidence for a BKCa splice variant localized to the inner mitochondrial membrane of murine and human BC cells (mitoBKCa). Through a combination of genetic knockdown and knockout along with cell permeable BKCa channel blocker, we show that mitoBKCa modulates overall cellular and mitochondrial energy production and mediates the metabolic rewiring referred to as the “Warburg effect”, thereby promoting BC cell proliferation in the presence and absence of oxygen. Additionally, we detect mitoBKCa and BKCa transcripts in low or high abundance, respectively, in clinical BC specimens. Together, our results emphasize, that targeting mitoBKCa could represent a treatment strategy for selected BC patients in future.
Acknowledgment
2024-04-08

The scope and selection of topics addressed in the final form of this book were crucially inspired by mentors with their guidance and by giving me the freedom to find my own approach to answering questions and solving problems.
Author Response: Retinal metabolism: Evidence for uncoupling of glycolysis and oxidative phosphorylation via Cori-, Cahill-, and mini-Krebs-cycle
2024-04-08

The retina consumes massive amounts of energy, yet its metabolism and substrate exploitation remain poorly understood. Here, we used a murine explant model to manipulate retinal energy metabolism under entirely controlled conditions and utilized 1H-NMR spectroscopy-based metabolomics, in situenzyme detection, and cell viability readouts to uncover the pathways of retinal energy production. Our experimental manipulations resulted in varying degrees of photoreceptor degeneration, while the inner retina and retinal pigment epithelium were essentially unaffected. This selective vulnerability of photoreceptors suggested very specific adaptations in their energy metabolism. Rod photoreceptors were found to rely strongly on oxidative phosphorylation, but only mildly on glycolysis. Conversely, cone photoreceptors were dependent on glycolysis but insensitive to electron transport chain decoupling. Importantly, photoreceptors appeared to uncouple glycolytic and Krebs-cycle metabolism via three different pathways: 1) the mini-Krebs-cycle, fueled by glutamine and branched-chain amino acids, generating N-acetylaspartate; 2) the alanine-generating Cahill-cycle; 3) the lactate-releasing Cori-cycle. Moreover, the metabolomic data indicated a shuttling of taurine and hypotaurine between the retinal pigment epithelium and photoreceptors, likely resulting in an additional net transfer of reducing power to photoreceptors. These findings expand our understanding of retinal physiology and pathology and shed new light on neuronal energy homeostasis and the pathogenesis of neurodegenerative diseases.
The landscape of biomedical research
2024-04-09

The number of publications in biomedicine and life sciences has grown so much that it is difficult to keep track of new scientific works and to have an overview of the evolution of the field as a whole. Here, we present a two-dimensional (2D) map of the entire corpus of biomedical literature, based on the abstract texts of 21 million English articles from the PubMed database. To embed the abstracts into 2D, we used the large language model PubMedBERT, combined with <i>t</i>-SNE tailored to handle samples of this size. We used our map to study the emergence of the COVID-19 literature, the evolution of the neuroscience discipline, the uptake of machine learning, the distribution of gender imbalance in academic authorship, and the distribution of retracted paper mill articles. Furthermore, we present an interactive website that allows easy exploration and will enable further insights and facilitate future research.
Integrating research on bacterial pathogens and commensals to fight infections—an ecological perspective
2024-04-09

The incidence of antibiotic-resistant bacterial infections is increasing, and development of new antibiotics has been deprioritised by the pharmaceutical industry. Interdisciplinary research approaches, based on the ecological principles of bacterial fitness, competition, and transmission, could open new avenues to combat antibiotic-resistant infections. Many facultative bacterial pathogens use human mucosal surfaces as their major reservoirs and induce infectious diseases to aid their lateral transmission to new host organisms under some pathological states of the microbiome and host. Beneficial bacterial commensals can outcompete specific pathogens, thereby lowering the capacity of the pathogens to spread and cause serious infections. Despite the clinical relevance, however, the understanding of commensal-pathogen interactions in their natural habitats remains poor. In this Personal View, we highlight directions to intensify research on the interactions between bacterial pathogens and commensals in the context of human microbiomes and host biology that can lead to the development of innovative and sustainable ways of preventing and treating infectious diseases.
Early REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION): Study protocol of a phase III trial
2024-04-09

Rationale: Meta-analyses of case series of non-arteritic central retinal artery occlusion (CRAO) indicate beneficial effects of intravenous thrombolysis when initiated early after symptom onset. Randomized data are lacking to address this question. Aims: The REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION) investigates intravenous alteplase within 4.5 h of monocular vision loss due to acute CRAO. Methods: This study is the randomized (1:1), double-blind, placebo-controlled, multicenter adaptive phase III trial. Study outcomes: Primary outcome is functional recovery to normal or mildly impaired vision in the affected eye defined as best-corrected visual acuity of the Logarithm of the Minimum Angle of Resolution of 0.5 or less at 30 days (intention-to-treat analysis). Secondary efficacy outcomes include modified Rankin Score at 90 days and quality of life. Safety outcomes include symptomatic intracranial hemorrhage, major bleeding (International Society on Thrombosis and Haemostasis definition) and mortality. Exploratory analyses of optical coherence tomography/angiography, ultrasound and magnetic resonance imaging (MRI) biomarkers will be conducted. Sample size: Using an adaptive design with interim analysis at 120 patients, up to 422 participants (211 per arm) would be needed for 80% power (one-sided alpha = 0.025) to detect a difference of 15%, assuming functional recovery rates of 10% in the placebo arm and 25% in the alteplase arm. Discussion: By enrolling patients within 4.5 h of CRAO onset, REVISION uses insights from meta-analyses of CRAO case series and randomized thrombolysis trials in acute ischemic stroke. Increased rates of early reperfusion and good neurological outcomes in stroke may translate to CRAO with its similar pathophysiology. Trial registration: ClinicalTrials.gov: NCT04965038; EU Trial Number: 2023-507388-21-00.
Decoupling Measurements and Processes: On the Epiphenomenon Debate Surrounding Brain Oscillations in Field Potentials
2024-04-09

Various theories in neuroscience maintain that brain oscillations have an important role in neuronal computation, but opposing views claim that these macroscale dynamics are “exhaust fumes” of more relevant processes. Here, we argue that the question of whether oscillations are epiphenomenal is ill-defined and cannot be productively resolved without further refinement. Toward that end, we outline a conceptual framework that clarifies the dispute along two axes: first, we introduce a distinction between measurement and process to categorize the theoretical status of electrophysiology terms such as local field potentials and oscillations. Second, we consider the relationships between these disambiguated terms, evaluating based on experimental and computational evidence whether there exist causal or inferentially useful links between them. This decomposes the question of epiphenomenalism into a set of empirically tractable alternatives. Finally, we demarcate oscillations as a conceptually distinct entity where either processes or measurements exhibit periodic behavior, and we suggest that oscillatory processes orchestrate neural computation by implementing a temporal, spatial, and frequency syntax. Overall, our reframed evaluation supports the view that electric fields—oscillating or not—are causally relevant, and that their associated signals are informative. More broadly, we offer a vocabulary and starting point for scientific exchanges on the role and utility of brain signals and the biological processes they capture.
The Minimum Information about a Tailoring Enzyme/Maturase data standard for capturing natural product biosynthesis
2024-04-09

Natural products, also known as specialized or secondary metabolites, show extraordinary chemical diversity and potent biological activities. Their biosynthesis usually first encompasses scaffold generation, followed by additional tailoring and maturation steps, leading to the mature compound. The latter steps are often performed by accessory enzymes known as tailoring enzymes or maturases. While knowledge about reaction and substrate specificities of these enzymes is essential for natural product biosynthesis, it is often scattered in the literature, hampering understanding and computational processing. Here, we conceptualize the Minimum Information about a Tailoring Enzyme/Maturase (MITE) data standard. We envision this data standard to serve in collecting experimentally verified data on reaction, substrate specificity, and other metadata of tailoring enzymes. Closely associated with the previously established Minimum Information about a Biosynthetic Gene cluster (MIBiG) data standard, MITE will aim to capture tailoring enzyme reaction information that is currently not systemized. We anticipate that MITE will accelerate natural product structure predictions from sequence, evolutionary analyses of biosynthetic pathways and synthetic biology engineering of specialized metabolic pathways.
Predicting outcome in disorders of consciousness: A mega‐analysis
2024-04-09

Abstract Objective Assessing recovery potential in patients with disorders of consciousness (DoC) is pivotal for guiding clinical and ethical decisions. We conducted a mega‐analysis of individual patient data to understand (1) if a time threshold exists, beyond which regaining consciousness is almost impossible, and (2) how recovery varies based on factors such as diagnosis, etiology, age, sex, and neuropsychological status. Methods A systematic literature search revealed a total of 3290 patients. In this sample, we performed a Cox proportional hazards analysis for interval censored data. Results We observed a late saturation of probability to regain consciousness in Kaplan–Meier curves, and the annual rate of recovery was remarkably stable, in that approximately 35% of patients regained consciousness per year. Patients in minimally conscious state (MCS) recovered more frequently than patients in unresponsive wakefulness syndrome (UWS). No significant difference was observed between the recovery dynamics of MCS subgroups: MCS+ and MCS−. Patients with hypoxic brain lesions showed worse recovery rate than patients with traumatic brain injury and patients with vascular brain lesions, while the latter two categories did not differ from each other. Male patients had moderately better chance to regain consciousness. While younger UWS patients recovered more frequently than older patients, it was not the case in MCS. Interpretation Our findings highlight the necessity for neurologists to exercise caution when making negative predictions in individual cases, challenge traditional beliefs regarding recovery timelines, and underscore the importance of conducting detailed and prolonged assessments to better understand recovery prospects in DoC.
True colors SNARC: Semantic number processing is highly automatic
2024-04-09

Numbers are highly relevant in our everyday lives. Besides intentionally processing number magnitude when necessary, we often automatically process it even when not required. The SNARC (Spatial-Numerical Association of Response Codes; Dehaene et al., 1993) effect, describing faster left-/right-sided responses to smaller/larger numbers, respectively, provides evidence for this automaticity. It arises in semantic number-processing tasks both when number magnitude is task-relevant (e.g., magnitude classification) and task-irrelevant (e.g., parity judgment). However, findings on the SNARC effect in tasks requiring the processing of non-semantic number features are mixed: while it has been observed in orientation judgment tasks, it was mostly absent in color judgment tasks. Importantly, previous studies were underpowered or did not control for confounding variables. In two highly powered online experiments, we found a small but significant SNARC effect in both nominal color judgment (cyan vs. yellow; slope = 1.71 ms) and color intensity judgment (light cyan vs. dark cyan; slope = 1.13 ms) of Arabic digits from 1 to 9 excluding 5, which did not significantly differ in size. Further, we found little evidence for the MARC (Linguistic Markedness of Response Codes, i.e., faster left-/right-sided responses to odd/even numbers, respectively; Nuerk et al., 2004) effect. Moreover, the odd effect (i.e., faster responses to even than to odd numbers; Hines, 1990) was detected. Taken together, both magnitude and parity are processed automatically even if participants respond to physical non-semantic and non-spatial number features, but the spatial mapping seems more automatic for magnitude than for parity.
Evaluation of the e–Mental Health Intervention Make It Training From Patients' Perspectives: Qualitative Analysis Within the Reduct Trial
2024-04-09

Background Make It Training is an e–mental health intervention designed for individuals with cancer that aims to reduce psychological distress and improve disease-related coping and quality of life. Objective This study evaluated the experienced usefulness and usability of the web-based Make It Training intervention using a qualitative approach. Methods In this study, semistructured interviews were conducted with participants at different cancer stages and with different cancer entities. All participants had previously taken part in the Reduct trial, a randomized controlled trial that assessed the efficacy of the Make It Training intervention. The data were coded deductively by 2 independent researchers and analyzed iteratively using thematic codebook analysis. Results Analysis of experienced usefulness resulted in 4 themes (developing coping strategies to reduce psychological distress, improvement in quality of life, Make It Training vs traditional psychotherapy, and integration into daily life) with 11 subthemes. Analysis of experienced usability resulted in 3 themes (efficiency and accessibility, user-friendliness, and recommendations to design the Make It Training intervention to be more appealing) with 6 subthemes. Make It Training was evaluated as a user-friendly intervention helpful for developing functional coping strategies to reduce psychological distress and improve quality of life. The consensus regarding Make It Training was that it was described as a daily companion that integrates well into daily life and that it has the potential to be routinely implemented within oncological health care either as a stand-alone intervention or in addition to psychotherapy. Conclusions e–Mental health interventions such as Make It Training can target both the prevention of mental health issues and health promotion. Moreover, they offer a cost-efficient and low-threshold option to receive psycho-oncological support.
Filling the Blank Space: Branched 4-Nonylphenol Isomers Are Responsible for Robust Constitutive Androstane Receptor (CAR) Activation by Nonylphenol
2024-04-09

4-Nonylphenol (4-NP), a <i>para</i>-substituted phenolic compound with a straight or branched carbon chain, is a ubiquitous environmental pollutant and food contaminant. 4-NP, particularly the branched form, has been identified as an endocrine disruptor (ED) with potent activities on estrogen receptors. Constitutive Androstane Receptor (CAR) is another crucial nuclear receptor that regulates hepatic lipid, glucose, and steroid metabolism and is involved in the ED mechanism of action. An NP mixture has been described as an extremely potent activator of both human and rodent CAR. However, detailed mechanistic aspects of CAR activation by 4-NP are enigmatic, and it is not known if 4-NP can directly interact with the CAR ligand binding domain (LBD). Here, we examined interactions of individual branched (22NP, 33NP, and 353NP) and linear 4-NPs with CAR variants using molecular dynamics (MD) simulations, cellular experiments with various CAR expression constructs, recombinant CAR LBD in a TR-FRET assay, or a differentiated HepaRG hepatocyte cellular model. Our results demonstrate that branched 4-NPs display more stable poses to activate both wild-type CAR1 and CAR3 variant LBDs in MD simulations. Consistently, branched 4-NPs activated CAR3 and CAR1 LBD more efficiently than linear 4-NP. Furthermore, in HepaRG cells, we observed that all 4-NPs upregulated CYP2B6 mRNA, a relevant hallmark for CAR activation. This is the first study to provide detailed insights into the direct interaction between individual 4-NPs and human CAR-LBD, as well as its dominant variant CAR3. The work could contribute to the safer use of individual 4-NPs in many areas of industry.
GAA-FGF14 Disease: Defining Its Frequency, Molecular Basis, and 4-aminopyridine Response in a Large Cohort of Patients with Downbeat Nystagmus (P6-3.013)
2024-04-09

Reassess the clinical and molecular spectrum of GAA-FGF14 disease by studying the frequency of FGF14 (GAA)≥250 and (GAA)200–249 expansions in patients with idiopathic downbeat nystagmus (DBN) syndromes and their phenotypic spectrum. Provide real-world and placebo-controlled data on 4-aminopyridine treatment response.
Intramolecular feedback regulation of the LRRK2 Roc G domain by a LRRK2 kinase dependent mechanism
2024-04-09

Abstract The Parkinson’s Disease (PD)-linked protein Leucine Rich Repeat Kinase 2 (LRRK2) consists of seven domains, including a kinase and a Roc G-domain. Despite the availability of several high-resolution structures, the dynamic regulation of its unique intramolecular domain stack is nevertheless still not well understood. By in-depth biochemical analysis, assessing the Michaelis-Menten kinetics of the Roc G-domain, we have confirmed that LRRK2 has similar to other Roco protein family members a KM value of LRRK2 that lays within the range of the physiological GTP concentrations within the cell. Furthermore, the R1441G PD variant located within a mutational hotspot in the Roc domain showed an increased catalytic efficiency. The most common PD variant G2019S, located in the kinase domain showed an increased KM and reduced catalytic efficiency, suggesting a negative feedback mechanism from the kinase domain to the G domain. Auto-phosphorylation of the G1+2 residue (T1343) in the Roc P-loop motif is critical for this phosphoregulation of both the KM as well as the kcat values of the Roc-catalyzed GTP hydrolysis, most likely by changing the monomer-dimer equilibrium. Together our data reveal a novel intramolecular feedback regulation of the LRRK2 Roc G-domain by a LRRK2 kinase dependent mechanism. Interestingly, PD mutants differently change the kinetics of the GTPase cycle, which might in part explain the difference in penetrance of these mutations in PD patients.
Offline volunteering during COVID-19: a survey experiment with prior and prospective blood donors
2024-04-09

Abstract Offline volunteering was faced with new challenges during the COVID-19 pandemic. Using a survey experiment with 1207 student participants, we test the impact of informing subjects about blood donation urgency (shortage information), and secondly, the effect of providing information about measures taken to reduce SARS-CoV-2 transmission at blood donation centers (hygiene information), on their inclination to donate during and after the COVID-19 lockdown. The results show that shortage information increases extensive-margin willingness to donate for non-donors by 15 percentage points (pp), on average, and increases the willingness to donate quickly for all respondents. Hygiene information, however, reduces prior donors’ intention to donate again by 8pp, on average, and reduces the willingness of non-donors to donate quickly.
Entropic relations for indistinguishable quantum particles
2024-04-09

Abstract The von Neumann entropy of a k -body-reduced density matrix γ k quantifies the entanglement between k quantum particles and the remaining ones. In this paper, we rigorously prove general properties of this entanglement entropy as a function of k ; it is concave for all <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mrow> <mml:mn>1</mml:mn> <mml:mtext>⩽</mml:mtext> <mml:mi>k</mml:mi> <mml:mtext>⩽</mml:mtext> <mml:mi>N</mml:mi> </mml:mrow> </mml:math> and non-decreasing until the midpoint <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mrow> <mml:mi>k</mml:mi> <mml:mtext>⩽</mml:mtext> <mml:mo fence="false" stretchy="false">⌊</mml:mo> <mml:mrow> <mml:mi>N</mml:mi> <mml:mrow> <mml:mo>/</mml:mo> </mml:mrow> <mml:mn>2</mml:mn> </mml:mrow> <mml:mo fence="false" stretchy="false">⌋</mml:mo> </mml:mrow> </mml:math> . The results hold for indistinguishable quantum particles and are independent of the statistics.