Miracle-dz/UniFAR-FTUs huggingface dataset:
Going beyond Binary: Rapid Identification of Protein–Protein Interaction Modulators Using a Multifragment Kinetic Target-Guided Synthesis Approach

Kinetic target-guided synthesis (KTGS) is a powerful screening approach that enables identification of small molecule modulators for biomolecules. While many KTGS variants have emerged, a majority of the examples suffer from limited throughput and a poor signal/noise ratio, hampering reliable hit detection. Herein, we present our optimized multifragment KTGS screening strategy that tackles these limitations. This approach utilizes selected reaction monitoring liquid chromatography tandem mass spectrometry for hit detection, enabling the incubation of 190 fragment combinations per screening well. Consequentially, our fragment library was expanded from 81 possible combinations to 1710, representing the largest KTGS screening library assembled to date. The expanded library was screened against Mcl-1, leading to the discovery of 24 inhibitors. This work unveils the true potential of KTGS with respect to the rapid and reliable identification of hits, further highlighting its utility as a complement to the existing repertoire of screening methods used in drug discovery.
The Skill of Seasonal Ensemble Prediction Systems to Forecast Wintertime Windstorm Frequency over the North Atlantic and Europe

AbstractThe science of seasonal predictions has advanced considerably in the last decade. Today, operational predictions are generated by several institutions, especially for variables such as (sea) surface temperatures and precipitation. In contrast, few studies have been conducted on the seasonal predictability of extreme meteorological events such as European windstorms in winter. In this study, the predictive skill of extratropical wintertime windstorms in the North Atlantic/European region is explored in sets of seasonal hindcast ensembles from the Development of a European Multimodel Ensemble System for Seasonal-to-Interannual Prediction (DEMETER) and the ENSEMBLE-based predictions of climate changes and their impacts (ENSEMBLES) projects.The observed temporal and spatial climatological distributions of these windstorms are reasonably well reproduced in the hindcast data. Using hindcasts starting on 1 November, significant predictive skill is found for the December–February windstorm frequency in th.
Recent Advances in Epigenetic Triggering of Climacteric Fruit Ripening.

During ripening, fleshy fruits undergo irreversible changes in color, texture, sugar content, aroma, and flavor to appeal to seed-dispersal vectors. The onset of climacteric fruit ripening is accompanied by an ethylene burst. Understanding the factors triggering this ethylene burst is important for manipulating climacteric fruit ripening. Here, we review the current understanding and recent insights into the possible factors triggering climacteric fruit ripening: DNA methylation and histone modification, including methylation and acetylation. Understanding the initiation factors of fruit ripening is important for exploring and accurately regulating the mechanisms of fruit ripening. Lastly, we discuss the potential mechanisms responsible for climacteric fruit ripening.
An integrated computational approach to infer therapeutic targets from Campylobacter concisus and peptidomimetic based inhibition of its pyrimidine metabolism pathway

Abstract Campylobacter concisus is a commensal of the human oral flora that has been allied with persistent diarrhea and inflammatory bowel disease (IBD). In children under the age of two, Campylobacter infections are common in the developing countries and have frequently been associated with mortality. They are becoming a prevalent cause of bacterial diarrhea in early adulthood in developed countries as well. The need for identifying new therapeutic targets and drugs is crucial for curbing such infections. Therefore, we identified 18 cytoplasmic potential therapeutic candidates against the type strain of C. concisus and deoxycytidine triphosphate deaminase (dCTP deaminase), involved in pyrimidine synthesis was selected for screening of peptidomimetic inhibitors (n > 30,000 peptidomimetics) against it. To the best of our knowledge, this target has not been studied for Campylobacter spp. Three potent inhibitors of this enzyme were prioritized i.e. peptidomimetic 27, 64, and 150. Dynamics simulation of 100 ns was carried out to validate findings for top-scored inhibitors along with physiology-based pharmacokinetics to estimate behavior in human body and predict dosing parameters. This verification demonstrates a first-in-human pharmacokinetic simulation for these peptidomimetics and can help enhance confidence in these peptide-like structures. Moiety 27 (IUPAC name: 5-[(3,5-dimethyl-1H-pyrazol-1-yl)methyl]-N-{[2-(2-methoxyethyl)-1-oxo-1H,2H,3H,4H-pyrrolo[1,2-a]pyrazin-3-yl]methyl}furan-2-carboxamide), 64 (IUPAC name: 3-(2-methylpropyl)-1-{3-[5-(5-oxo-1-phenylpyrrolidin-3-yl)-1,2,4-oxadiazol-3-yl]phenyl}urea), and 150 (IUPAC name: N-(3-methoxypropyl)-1-[6-(4-methylphenyl)-4H,6H,7H-[1,2,3]triazolo[4,3-c][1,4]oxazine-3-carbonyl]piperidine-4-carboxamide) were identified as potent inhibitors of C. concisus. Communicated by Ramaswamy H. Sarma
Structural Biochemistry of Muscle Contraction.

Muscles are essential for movement and heart function. Contraction and relaxation of muscles relies on the sliding of two types of filaments-the thin filament and the thick myosin filament. The thin filament is composed mainly of filamentous actin (F-actin), tropomyosin, and troponin. Additionally, several other proteins are involved in the contraction mechanism, and their malfunction can lead to diverse muscle diseases, such as cardiomyopathies. We review recent high-resolution structural data that explain the mechanism of action of muscle proteins at an unprecedented level of molecular detail. We focus on the molecular structures of the components of the thin and thick filaments and highlight the mechanisms underlying force generation through actin-myosin interactions, as well as Ca2+-dependent regulation via the dihydropyridine receptor, the ryanodine receptor, and troponin. We particularly emphasize the impact of cryo-electron microscopy and cryo-electron tomography in leading muscle research into a new era. Expected final online publication date for the Annual Review of Biochemistry, Volume 92 is June 2023. Please see http://www.annualreviews. org/page/journal/pubdates for revised estimates.
DARPP‐32 cells and neuropil define striosomal system and isolated matrix cells in human striatum

The dorsal striatum forms a central node of the basal ganglia interconnecting the neocortex and thalamus with circuits modulating mood and movement. Striatal projection neurons (SPNs) include relatively intermixed populations expressing D1‐type or D2‐type dopamine receptors (dSPNs and iSPNs) that give rise to the direct (D1) and indirect (D2) output systems of the basal ganglia. Overlaid on this organization is a compartmental organization, in which a labyrinthine system of striosomes made up of sequestered SPNs is embedded within the larger striatal matrix. Striosomal SPNs also include D1‐SPNs and D2‐SPNs, but they can be distinguished from matrix SPNs by many neurochemical markers. In the rodent striatum the key signaling molecule, DARPP‐32, is a exception to these compartmental expression patterns, thought to befit its functions through opposite actions in both D1‐ and D2‐expressing SPNs. We demonstrate here, however, that in the dorsal human striatum, DARPP‐32 is concentrated in the neuropil and SPNs of striosomes, especially in the caudate nucleus and dorsomedial putamen, relative to the matrix neuropil in these regions. The generally DARPP‐32‐poor matrix contains scattered DARPP‐32‐positive cells. DARPP‐32 cell bodies in both compartments proved negative for conventional intraneuronal markers. These findings raise the potential for specialized DARPP‐32 expression in the human striosomal system and in a set of DARPP‐32‐positive neurons in the matrix. If DARPP‐32 immunohistochemical positivity predicts differential functional DARPP‐32 activity, then the distributions demonstrated here could render striosomes and dispersed matrix cells susceptible to differential signaling through cAMP and other signaling systems in health and disease. DARPP‐32 is highly concentrated in cells and neuropil of striosomes in post‐mortem human brain tissue, particularly in the dorsal caudate nucleus. Scattered DARPP‐32‐positive cells are found in the human striatal matrix. Calbindin and DARPP‐32 do not colocalize within every spiny projection neuron in the dorsal human caudate nucleus.
Antioxidant-rich Terminalia catappa fruit exerts antihypertensive effect via modulation of angiotensin-1-converting enzyme activity and H2S/NO/cGMP signalling pathway in Wistar rats

Abstract Introduction The present study aimed at investigating the effect of Terminalia catappa fruits on blood pressure, NO/cGMP signalling pathway, angiotensin-1-converting enzyme and arginase activity, and oxidative stress biomarkers in L-NAME-induced hypertensive rats. Materials and methods Forty-two Wistar rats were divided into seven groups. Hypertension was induced via oral administration of 40 mg/kg of L-NAME for 21 days. Thereafter, the hypertensive rats were treated with Terminalia catappa fruit-supplemented diet and sildenafil citrate for 21 days. The blood pressure was measured and cardiac homogenate was prepared for biochemical analyses. Results The results showed that L-NAME caused a significant (p < 0.05) increase in systolic and diastolic blood pressure, and heart rate as well as ACE, arginase and PDE-5 activity, with a simultaneous decrease in NO and H2S levels as well as increased oxidative stress biomarkers. However, treatment with Terminalia catappa fruits-supplemented diets and sildenafil citrate lowered blood pressure and modulated ACE, arginase, and PDE-5 activity, improved NO and H2S levels, as well as antioxidant status. Conclusion Findings presented in this study provide useful information on the antihypertensive property of Terminalia catappa fruits, alongside some possible mechanisms. Hence, Terminalia catappa fruits could be considered a dietary regimen and functional food in alleviating hypertension.
Nuclear factor-Y mediates pancreatic β-cell compensation by repressing reactive oxygen species-induced apoptosis under metabolic stress

Abstract Background: Pancreatic β-cells elevate insulin production and secretion through a compensatory mechanism to override insulin resistance under metabolic stress conditions. Deficits in β-cell compensatory capacity result in hyperglycemia and type 2 diabetes (T2D). However, the mechanism in the regulation of β-cell compensative capacity remains elusive. Nuclear factor-Y (NF-Y) is critical for pancreatic islets' homeostasis under physiological conditions, but its role in β-cell compensatory response to insulin resistance in obesity is unclear. Methods: In this study, using obese (ob/ob) mice with an absence of NF-Y subunit A (NF-YA) in β-cells (ob, Nf-ya βKO) as well as rat insulinoma cell line (INS1)-based models, we determined whether NF-Y-mediated apoptosis makes an essential contribution to β-cell compensation upon metabolic stress. Results: Obese animals had markedly augmented NF-Y expression in pancreatic islets. Deletion of β-cell Nf-ya in obese mice worsened glucose intolerance and resulted in β-cell dysfunction, which was attributable to augmented β-cell apoptosis and reactive oxygen species (ROS). Furthermore, primary pancreatic islets from Nf-ya βKO mice were sensitive to palmitate-induced β-cell apoptosis due to mitochondrial impairment and the attenuated antioxidant response, which resulted in the aggravation of phosphorylated c-Jun N-terminal kinase (JNK) and cleaved caspase-3. These detrimental effects were completely relieved by ROS scavenger. Ultimately, forced overexpression of NF-Y in INS1 β-cell line could rescue palmitate-induced β-cell apoptosis, dysfunction, and mitochondrial impairment. Conclusion: Pancreatic NF-Y might be an essential regulator of β-cell compensation under metabolic stress.
Associated substitution and complementation patterns of processed discretionary foods and drinks on total energy and added sugar intake.

BACKGROUND Processed discretionary foods and drinks (industrialized sugary drinks, sweet and savory snacks, and grain-based sweets) are often target of policies aimed at regulating the food environment. We aimed to understand if a lower intake of processed foods or drinks is associated with substitution or complementation patterns and overall intake. METHODS We analyzed a subsample with two 24-hr dietary recalls of the Mexican National Health and Nutrition Survey 2012 (358 children, 253 adolescents, and 278 adults). We compared within-person, energy and added sugar intakes between days with and without consumption of each food group with fixed-effects regressions. We estimated the relative change (change in intake when not consumed/average intake when consumed *100) RESULTS: Processed discretionary foods were not fully substituted, as total energy was 200 to 400 kcal/d lower when these foods were not consumed. The change in total intake was larger than the intake when consumed (i.e., complemented) for industrialized sugary drinks in adolescents (-136%) and adults (-215%), and sweet, savory snacks for children (-141%). The change was lower (i.e., partially substituted) for grain-based sweets among children (-78%) and adolescents (-73%). For added sugars, most processed discretionary groups were complemented. CONCLUSIONS Days without intake of processed discretionary foods were associated with lower total energy and added sugar intake compared to days when those discretionary foods were consumed. This suggests that regulatory policies to reduce the intake of processed foods could have a meaningful impact on improving overall diet. This article is protected by copyright. All rights reserved.
EEG-based classification of imagined digits using a recurrent neural network

Objective. In recent years, imagined speech brain–computer (machine) interface applications have been an important field of study that can improve the lives of patients with speech problems through alternative verbal communication. This study aims to classify the imagined speech of numerical digits from electroencephalography (EEG) signals by exploiting the past and future temporal characteristics of the signal using several deep learning models. Approach. This study proposes a methodological combination of EEG signal processing techniques and deep learning models for the recognition of imagined speech signals. EEG signals were filtered and preprocessed using the discrete wavelet transform to remove artifacts and retrieve feature information. To classify the preprocessed imagined speech neural signals, multiple versions of multilayer bidirectional recurrent neural networks were used. Main results. The method is examined by leveraging MUSE and EPOC signals from MNIST imagined digits in the MindBigData open-access database. The presented methodology’s classification performance accuracy was noteworthy, with the model’s multiclass overall classification accuracy reaching a maximum of 96.18% on MUSE signals and 71.60% on EPOC signals. Significance. This study shows that the proposed signal preprocessing approach and the stacked bidirectional recurrent network model are suitable for extracting the high temporal resolution of EEG signals in order to classify imagined digits, indicating the unique neural identity of each imagined digit class that distinguishes it from the others.
Presequence protease reverses mitochondria‐specific amyloid‐β‐induced mitophagy to protect mitochondria

Amyloid‐β (Aβ) peptide is accumulated in the mitochondria and has been shown to play a central role in the development of Alzheimer's disease (AD). It has been shown that exposure of neurons to aggregated Aβ can result in damaged mitochondria and dysregulated mitophagy, indicating that changes in the Aβ content of mitochondria may affect the levels of mitophagy and interfere with the progression of AD. However, the direct influence of mitochondrial Aβ on mitophagy has not been elucidated. In the present study, the effect of the mitochondria‐specific Aβ was assessed following a direct change of Aβ content in the mitochondria. We directly change mitochondrial Aβ by transfecting cells with mitochondria‐associated plasmids, including the mitochondrial outer membrane protein translocase 22 (TOMM22) and 40 (TOMM40) or presequence protease (PreP) overexpression plasmids. The changes in the levels of mitophagy were assessed by TEM, Western blot, mito‐Keima construct, organelle tracker, and probe JC‐1 assay. We demonstrated that increased mitochondrial Aβ content enhance mitophagy levels; overexpression of PreP could reverse the mitochondrial Aβ‐induced mitophagy levels in vivo and in vitro by reversing the levels of reactive oxygen species (ROS) and the mitochondrial membrane potential. The data provide novel insight into the role of mitochondria‐specific Aβ in the progression of AD pathophysiology.
Evidence‐based rationale for low dose nivolumab in critically ill patients with sepsis‐induced immunosuppression

A substantial part of critically ill patients suffer from sepsis‐induced immunosuppression. Reversal of immunosuppression through PD‐1 checkpoint inhibition has been proposed as a treatment strategy to overcome immunosuppression in these patients. The PD‐1 inhibitor nivolumab, currently used in treatment of cancer, has been evaluated in phase I/II studies in patients with sepsis, demonstrating tolerability and signs of clinical efficacy. No proper dose finding was performed in these studies and, after a single high dose of 480 mg or 960 mg nivolumab, PD‐1 inhibition persisted beyond 90 days in the majority of cases. As the duration of sepsis is ~7–10 days, prolonged PD‐1 inhibition may unnecessarily induce longer‐term immune‐related side effects. Based on previously published pharmacokinetic and pharmacodynamic data of nivolumab, a thorough in silico dose finding study for nivolumab in critically ill patients was performed. We found that volume of distribution and clearance of nivolumab were not higher in patients with sepsis compared to the cancer population for which nivolumab is currently approved and showed profound variability. We found that with a single dose of 20 mg nivolumab, the PD‐1 receptor occupancy is predicted to stay above the 90% threshold for a median of 23 days (90% prediction interval of 7–78 days). We propose to investigate this dose in critically ill patients as a potential safe and cost‐effective pharmacotherapeutic intervention to treat sepsis‐induced immunosuppression.
3′-End Processing of Eukaryotic mRNA: Machinery, Regulation, and Impact on Gene Expression

Formation of the 3′end of a eukaryotic mRNA is a key step in the production of a mature transcript. This process is mediated by a number of protein factors that cleave the pre-mRNA, add a poly(A) tail, and regulate transcription by protein dephosphorylation. Cleavage and polyadenylation specificity factor (CPSF) in humans, or cleavage and polyadenylation factor (CPF) in yeast, coordinates these enzymatic activities with each other, with RNA recognition, and with transcription. The site of pre-mRNA cleavage can strongly influence the translation, stability, and localization of the mRNA. Hence, cleavage site selection is highly regulated. The length of the poly(A) tail is also controlled to ensure that every transcript has a similar tail when it is exported from the nucleus. In this review, we summarize new mechanistic insights into mRNA 3′-end processing obtained through structural studies and biochemical reconstitution and outline outstanding questions in the field.
Impact of Work from Home and Family Support on Indian Women’s Work Productivity During COVID-19

The work-from-home practices initiated during the COVID-19 pandemic have caused a paradigmatic shift in how we work. Work from home (WFH) led to an intermingling of the domestic and professional spaces, and the WFH phenomenon has asymmetrically impacted women’s work. In such a scenario, women professionals experience a greater work–life conflict, and the significance of family support comes to the fore. Studying this phenomenon in the Indian context is interesting because the primary responsibility for Indian women lies in the domestic arena. Female Indian professionals are expected to seamlessly fulfil their domestic duties no matter how demanding their job is. The multiplicity of challenges that affect women professionals’ productivity at work only gets compounded when women are expected to work from the domestic sphere where the demand of domestic duties constantly confronts them. Several global scholars have indicated that the burden of domestic duties was greater for women during the COVID-19 pandemic, and the burden of child-care, elderly care and cooking activities increased as outsourcing such activities was not an easily available option during the lockdowns which led to reduced work productivity amongst women. However, this study revealed that Indian female professionals reported better work productivity than female professionals working from their workspace. Indian women are used to fulfilling domestic and professional duties even prior to the pandemic, and Indians perceive greater satisfaction in interpersonal relational experiences rather than individualistic career goals. The study also revealed that family support did not increase when women were working from home, but the increase in family support increased women’s work productivity. Findings also indicate that female professionals with children showed significantly lower work productivity than female professionals (married and unmarried) without children.
Relationship Between Quadriceps Strength and Knee Joint Power During Jumping After ACLR

Background: Knee joint power is significantly impaired during the propulsive phase of jumping after anterior cruciate ligament reconstruction (ACLR); however, it is currently unknown how quadriceps strength influences knee joint power. Purpose: To (1) evaluate the relationship between quadriceps strength, joint power, and the percentage contribution of the hip, knee, and ankle joints to total limb power during the propulsive phase of jumping and (2) establish a quadriceps strength cutoff value for maximizing the likelihood of having knee joint power characteristics similar to healthy participants. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 75 participants were included in this study—40 patients who underwent ACLR 6 months before (18 females; mean age, 19.3 ± 5.7 years) and 35 healthy controls (HC) (20 females; mean age, 21.5 ± 4.5 years). Participants performed a drop vertical jump and underwent isometric quadriceps strength testing. The peak joint power was calculated as the product of the internal joint moment and joint angular velocity. Pearson product-moment correlations were used to assess the relationship between quadriceps strength and knee joint power. Paired samples t tests were used to quantify differences between limbs. Receiver operating characteristic (ROC) curve analysis was used to determine a quadriceps strength cutoff. Results: The involved limbs of the ACLR cohort (INV) had significantly lower peak knee joint power and percentage contribution from the knee joint during jumping compared with the uninvolved limbs (NON) and limbs of the controls (INV, 2.5 ± 1.2 W/kg; NON, 4.4 ± 1.5 W/kg; HC, 4.3 ± 1.7 W/kg [P < .0001]). Quadriceps strength was associated with knee joint power in involved limbs and limbs of controls (INV, r = 0.50; HC, r = 0.60). A quadriceps strength cutoff value of 2.07 N·m/kg had an area under the ROC curve of 0.842, indicating good predictive accuracy. Conclusion: Athletes at 6 months after ACLR demonstrated knee-avoidant jumping mechanics and had significant reductions in knee joint power on the involved limb. A quadriceps strength cutoff value of 2.07 N·m/kg can help predict which athletes will display knee joint power characteristics similar to those of healthy controls.