bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of non-linear mixed effects model-based approaches to test for drug effect using simulated data: type I error and power properties
Authors: Chasseloup E. , Tessier A. , Karlsson M.O. 
Published: April 2024

1AbstractPharmacometric approaches achieves higher power to detect a drug effect compared to traditional statistical hypothesis tests. Known drawbacks come from the model building process where multiple testing and model misspecification are major causes for type I error inflation. IMA is a new approach using mixture models and the likelihood ratio test (LRT) to test for drug effect. It previously showed type I error control and unbiased drug estimates in the context of two-arms balanced designs using real placebo data, in comparison to the standard approach (STD). The aim of this study was to extend the assessment of IMA and STD regarding type I error, power, and bias in the drug effect estimates under various types of model misspecification, with or without LRT calibration. Two classical statistical approaches, t-test and Mixed-Effect Model Repeated Measure (MMRM), were also added to the comparison. The focus was a simulation study where the extent of the model misspecification is known, using a response model with or without drug effect as motivating example in two sample size scenarios.The IMA performances were overall not impacted by the sample size or the LRT calibration, contrary to STD which had better type I error results with the larger sample size and calibrated LRT. In terms of power STD required LRT calibration to outperform IMA. T-test and MMRM had both controlled type I error. The t-test had a lower power than both STD and IMA while MMRM had power predictions similar to IMA. IMA and STD had similarly unbiased drug effect estimates, with few exceptions.IMA showed again encouraging performances (type I error control and unbiased drug estimates) and presented reasonable power predictions. The IMA performances were overall more robust towards model mis-specification compared to STD. IMA confirmed its status of promising NLMEM-based approach for hypothesis testing of the drug effect and could be used in the future, after further evaluations, as primary analysis in confirmatory trials.
Lipid profiles in ST-elevation myocardial infarction with and without diabetes: the gap between prescription and targets
Authors: Biasin Marco , Cordioli Nicolò , Armani Ilaria , Guerrieri Ludovica , Parmegian Giulia , Sarai Alessandro , Ribichini Flavio Luciano , Gamabaro Alessia 
Published: April 2024

ABSTRACTINTRODUCTIONLipids are critical in coronary atherosclerosis, making lipid reduction essential for prevention of cardiovascular disease. Achieving guideline-recommended LDL cholesterol (LDL-C) targets remains challenging for patients with and without diabetes. This study aims to compare clinical differences between STEMI patients with and without diabetes and evaluate lipid-lowering strategies on admission and on discharge.METHODSRetrospective study on STEMI patients admitted to our center between 2021 and 2023. Data included anthropometric details, lipid profiles, cardiovascular risk scores and drug therapy. Theoretical LLT potency allowed computation of LDL-C levels as if they hadn’t undergone any LLT therapy (wild LDL-C).RESULTSOf 467 screened patients, 443 were included, with 72 having diabetes. Statistically significant differences were observed in hypertension (72.2% vs. 56.3%, p < 0.001) and peripheral arterial disease prevalence (15.2% vs. 6.2%, p = 0.01). Non-diabetic patients had higher total cholesterol, HDL-C, and LDL-C levels but similar wild LDL-C (110.7 mg/dL vs. 117.5 mg/dL, p = 0.30). At admission, 50.0% (diabetic) and 81.1% (non-diabetic) did not achieve LDL-C targets (p < 0.001). At discharge, 31.9% (diabetic) and 36.6% (non-diabetic) were discharged without sufficient LLT to achieve target cholesterol levels (p < 0.001).CONCLUSIONA significant proportion of patients, especially those with diabetes, failed to attain recommended LDL-C targets at STEMI admission. Aggressive lipid-lowering interventions, in particular with the support of electronic tools to assess LLT potency, are crucial for prompt LDL-C target attainment.HighlightsAt admission significant proportion of STEMI patients, including those with diabetes, fail to achieve LDL-C targets for their risk class in primary prevention.Limited adoption of combination therapies with ezetimibe.High-potency statins commonly prescribed at discharge, but many patients forecasted not to achieve LDL-C targets.Tailored treatment regimens utilizing electronic tools crucial for prompt attainment of LDL-C targets post-STEMI.Graphical abstract
A minimal presynaptic protein machinery mediating synchronous and asynchronous exocytosis and short-term plasticity
Authors: Bose Dipayan , Bera Manindra , Norman Chris A. , Timofeeva Yulia , Volynski Kirill E. , Krishnakumar Shyam S. 
Published: April 2024

AbstractNeurotransmitters are released from synaptic vesicles with remarkable precision in response to presynaptic Ca2+influx but exhibit significant heterogeneity in exocytosis timing and efficacy based on the recent history of activity. This heterogeneity is critical for information transfer in the brain, yet its molecular basis remains poorly understood. Here, we employ a biochemically-defined fusion assay under physiologically-relevant conditions to delineate the minimal protein machinery sufficient to account for different modes of Ca2+-triggered vesicle fusion and short-term facilitation. We find that Synaptotagmin-1, Synaptotagmin-7, and Complexin, synergistically restrain SNARE complex assembly, thus preserving vesicles in a stably docked state at rest. Upon Ca2+activation, Synaptotagmin-1 induces rapid vesicle fusion, while Synaptotagmin-7 mediates delayed fusion. Competitive binding of Synaptotagmin-1 and Synaptotagmin-7 to the same SNAREs, coupled with differential rates of Ca2+-triggered fusion clamp reversal, govern the kinetics of vesicular fusion. Under conditions mimicking sustained neuronal activity, the Synaptotagmin-7 fusion clamp is destabilized by the elevated basal Ca2+concentration, thereby enhancing the synchronous component of fusion. These findings provide a direct demonstration that a small set of proteins is sufficient to account for how nerve terminals adapt and regulate the Ca2+-evoked neurotransmitter exocytosis process to support their specialized functions in the nervous system.
Fine Mapping and Candidate Gene Analysis of Dravet Syndrome Modifier Loci on Mouse Chromosomes 7 and 8
Authors: Hawkins Nicole A. , Speakes Nathan , Kearney Jennifer A. 
Published: April 2024

ABSTRACTDravet syndrome is a developmental and epileptic encephalopathy (DEE) characterized by intractable seizures, comorbidities related to developmental, cognitive, and motor delays, and a high mortality burden due to sudden unexpected death in epilepsy (SUDEP). Most Dravet syndrome cases are attributed toSCN1Ahaploinsufficiency, with genetic modifiers and environmental factors influencing disease severity. Mouse models with heterozygous deletion ofScn1arecapitulate key features of Dravet syndrome, including seizures and premature mortality; however, severity varies depending on genetic background. Here, we refined two Dravet survival modifier (Dsm) loci,Dsm2on chromosome 7 andDsm3on chromosome 8, using interval-specific congenic (ISC) mapping.Dsm2was complex and encompassed at least two separate loci, whileDsm3was refined to a single locus. Candidate modifier genes within these refined loci were prioritized based on brain expression, strain-dependent differences, and biological relevance to seizures or epilepsy. High priority candidate genes forDsm2includeNav2, Ptpn5, Ldha, Dbx1, Prmt3andSlc6a5, whileDsm3has a single high priority candidate,Psd3. This study underscores the complex genetic architecture underlying Dravet syndrome and provides insights into potential modifier genes that could influence disease severity and serve as novel therapeutic targets.
PIP4K2C inhibition reverses autophagic flux impairment induced by SARS-CoV-2
Authors: Karim Marwah , Mishra Manjari , Lo Chieh-Wen , Saul Sirle , Cagirici Halise Busra , Nhu Tran Do Hoang , Agrawal Aditi , Ghita Luca , Ojha Amrita , East Michael P. , Gammeltoft Karen Anbro , Sahoo Malaya Kumar , Johnson Gary L. , Das Soumita , Jochmans Dirk , Cohen Courtney A. , Gottwein Judith , Dye John , Neff Norma , Pinsky Benjamin A. , Laitinen Tuomo , Pantsar Tatu , Poso Antti , Zanini Fabio , De Jonghe Steven , Asquith Christopher R M , Einav Shirit 
Published: April 2024

AbstractIn search for broad-spectrum antivirals, we discovered a small molecule inhibitor, RMC-113, that potently suppresses the replication of multiple RNA viruses including SARS-CoV-2 in human lung organoids. We demonstrated selective dual inhibition of the lipid kinases PIP4K2C and PIKfyve by RMC-113 and target engagement by its clickable analog. Advanced lipidomics revealed alteration of SARS-CoV-2-induced phosphoinositide signature by RMC-113 and linked its antiviral effect with functional PIP4K2C and PIKfyve inhibition. We discovered PIP4K2C’s roles in SARS-CoV-2 entry, RNA replication, and assembly/egress, validating it as a druggable antiviral target. Integrating proteomics, single-cell transcriptomics, and functional assays revealed that PIP4K2C binds SARS-CoV-2 nonstructural protein 6 and regulates virus-induced impairment of autophagic flux. Reversing this autophagic flux impairment is a mechanism of antiviral action of RMC-113. These findings reveal virus-induced autophagy regulation via PIP4K2C, an understudied kinase, and propose dual inhibition of PIP4K2C and PIKfyve as a candidate strategy to combat emerging viruses.
Contrasting morphological and acoustic trait spaces suggest distinct benefits to participants in mixed-species bird flocks
Authors: Abhijith A V , Agnihotri Samira , Bangal Priti , Krishnan Anand 
Published: April 2024

AbstractMixed-species bird flocks are dynamic associations that exhibit compositional turnover over relatively small timescales. Morphological diversity and foraging behaviour of species in flocks influences the relative benefits and costs of flock participation. In addition, species within flocks are highly acoustically active. However, the role of acoustic signals in flock assembly remains poorly understood. Here, we examined the relationship between acoustic and morphological trait spaces of bird flocks in peninsular India. We found that participant species are generally more similar in body mass than expected by chance. Flocks in general were dominated by smaller-sized species. Conversely, we found that flock participants are not similar in acoustic traits. Much literature suggests that morphology and acoustic signal parameters are known to be correlated, but we present evidence to suggest that these two trait spaces are decoupled at the community scale. This may enable species to derive distinct sets of benefits from both sets of traits, and provides valuable insight into the dynamic processes driving flock assembly.Lay summaryParticipants in mixed-species bird flocks tend to group together with similar-sized individuals. This morphological similarity in a crowded flock may result in acoustic signal overlap, as the two sets of traits are correlated to each other. Here, we find evidence to suggest that morphological and acoustic traits are decoupled in these interspecific associations, putatively enabling species to derive benefits from flocking with similar-sized species, and simultaneously minimize acoustic masking interference.
Anatomical and functional studies of isolated vestibular neuroepithelia from Ménière’s Disease patients
Authors: Drury Hannah R , Tadros Melissa A , Callister Robert J , Brichta Alan M , Eisenberg Robert , Lim Rebecca 
Published: April 2024

AbstractSurgical removal of vestibular end organs is a final treatment option for people with intractable Ménière’s Disease. We describe the use of surgically excised vestibular neuroepithelium from patients with Ménière’s Disease for 1) anatomical investigation of hair cell and nerve fibres markers using immunohistochemistry and 2) functional studies using electrophysiological recordings of voltage-activated currents. Our data shows considerable reduction in and disorganization of vestibular hair cells in the cristae ampullares while nerve fibres are in contact with remaining sensory receptors but appear thin in regions where hair cells are absent. Electrophysiological recordings of voltage-activated potassium currents from surviving hair cells demonstrate normal activity in both type I and type II vestibular hair cells. In addition, current-voltage plots from type I vestibular hair cells are consistent with the presence of a surrounding calyx afferent terminal. These data indicate surviving hair cells in Ménière’s Disease patients remain functional and capable of transmitting sensory information to the central nervous system. Determining functionality of vestibular receptors and nerves is critical for vestibular implant research to restore balance in people with Ménière’s Disease.Summary StatementThis study shows, that while there is significant hair cell loss in Ménière’s Disease patients, surviving type I and type II vestibular hair cells have normal voltage-activated conductances.
Pan-cancer proteogenomic landscape of whole-genome doubling reveals putative therapeutic targets in various cancer types
Authors: Chang Eunhyong , Hwang Hee Sang , Song Kyu Jin , Kim Kwoneel , Kim Min-Sik , Jang Se Jin , Kim Kwang Pyo , You Sungyong , An Joon-Yong 
Published: April 2024

AbstractBackgroundWhole-genome doubling (WGD) is prevalent in cancer and drives tumor development and chromosomal instability. Driver mutations in mitotic cell cycle genes and cell cycle upregulation have been reported as the major molecular underpinnings of WGD tumors. However, the underlying genomic signatures and regulatory networks involved in gene transcription and kinase phosphorylation remain unclear. Here, we aimed to comprehensively decipher the molecular landscape underlying WGD tumors.MethodsWe performed a pan-cancer proteogenomic analysis and compared 10 cancer types by integrating genomic, transcriptomic, proteomic, and phosphoproteomic datasets from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). We also integrated the cancer dependency data of each cancer cell line and the survival properties of each cancer patient to propose promising therapeutic targets for patients with WGD.ResultsOur study delineated distinct copy number signatures characterizing WGD-positive tumors into three major groups: highly unstable genome, focal instability, and tetraploidy. Furthermore, the analysis revealed the heterogeneous mechanisms underlying WGD across cancer types with specific structural variation patterns. Upregulation of the cell cycle and downregulation of the immune response were found to be specific to certain WGD tumor types. Transcription factors (TFs) and kinases exhibit cancer-specific activities, emphasizing the need for tailored therapeutic approaches.ConclusionThis study introduces an integrative approach to identify potential TF targets for drug development, highlighting BPTF as a promising candidate for the treatment of head and neck squamous cell carcinoma. Additionally, drug repurposing strategies have been proposed, suggesting potential drugs for the treatment of WGD-associated cancers. Our findings offer insights into the heterogeneity of WGD and have implications for precision medicine approaches for cancer treatment.
A randomized open-label, observational study of the novel ketone ester, bis octanoyl (R)-1,3-butanediol, and its acute effect on ß-hydroxybutyrate and glucose concentrations in healthy older adults
Authors: Stephens Elizabeth B. , Senadheera Chatura , Roa-Diaz Stephanie , Peralta Sawyer , Alexander Laura , Silverman-Martin Wendie , Yukawa Michi , Morris Jenifer , Johnson James B. , Newman John C. , Stubbs Brianna J. 
Published: April 2024

AbstractBis-octanoyl (R)-1,3-butanediol (BO-BD) is a novel ketone ester (KE) ingredient which increases blood beta-hydroxybutyrate (BHB) concentrations rapidly after ingestion. KE is hypothesized to have beneficial metabolic effects on health and performance, especially in older adults. Whilst many studies have investigated the ketogenic effect of KE in young adults, they have not been studied in an exclusively older adult population, for whom age-related differences in body composition and metabolism may alter the effects. This randomized, observational, open-label study in healthy older adults (n = 30, 50% male, age = 76.5 years, BMI = 25.2 kg/m2) aimed to elucidate acute tolerance, blood BHB and blood glucose concentrations for 4 hours following consumption of either 12.5 or 25 g of BO-BD formulated firstly as a ready-to-drink beverage (n = 30), then as a re-constituted powder (n = 21), taken with a standard meal. Both serving sizes and formulations of BO-BD were well tolerated, and increased blood BHB, inducing nutritional ketosis (≥ 0.5mM) that lasted until the end of the study. Ketosis was dose responsive; peak BHB concentration (Cmax) and incremental area under the curve (iAUC) were significantly greater with 25 g compared to 12.5 g of BO-BD in both formulations. There were no significant differences in Cmaxor iAUC between formulations. Blood glucose increased in all conditions following the meal; there were no consistent significant differences in glucose response between conditions. These results demonstrate that both powder and beverage formulations of the novel KE, BO-BD, induce ketosis in healthy older adults, facilitating future research on functional effects of this ingredient in aging.
SARS-CoV2 infection triggers reactive astrocyte states and inflammatory conditions in long-term Human Cortical Organoids
Authors: Colinet M. , Chiver I. , Bonafina A. , Masset G. , Almansa D. , Di Valentin E. , Twizere J.C. , Nguyen L. , Espuny-Camacho I. 
Published: April 2024

AbstractSARS-CoV2, severe acute respiratory syndrome coronavirus 2, is frequently associated with neurological manifestations. Despite the presence of mild to severe CNS-related symptoms in a cohort of patients, there is no consensus whether the virus can infect directly brain tissue or if the symptoms in patients are a consequence of peripheral infectivity of the virus. Here, we use long-term human stem cell-derived cortical organoids to assess SARS-CoV2 infectivity of brain cells and unravel the cell-type tropism and its downstream pathological effects. Our results show consistent and reproducible low levels of SARS-CoV2 infection of astrocytes, deep projection neurons, upper callosal neurons and inhibitory neurons in 6 months human cortical organoids. Interestingly, astrocytes showed the highest infection rate among all infected cell populations that led to increased presence of reactive states. Further, transcriptomic analysis revealed overall changes in expression of genes related to cell metabolism, astrocyte activation and, inflammation and further, upregulation of cell survival pathways. Thus, local and minor infectivity of SARS-CoV2 in the brain may induce widespread adverse effects and may lead to resilience of dysregulated neurons and astrocytes within an inflammatory environment.
Dysconnectivity of the cerebellum and somatomotor network correlates with the severity of alogia in chronic schizophrenia
Authors: Więcławski Wiktor , Bielski Krzysztof , Jani Martin , Binder Marek , Adamczyk Przemysław 
Published: April 2024

AbstractRecent fMRI resting-state findings show aberrant functional connectivity within somatomotor network (SMN) in schizophrenia. Moreover, functional connectivity aberrations of the motor system are often reported to be related to the severity of psychotic symptoms. Thus, it is important to validate those findings and confirm their relationship with psychopathology. Therefore, we decided to take an entirely data-driven approach in our fMRI resting-state study of 30 chronic schizophrenia outpatients and 30 matched control subjects. We used independent component analysis (ICA), dual regression, and seed-based connectivity analysis. We found reduced functional connectivity within SMN in schizophrenia patients compared to controls and SMN hypoconnectivity with the cerebellum in schizophrenia patients. The latter is strongly correlated with the intensity of alogia, i.e. poverty of speech and reduction in spontaneous speech, demonstrated by patients. Our results are consistent with the recent knowledge about the role of the cerebellum in cognitive functioning and its abnormalities in psychiatric disorders, e.g. schizophrenia. In conclusion, the presented results, for the first time clearly showed the involvement of the cerebellum hypoconnectivity with SMN in the persistence and severity of alogia symptoms in schizophrenia.
CRISPR/Cas-based genome editing for cyanophage ofAnabeana sp
Authors: Yuan Shengjian , Li Yanchen , Kou Chunhua , Sun YiChen , Ma Yingfei 
Published: April 2024

AbstractEfforts have been directed towards genome editing in cyanobacteria, yet achieving genome reduction in cyanophages remains a challenging task. In this study, we utilized the CRISPR-Cas12a system to successfully delete multiple genes within A-1(L) and A-4(L) cyanophages. Through careful manipulation, we generated a deletion mutant cyanophage with a 2,778 bp reduction in genome size, representing a 6.6% decrease compared to the wild type (WT). In summary, our research has introduced a robust method for gene editing in cyanophages, facilitating the identification of nonessential genes essential for cyanophage propagation. This advancement holds promise in addressing the widespread issue of water blooms and the associated environmental hazards.
Directed evolution-based discovery of ligands for in vivo restimulation of CAR-T cells
Authors: Grzywa Tomasz M. , Neeser Alexandra , Ramasubramanian Ranjani , Romanov Anna , Tannir Ryan , Mehta Naveen K. , Cossette Benjamin , Morgan Duncan M. , Goncalves Beatriz , Sukaj Ina , Bergaggio Elisa , Kadauke Stephan , Myers Regina M. , Paruzzo Luca , Ghilardi Guido , Cozzone Austin , Schuster Stephen J. , Frey Noelle , Zhang Libin , Yousefpour Parisa , Abraham Wuhbet , Suh Heikyung , Ruella Marco , Grupp Stephan A. , Chiarle Roberto , Wittrup K. Dane , Ma Leyuan , Irvine Darrell J. 
Published: April 2024

AbstractChimeric antigen receptor (CAR) T cell therapy targeting CD19 elicits remarkable clinical efficacy in B-cell malignancies, but many patients relapse due to failed expansion and/or progressive loss of CAR-T cells. We recently reported a strategy to potently restimulate CAR-T cellsin vivo, enhancing their functionality by administration of a vaccine-like stimulus comprised of surrogate peptide ligands for a CAR linked to a lymph node-targeting amphiphilic PEG-lipid (termed CAR-T-vax). Here, we demonstrate a general strategy to generate and optimize peptide mimotopes enabling CAR-T-vax generation for any CAR. Using the clinical CD19 CAR (FMC63) as a test case, we employed yeast surface display to identify peptide binders to soluble IgG versions of FMC63, which were subsequently affinity matured by directed evolution. CAR-T vaccines using these optimized mimotopes triggered marked expansion and memory development of CD19 CAR-T cells in both syngeneic and humanized mouse models of B-ALL/Lymphoma, and enhanced control of disease progression. This approach thus enables vaccine boosting to be applied to any clinically relevant CAR-T cell product.