bluuebunny/crossref_metadata_2025 huggingface dataset:
Asymmetrical atrophy of the paraspinal muscles in patients undergoing unilateral lumbar medial branch radiofrequency neurotomy
Authors: Guven Ali E. , Evangelisti Gisberto , Burkhard Marco D. , Köhli Paul , Hambrecht Jan , Zhu Jiaqi , Chiapparelli Erika , Kelly Michael , Tsuchiya Koki , Amoroso Krizia , Zadeh Arman , Shue Jennifer , Tan Ek Tsoon , Sama Andrew A. , Girardi Federico P. , Cammisa Frank P. , Hughes Alexander P.
Published: April 2024

Lumbar medial branch radiofrequency neurotomy (RFN), a common treatment for chronic low back pain due to facet joint osteoarthritis (FJOA), may amplify paraspinal muscle atrophy due to denervation. This study aimed to investigate the asymmetry of paraspinal muscle morphology change in patients undergoing unilateral lumbar medial branch RFN. Data from patients who underwent RFN between March 2016 and October 2021 were retrospectively analyzed. Lumbar foramina stenosis (LFS), FJOA, and fatty infiltration (FI) functional cross-sectional area (fCSA) of the paraspinal muscles were assessed on preinterventional and minimum 2-year postinterventional MRI. Wilcoxon signed-rank tests compared measurements between sides. A total of 51 levels of 24 patients were included in the analysis, with 102 sides compared. Baseline MRI measurements did not differ significantly between the RFN side and the contralateral side. The RFN side had a higher increase in multifidus FI (+4.2% [0.3-7.8] vs +2.0% [−2.2 to 6.2], P = 0.005) and a higher decrease in multifidus fCSA (−60.9 mm2 [−116.0 to 10.8] vs −19.6 mm2 [−80.3 to 44.8], P = 0.003) compared with the contralateral side. The change in erector spinae FI and fCSA did not differ between sides. The RFN side had a higher increase in multifidus muscle atrophy compared with the contralateral side. The absence of significant preinterventional degenerative asymmetry and the specificity of the effect to the multifidus muscle suggest a link to RFN. These findings highlight the importance of considering the long-term effects of lumbar medial branch RFN on paraspinal muscle health.
Painful distortions: people with painful knee osteoarthritis have biased visuospatial perception of the environment
Authors: MacIntyre Erin , Braithwaite Felicity A. , Stanton Tasha R.
Published: April 2024

Visuospatial perception is thought to be adaptive—ie, hills are perceived as steeper when capacity is low, or threat is high—guiding appropriate interaction with the environment. Pain (bodily threat) may similarly modulate visuospatial perception, with the extent of modulation influenced by threat magnitude (pain intensity, fear) and associated with behaviour (physical activity). We compared visuospatial perception of the environment between 50 people with painful knee osteoarthritis and 50 age-/sex-matched pain-free control participants using 3 virtual reality tasks (uphill steepness estimation, downhill steepness estimation, and a distance-on-hill measure), exploring associations between visuospatial perception, clinical characteristics (pain intensity, state and trait fear), and behaviour (wrist-worn accelerometry) within a larger knee osteoarthritis group (n = 85). People with knee osteoarthritis overestimated uphill (F1,485 = 19.4, P < 0.001) and downhill (F1,480 = 32.3, P < 0.001) steepness more so than pain-free controls, but the groups did not differ for distance-on-hill measures (U = 1273, P = 0.61). There was also a significant group x steepness interaction for the downhill steepness task (F4,480 = 3.11, P = 0.02). Heightened overestimation in people with knee osteoarthritis relative to pain-free controls increased as downhill slopes became steeper. Results were unchanged in a replication analysis using all knee osteoarthritis participants (n = 85), except the downhill steepness interaction was no longer significant. In people with knee osteoarthritis, higher state fear was associated with greater over-estimation of downhill slope steepness (rho = 0.69, P < 0.001), and greater visuospatial overestimation (distance-on-hill) was associated with lower physical activity levels (rho = −0.22, P = 0.045). These findings suggest that chronic pain may shift perception of the environment in line with protection, with overestimation heightened when threat is greater (steeper hills, more fearful), although impact on real-world behaviour is uncertain.
One Pump for Two Hearts: Using an Impella 5.5 Micro-Axial Pump in Peripartum Cardiogenic Shock
Authors: Pillai Ashwin A. , Badr Mai , Mai Xingchen , Dilip Anum , Bell Jennifer
Published: April 2024

Cardiogenic shock (CS) occurs infrequently in pregnancy and has a high mortality rate. Medical treatment options are few, with limited evidence of efficacy. Temporary mechanical circulatory supports (tMCS) may play a key role in addressing this therapeutic lacuna. We report successfully managing second-trimester CS using an Impella 5.5 micro-axial pump. Our patient presented in the second-trimester with CS. Hemodynamic parameters indicated biventricular dysfunction (low cardiac index, low pulmonary artery pulsatility index). She received diuresis and inotropic support to optimize her fluid status and cardiac function. However, failure to improve to the point where she would be able to tolerate the hemodynamic stresses of labor despite optimizing medical therapy prompted consideration of tMCS. The Impella 5.5 was chosen for its higher output (to maximize fetal perfusion), relative longevity, and lower hemolysis rates compared to other devices. It was used to support her from gestational weeks 28–30 and through the delivery. Support was continued for 4 weeks postpartum to allow for any potential cardiac recovery. Hope unrealized, a workup for destination therapy was initiated. Patient preference and high panel reactive antibodies informed the decision to pursue destination left ventricular assist device (LVAD) therapy. After a 3 month neonatal intensive care unit (NICU) stay, mother and baby were successfully discharged home.
Investigating the fluctuating nature of post-COVID pain symptoms in previously hospitalized COVID-19 survivors: the LONG-COVID-EXP multicenter study
Authors: Fernández-de-las-Peñas César , Pellicer-Valero Oscar J. , Martín-Guerrero José D. , Hernández-Barrera Valentín , Arendt-Nielsen Lars
Published: April 2024

Objective:

This cohort study used Sankey plots and exponential bar plots for visualizing the fluctuating nature and trajectory of post-COVID pain in previously hospitalized COVID-19 survivors.

Methods:

A cohort of 1266 subjects hospitalised because of COVID-19 during the first wave of the pandemic were scheduled for a telephone interview at 8.4 (T1), 13.2 (T2), and 18.3 (T3) months in average after hospitalization for collecting data about post-COVID pain. Patients were asked for about pain symptomatology that was attributed to the infection. Hospitalization and clinical data were collected from medical records.

Results:

The prevalence of myalgia as COVID-19–associated symptom was 29.82% (n = 389) at hospitalization (T0). The prevalence of post-COVID pain was 41.07% (n = 520) at T1, 34.29% (n = 434) at T2, and 28.47% (n = 360) at T3. The recovery exponential curve revealed a decrease trend visualizing that post-COVID pain improved over the time span investigated. Pain in the lower extremity and widespread pain were the most prevalent locations. Female sex (OR 1.507, 95% CI 1.047–2.169), pre-existing pain symptoms (OR 1.724, 95% CI 1.237–2.403), headache as onset-symptom (OR 2.374, 95% CI 1.550–3.639), days at hospital (OR 1.012, 95% CI 1.000–1.025), and presence of post-COVID pain at T1 (OR 13.243, 95% CI 9.428–18.601) were associated with post-COVID pain at T2. Only the presence of post-COVID pain at T1 (OR 5.383, 95% CI 3.896–7.439) was associated with post-COVID pain at T3.

Conclusion:

Current results show a fluctuating evolution with a decreasing tendency of post-COVID pain during the first years after hospitalization. The development of post-COVID pain soon after SARS-CoV-2 infection predispose for long-lasting chronic pain.
Thin Free Perforator Flap as a Viable Option for Forefoot Reconstruction: Comprehensive Evaluation of Outcomes
Authors: Lee Eun Song , Kim Da Eun , Lee Kyeong-Tae
Published: April 2024

Background:

Reconstruction of forefoot defects often necessitates free tissue transfer due to the limited availability of local tissue. Microsurgical reconstruction of the forefoot remains challenging, as it requires durable yet thin soft-tissue coverage for functional restoration. This study aimed to evaluate the efficacy of free thin perforator flaps for forefoot reconstruction, with a focus on functional outcomes.

Methods:

Records of patients who underwent microsurgical forefoot reconstruction between March of 2020 and September of 2023 were reviewed. Development of postoperative complications and functional outcomes were evaluated.

Results:

In total, 53 patients (mean age, 62.7 years) were analyzed. The most common cause of defects was oncologic surgery, followed by chronic wound, with a majority involving the plantar side. The superthin anterolateral thigh flap and superficial circumflex iliac artery perforator flap were predominantly used. The median flap thickness was 4.0 mm. Digital vessels were the most frequently used as recipients. All but one flap survived, resulting in a success rate of 98.1%. Postoperative flap site complications developed in 20 patients, the majority of which resolved with conservative treatment. The median hospital stay was 8.0 days, and the mean time for initiating weight-bearing ambulation was 12.4 days. In the postoperative Foot Function Index questionnaire survey, the overall score was 9.41, showing minimal impairment, and it did not differ according to defect size or location. A secondary debulking operation was needed in 7 patients.

Conclusion:

Use of thin free perforator flaps might provide reliable outcomes with rapid recovery and excellent postoperative function in forefoot reconstruction.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
Medial Femoral Condyle Periosteal Free Flap for Bone Coverage Following Debridement of Intermediate-Stage Osteoradionecrosis of the Jaw
Authors: Hurrell Michael J.L. , Leinkram David , Stokan Murray J. , Clark Jonathan R.
Published: April 2024

Study design: Case report. Osteoradionecrosis (ORN) of the jaw is a potentially devastating consequence of head and neck irradiation. The progression of ORN can lead to loss of bone, teeth, soft tissue necrosis, pathologic fracture, and oro-cutaneous fistula. Reconstructive surgery has mostly been reserved for late-stage disease where segmental resections are frequently necessary. Evidence is emerging to support earlier treatment in the form of debridement in combination with soft tissue free flaps for intermediate-stage ORN. The authors present a case of a 76-year-old male with persistent Notani 2 ORN of the mandible, treated with surgical removal of all remaining mandibular teeth, transoral debridement of all necrotic mandibular bone, and bone coverage with a left medial femoral condyle (MFC) periosteal free flap based on the descending genicular artery. Treatment was uneventful both intraoperatively and postoperatively. Since surgery (15 mo) the patient has remained free from clinical and radiologic signs of ORN. The MFP periosteal free flap provided an excellent result with minimal surgical complexity and morbidity in this case. Such treatment at an intermediate stage likely results in a reduction in segmental resections, less donor site morbidity, less operative time, less overall treatment time, and possibly fewer postoperative complications compared with the status quo.
Identification of Differentially Expressed Genes in Cold Storage–associated Kidney Transplantation
Authors: Zhu Jiefu , Xiang Xiaohong , Shi Lang , Song Zhixia , Dong Zheng
Published: April 2024

Background.

Although it is acknowledged that ischemia–reperfusion injury is the primary pathology of cold storage–associated kidney transplantation, its underlying mechanism is not well elucidated.

Methods.

To extend the understanding of molecular events and mine hub genes posttransplantation, we performed bulk RNA sequencing at different time points (24 h, day 7, and day 14) on a murine kidney transplantation model with prolonged cold storage (10 h).

Results.

In the present study, we showed that genes related to the regulation of apoptotic process, DNA damage response, cell cycle/proliferation, and inflammatory response were steadily elevated at 24 h and day 7. The upregulated gene profiling delicately transformed to extracellular matrix organization and fibrosis at day 14. It is prominent that metabolism-associated genes persistently took the first place among downregulated genes. The gene ontology terms of particular note to enrich are fatty acid oxidation and mitochondria energy metabolism. Correspondingly, the key enzymes of the above processes were the products of hub genes as recognized. Moreover, we highlighted the proximal tubular cell-specific increased genes at 24 h by combining the data with public RNA-Seq performed on proximal tubules. We also focused on ferroptosis-related genes and fatty acid oxidation genes to show profound gene dysregulation in kidney transplantation.

Conclusions.

The comprehensive characterization of transcriptomic analysis may help provide diagnostic biomarkers and therapeutic targets in kidney transplantation.
Genome sequencing and analysis of Salmonella enterica subsp. enterica serotype Enteritidis PT4 578
Authors: Carneiro Deisy Guimarães , Vidigal Pedro Marcus , Morgan Túlio , Vanetti Maria Cristina Dantas
Published: April 2024

Salmonella enterica serotype Enteritidis is a generalist serotype that adapts to different hosts and transmission niches. It has significant epidemiological relevance and is among the most prevalent serotypes distributed in several countries. Salmonella Enteritidis causes self-limited gastroenteritis in humans, which can progress to systemic infection in immunocompromised individuals. Poultry products are considered significant reservoirs of many Salmonella serotypes, and Salmonella Enteritidis infections are often related to the consumption of chicken meat and eggs. This study reports the whole-genome sequence of Salmonella Enteritidis PT4 strain 578. A total of 165 genes (3.66%) of the 4,506 coding sequences (CDS) predicted in its genome are virulence factors associated with cell invasion, intestinal colonization, and intracellular survival. The genome harbors twelve Salmonella pathogenicity islands (SPIs), with the SPI-1 and SPI-2 genes encoding type III secretion systems (T3SS) showing high conservation. Six prophage-related sequences were found, with regions of intact prophages corresponding to Salmon_118970_sal3 and Gifsy-2. The genome also contains two CRISPR systems. Comparative genome analysis with three other serotypes of Salmonella demonstrates that most unshared genes are related to metabolism, membrane, and hypothetical proteins. Finally, the phenotypic characterization evidenced differences among Salmonella Enteritidis PT4 578 and the other three serotypes regarding the expression of the red, dry, and rough (rdar) morphotype and biofilm formation. Overall, the genomic characterization and phenotypic properties expand knowledge of the mechanisms of pathogenicity in Salmonella Enteritidis PT4 578.
Human Metapneumovirus (hMPV): An associated etiology of Severe Acute Respiratory Infection in Children of Eastern Uttar Pradesh, India.
Authors: Deval Hirawati , Kumar Niraj , Srivastava Mitali , Potdar Varsha , Mehta Anita , Verma Ayushi , Singh Rajeev , Kavathekar Asif , Kant Rajni , Murhekar Manoj
Published: April 2024

Acute respiratory infections (ARIs) are a serious public health concern across the world, causing considerable morbidity and mortality. Every year, around 13 million children under the age of five die. Approximately 95% of them are from developing nations, and ARIs are responsible for one-third of all deaths. Human Metapneumovirus (hMPV) is one of the causative agents associated with respiratory tract infections. There is lack of information about hMPV from the eastern region of Uttar Pradesh. In our centre, Indian Council of Medical Research- Regional Medical Research Centre Gorakhpur (ICMR‐RMRC Gorakhpur) at Gorakhpur, Uttar Pradesh, India; we tested for respiratory pathogens in under-five patients presenting with ARI and severe acute respiratory illness (SARI) through semi nested PCR. A total of 100 nasal and throat specimens were collected from the OPD and IPD of Department of Paediatrics, BRD Medical College, Gorakhpur during from February 2022 to April 2022. Out of 100 enrolled pediatric patients, 4 (4%) were found to be positive. Among the patients who tested positive for hMPV, 25% (1/4) patient unfortunately died. The phylogenetic analysis of hMPV showed the close resemblance with the clade of Singapore and USA hMPV isolates. Our work underlines the importance of hMPV as the cause of acute respiratory infections in children and the need for routine testing for this virus in laboratories. Further comprehensive information regarding the incidence of hMPV in this area is needed.
Generation of human iPSC-derived phrenic-like motor neurons to model respiratory motor neuron degeneration in ALS
Authors: Thiry Louise , Sirois Julien , Durcan Thomas M. , Stifani Stefano
Published: April 2024

The fatal motor neuron (MN) disease Amyotrophic Lateral Sclerosis (ALS) is characterized by progressive MN degeneration. Phrenic MNs (phMNs) controlling the activity of the diaphragm are prone to degeneration in ALS, leading to death by respiratory failure. Understanding of the mechanisms of phMN degeneration in ALS is limited, mainly because human experimental models to study phMNs are lacking. Here we describe a method enabling the derivation of phrenic-like MNs from human iPSCs (hiPSC-phMNs) within 30 days. This protocol uses an optimized combination of small molecules followed by cell-sorting based on a cell-surface protein enriched in hiPSC-phMNs, and is highly reproducible using several hiPSC lines. We show further that hiPSC-phMNs harbouring ALS-associated amplification of theC9orf72gene progressively lose their activity and undergo increased death compared to isogenic controls. These studies establish a previously unavailable protocol to generate human phMNs, offering a disease-relevant system to study mechanisms of respiratory MN dysfunction.
“Holy cow, where do I sign up?” Attitudes of Military Veterans toward Epigenomic Biomarker Toxic Exposure Testing
Authors: Pereira Stacey , Apodaca Calvin , Slominski Kyle , Lipsky Rachele K. , Coarfa Cristian , Walker Cheryl L. , McGuire Amy L. , Steele Lea , Helmer Drew A.
Published: April 2024

Abstract

Background

With the signing of the PACT Act in 2022, there is great interest and investment in studying toxic exposures encountered during military service. One way to address this is through the identification of epigenomic biomarkers associated with exposures. There is increasing evidence suggesting that exposure to toxic substances may result in alterations to DNA methylation and resultant gene expression. These epigenomic changes may lead to adverse health effects for exposed individuals and their offspring. While the development of epigenomic biomarkers for exposures could facilitate understanding of these exposure-related health effects, such testing could also provide unwanted information.

Objectives

Explore Veterans’ attitudes toward epigenomic biomarker research and the potential to test for past exposures that could pose intergenerational risk.

Methods

Semi-structured interviews with Veterans (n=22) who experienced potentially harmful exposures during their military service.

Results

Twenty Veterans said they would hypothetically want to receive epigenomic information related to their toxic exposures and potential health impacts as part of a research study. Veterans identified nine potential benefits of this research, including promoting insights concerning intergenerational health, identification of early health interventions to mitigate the impact of exposures, and additional knowledge or explanation for their experiences. At the same time, 16 participants noted potential risks, including psychological distress in response to results, concerns about receiving non-actionable, uncertain, or inaccurate results, and issues related to privacy and discrimination. Ten participants also identified at least one condition in their children that they thought could be related to their exposure and most said they would be interested in receiving research results related to their children’s and grandchildren’s risk of developing a health condition associated with their exposure.

Discussion

Results suggest that Veterans might welcome benefits of epigenomic research related to military exposures yet have some concerns about potential negative impacts.
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

1

Pharmacometric 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

INTRODUCTION

Lipids 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.

METHODS

Retrospective 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).

RESULTS

Of 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).

CONCLUSION

A 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.

Highlights

At 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
Molecular epidemiology of Western equine encephalitis virus in Brazil, 2023-2024
Authors: Campos Aline Scarpellini , Franco Ana Claudia , Godinho Fernanda , Huff Rosana , Cardoso Jader da Cruz , Morais Paola , Franceschin Carolina , Bermann Thales de Lima , dos Santos Franciellen Machado , Bauermann Milena , Selayaran Taina Machado , Ruivo Amanda Pellenz , Santin Cristiane , Bonella Juciane , Rodenbusch Carla , Ferreira Jose Carlos , Weaver Scott C , Gewehr Vilar Ricardo , Wallau Gabriel Luz , de Souza William M. , Salvato Richard Steiner
Published: April 2024

During the ongoing western equine encephalitis virus (WEEV) outbreak in South America, we described three fatal cases in horses from Rio Grande do Sul, Brazil. We sequenced WEEV strains and identified a novel lineage causing these cases. Continued surveillance and horse immunization are needed to mitigate the WEEV burden.
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

Neurotransmitters 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

Dravet 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.
Gut dysbiosis was inevitable, but tolerance was not: temporal responses of the murine microbiota that maintain its capacity for butyrate production correlate with sustained antinociception to chronic morphine
Authors: Sall Izabella J , Foxall Randi , Felth Lindsey , Maret Soren , Rosa Zachary , Gaur Anirudh , Calawa Jennifer , Pavlik Nadia , Whistler Jennifer , Whistler Cheryl A
Published: April 2024

The therapeutic benefits of opioids are compromised by the development of analgesic tolerance, which necessitates higher dosing for pain management thereby increasing the liability for drug dependence and addiction. Rodent models indicate opposing roles of the gut microbiota in tolerance: morphine-induced gut dysbiosis exacerbates tolerance, whereas probiotics ameliorate tolerance. Not all individuals develop tolerance which could be influenced by differences in microbiota, and yet no study design has capitalized upon this natural variation. We leveraged natural behavioral variation in a murine model of voluntary oral morphine self-administration to elucidate the mechanisms by which microbiota influences tolerance. Although all mice shared similar morphine-driven microbiota changes that largely masked informative associations with variability in tolerance, our high-resolution temporal analyses revealed a divergence in the progression of dysbiosis that best explained sustained antinociception. Mice that did not develop tolerance maintained a higher capacity for production of the short-chain fatty acid (SCFA) butyrate known to bolster intestinal barriers and promote neuronal homeostasis. Both fecal microbial transplantation (FMT) from donor mice that did not develop tolerance and dietary butyrate supplementation significantly reduced the development of tolerance independently of suppression of systemic inflammation. These findings could inform immediate therapies to extend the analgesic efficacy of opioids.
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

In 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

Mixed-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 summary

Participants 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

Surgical 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 Statement

This 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

Background

Whole-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.

Methods

We 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.

Results

Our 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.

Conclusion

This 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

Bis-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

SARS-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

Recent 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

Efforts 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.
Connectome-driven neural inventory of a complete visual system
Authors: Nern Aljoscha , Loesche Frank , Takemura Shin-ya , Burnett Laura E , Dreher Marisa , Gruntman Eyal , Hoeller Judith , Huang Gary B , Januszewski Michal , Klapoetke Nathan C , Koskela Sanna , Longden Kit D , Lu Zhiyuan , Preibisch Stephan , Qiu Wei , Rogers Edward M , Seenivasan Pavithraa , Zhao Arthur , Bogovic John , Canino Brandon S , Clements Jody , Cook Michael , Finley-May Samantha , Flynn Miriam A , Fragniere Alexandra MC , Hameed Imran , Hayworth Kenneth J , Hopkins Gary Patrick , Hubbard Philip M , Katz William T , Kovalyak Julie , Lauchie Shirley A , Leonard Meghan , Lohff Alanna , Maldonado Charli A , Mooney Caroline , Okeoma Nneoma , Olbris Donald J , Ordish Christopher , Paterson Tyler , Phillips Emily M , Pietzsch Tobias , Rivas Salinas Jennifer , Rivlin Patricia K , Schlegel Philipp , Scott Ashley L , Scuderi Louis A , Takemura Satoko , Talebi Iris , Thomson Alexander , Trautman Eric T , Umayam Lowell , Walsh Claire , Walsh John J , Xu C Shan , Yakal Emily A , Yang Tansy , Zhao Ting , Funke Jan , George Reed , Hess Harald F , Jefferis Gregory S X E , Knecht Christopher , Korff Wyatt , Plaza Stephen M , Romani Sandro , Saalfeld Stephan , Scheffer Louis K , Berg Stuart , Rubin Gerald M , Reiser Michael B
Published: April 2024

Vision provides animals with detailed information about their surroundings, conveying diverse features such as color, form, and movement across the visual scene. Computing these parallel spatial features requires a large and diverse network of neurons, such that in animals as distant as flies and humans, visual regions comprise half the brain's volume. These visual brain regions often reveal remarkable structure-function relationships, with neurons organized along spatial maps with shapes that directly relate to their roles in visual processing. To unravel the stunning diversity of a complex visual system, a careful mapping of the neural architecture matched to tools for targeted exploration of that circuitry is essential. Here, we report a new connectome of the right optic lobe from a male Drosophila central nervous system FIB-SEM volume and a comprehensive inventory of the fly's visual neurons. We developed a computational framework to quantify the anatomy of visual neurons, establishing a basis for interpreting how their shapes relate to spatial vision. By integrating this analysis with connectivity information, neurotransmitter identity, and expert curation, we classified the ~53,000 neurons into 727 types, about half of which are systematically described and named for the first time. Finally, we share an extensive collection of split-GAL4 lines matched to our neuron type catalog. Together, this comprehensive set of tools and data unlock new possibilities for systematic investigations of vision in Drosophila, a foundation for a deeper understanding of sensory processing.