bluuebunny/crossref_metadata_2025 huggingface dataset:
Rate of hydrolysis of the phosphate esters of B vitamins is reduced by zinc deficiency: In vitro and in vivo
Authors: Yuasa Hana , Miyazaki Kiyoshi , Kido Takamasa , Nishino Katsutoshi , Shiotsu Miku , Fukuwatari Tsutomu , Suka Machi , Nagao Masaya , Kambe Taiho
Published: September 2024

Extracellular hydrolysis of the phosphate esters of B vitamins (B1, B2, and B6) is crucial for their cellular uptake and metabolism. Although a few zinc‐dependent enzymes have been implicated in these processes, their exact mechanisms of action remain largely unknown. This study investigated the potential involvement of phosphate group hydrolyzing enzymes in the hydrolysis of B vitamin phosphate esters. We evaluated enzyme activity in membrane lysates prepared from cells transiently transfected with these enzymes or those endogenously expressing them. Specifically, we investigated how zinc deficiency affects the rate of hydrolysis of B vitamin phosphate esters in cellular lysates. Assessment of the activities of zinc‐dependent ectoenzymes in the lysates prepared from cells cultured in zinc‐deficient conditions and in the serum of rats fed zinc‐deficient diets revealed that zinc deficiency reduced the extracellular hydrolysis activity of B vitamin phosphate esters. Furthermore, our findings explain the similarities between several symptoms of B vitamin and zinc deficiencies. Collectively, this study provides novel insights into the diverse symptoms of zinc deficiency and could guide the development of appropriate clinical strategies.
Mechanoresponsive regulation of tissue regeneration during distraction osteogenesis
Authors: Hu Wenzhong , Guo Zeyou , Tang Weibing , Long Jie
Published: September 2024

Distraction osteogenesis is widely used for bone tissue engineering. Mechanical stimulation plays a central role in the massive tissue regeneration observed during distraction osteogenesis. Although distraction osteogenesis has been a boon for patients with bone defects, we still have limited knowledge about the intrinsic mechanotransduction that converts physical forces into biochemical signals capable of inducing cell behavior changes and new tissue formation. In this review, we summarize the findings for mechanoresponsive factors, including cells, genes, and signaling pathways, during the distraction osteogenesis different phases. These elements function for coupling of osteogenesis and angiogenesis via the Integrin‐FAK, TGF‐β/BMP, Wnt/β‐catenin, Hippo, MAPK, PI3K/Akt, and HIF‐1α signaling pathways in a mechanoresponsive niche. The available evidence further suggests the existence of a balance between the epithelial–mesenchymal transition and mesenchymal–epithelial transition under hypoxic stress. We also briefly summarize the current in silico simulation algorithms and propose several future research directions that may advance understanding of distraction osteogenesis in the era of bioinformation, particularly the integration of artificial intelligence models with reliable single‐cell RNA sequencing datasets. The objective of this review is to utilize established knowledge to further optimize existing distraction protocols and to identify potential therapeutic targets.
Effects of Serratus Anterior Plane Block on Early Recovery from Thoracoscopic Lung Resection: A Randomized, Blinded, Placebo-controlled Trial
Authors: Jackson Jacob C. , Tan Kay See , Pedoto Alessia , Park Bernard J. , Rusch Valerie W. , Jones David R. , Zhang Hao , Desiderio Dawn , Fischer Gregory W. , Amar David
Published: September 2024

Background:

The efficacy of serratus anterior plane block for treatment of pain after minimally invasive thoracic surgery remains unclear. This trial assesses the impact of serratus anterior plane block on postoperative opioid consumption and on measures of early recovery after thoracoscopic lung resection.

Methods:

Patients undergoing minimally invasive anatomic lung resection at a single center were randomized to undergo serratus anterior plane block with 40 ml injectate containing bupivacaine 0.25%, clonidine 100 μg, and dexamethasone 4 mg (serratus anterior plane block group) or sham block with 40 ml normal saline (placebo group) at the conclusion of surgery. The primary outcome was cumulative intravenous morphine equivalents during the first 24 h postoperatively. Secondary outcomes were intravenous morphine equivalents, pain scores at rest and with cough, inspiratory volume on incentive spirometry, incidence of nausea or vomiting during the first 48 h postoperatively, Quality of Recovery–15 score on postoperative day 7, and length of stay.

Results:

Using the protocol-specified intention-to-treat analysis, the median (interquartile range) intravenous morphine equivalents was 10.6 (5.0 to 27.1) mg in serratus anterior plane block patients (n = 46) versus 18.8 (9.9 to 29.6) mg in placebo patients (n = 46; 32% reduction; ratio, 0.68 [95% CI, 0.44 to 1.06]; P = 0.085). Of the secondary outcomes, only the composite pain with cough scores differed significantly in the serratus anterior plane block group by a coefficient of –0.41 (95% CI, –0.81 to –0.01; P = 0.044). A sensitivity as-treated analysis reported median (interquartile range) intravenous morphine equivalents of 10.0 (5.0 to 27.2) mg in serratus anterior plane block patients (n = 44) versus 19.9 (10.4 to 29.0) mg in placebo patients (n = 48; 36% reduction; ratio, 0.64 [95% CI, 0.41 to 1.00]; P = 0.048).

Conclusions:

The protocol-specified intention-to-treat analysis demonstrated that serratus anterior plane block did not result in a significant reduction in opioid consumption when added to a multimodal analgesic regimen after thoracoscopic anatomic lung resection. The sensitivity as-treated analysis showed a significant and modest clinical reduction in the primary outcome that warrants further investigation.
Koby Superficial Reticular Degeneration of the Cornea
Authors: Koulouri Ismini , Park Jennifer
Published: September 2024

Purpose:

Corneal reticular degeneration of Koby, a rare corneal degeneration, has not been previously reported in association with sarcoidosis. We report such a case presenting to our clinic after a prolonged course of bilateral panuveitis secondary to sarcoidosis.

Methods:

A 58-year-old woman with a history of chronic panuveitis secondary to sarcoidosis presented with new visual disturbances and the rare finding of superficial corneal reticular degeneration of Koby. The clinical presentation, diagnosis, and management of this unique ocular manifestation are discussed.

Results:

Corneal reticular degeneration of Koby is most likely a subvariant of band keratopathy that has been very rarely reported in the literature to date and not yet reported as a complication of sarcoidosis.

Conclusions:

Clinicians should be aware of this presentation of band keratopathy in patients and be able to recognize and treat it accordingly.
Multimodal Imaging of Posterior Corneal Opacities in Multicentric Osteolysis Nodulosis and Arthropathy
Authors: Eppley Sarah E. , Pasricha Neel D. , Seitzman Gerami D. , Joye Ashlin , Arboleda Alejandro , Qureshi Azam
Published: September 2024

Purpose:

Multicentric osteolysis nodulosis and arthropathy (MONA) syndrome is a rare autosomal recessive skeletal dysplasia. Caused by mutations in the matrix metalloproteinase 2 (MMP2) gene on chromosome 16q12, this syndrome has infrequently been associated with ophthalmic manifestations. Corneal opacities have been reported but not described or documented in detail.

Methods:

Complete ophthalmologic examination and multimodal anterior segment imaging were used to characterize the corneal findings in a patient with MONA syndrome.

Results:

A 19-year-old man with MONA syndrome was referred for an eye examination based on MONA screening recommendations. Visually insignificant peripheral corneal opacities were noted. Anterior segment optical coherence tomography demonstrated posterior stromal and endothelial hyperreflectivity. Confocal microscopy demonstrated an acellular peripheral endothelium with a normal central endothelium.

Conclusions:

Corneal opacities can occur with MONA syndrome, which is caused by mutations in the MMP2 gene. In the patient presented here, the corneal opacities are peripheral, deep stromal, with sparing of the anterior stroma and epithelium.
Left Middle Phalanx Tuberculous Dactylitis Masquerading as a Tumor: First Case Report in Saudi Arabia
Authors: Nukaly Houriah Yasir , Ahmed Ruqayyah Ali , Mousa Ahmed Hafez , Moallem Adnan Anas , Zubair Mohammed Talha Mohammed , AlAidarous Hasan Ali Abdullah , Alshanberi Asim Muhammed , Albalawi Ibrahim Abdullah S. , Abbas Fahad
Published: September 2024

Tuberculous dactylitis can cause osteomyelitis, which is a rare extrapulmonary manifestation of tuberculosis, often misdiagnosed due to its nonspecific presentation and resemblance to other conditions like neoplasms. A 15-year-old male patient reported to our clinic with a 1-year history of left index finger pain and swelling following a football-related injury. Despite conservative management, the symptoms had progressively worsened over the past few months. Clinical examination revealed deformity and swelling of the middle phalanx, along with induced pain on range of motion. Bacteriological analysis indicated polymorphic nuclear cells and the presence of coagulase-negative Staphylococcus (Staphylococcus hominis). Radiographic evaluation, including x-ray and magnetic resonance imaging, revealed medullary expansion, trabecular thinning, and focal soft tissue swelling. Magnetic resonance imaging displayed extensive soft tissue and bone marrow involvement, raising concerns of a tumor. An open biopsy was performed, yielding unexpected findings of necrotizing and suppurative granulomatous inflammation, strongly suggesting an ongoing infectious process. The subsequent Quantiferon TB Gold Test confirmed tuberculosis infection. Treatment encompassed debridement, synovectomy, and initiation of an antituberculosis regimen. The patient showed significant improvement after treatment. Timely diagnosis and treatment of tuberculous dactylitis are crucial, as highlighted by the patient’s positive response to combined surgical and pharmacological intervention, despite initial diagnostic challenges.
Updated Canadian Clinical Practice Guideline for the Rehabilitation of Adults With Moderate to Severe Traumatic Brain Injury: Mental Health Recommendations
Authors: Mehta Swati , Devito Lauren , Patsakos Eleni M. , Devito Julia , Velikonja Diana , Bayley Mark , Teasell Robert , MacKenzie Heather M.
Published: September 2024

Objective:

Objective: After sustaining a moderate to severe traumatic brain injury (MSTBI), individuals often experience comorbid mental health conditions that can impair the rehabilitation and recovery process. The objective of this initiative was to update recommendations on the assessment and management of mental health conditions for the Canadian Clinical Practice Guideline for the Rehabilitation of Adults with MSTBI (CAN-TBI 2023).

Objective:

Design: A systematic search was conducted by the Evidence-Based Review of Moderate to Severe Acquired Brain Injury to identify new and relevant articles. Expert Panel reviewed and discussed the new and existing evidence, evaluated its quality, and added, removed, or modified recommendations and tools as needed. A consensus process was followed to achieve agreement on recommendations.

Objective:

Results: CAN-TBI 2023 includes 20 recommendations regarding best practices for the assessment and management of mental health conditions post-MSTBI. About 17 recommendations were updated, 1 new recommendation was formed, and 2 recommendations remained unchanged. The Guideline emphasizes the importance of screening and assessment of mental health conditions throughout the rehabilitation continuum. The Expert Panel recommended incorporating multimodal treatments that include pharmacological and nonpharmacological approaches to manage mental health concerns.

Objective:

Conclusion: The CAN-TBI 2023 recommendations for the assessment and management of mental health conditions should be used to inform clinical practice. Additional high-quality research in this area is needed, as 13 recommendations are based on level C evidence, 4 on level B evidence, and 3 on level A evidence.
Evidence-Based Review of Randomized Controlled Trials of Interventions for the Management of Behavioral Issues in Individuals With Moderate to Severe Traumatic Brain Injury
Authors: MacKenzie Heather M. , Flores-Sandoval Cecilia , Bateman Emma A. , McIntyre Amanda , Barua Ujjoyinee , Mehta Swati , Bayley Mark , Teasell Robert
Published: September 2024

Objective:

To present an evidence-based review of randomized controlled trials (RCTs) evaluating interventions for the management of behavioral issues post moderate to severe traumatic brain injury (MSTBI), as part of an extensive database that has been conceptualized as a living systematic review.

Methods:

Systematic searches were conducted in MEDLINE, PubMed, Scopus, CINAHL, EMBASE and PsycINFO, up to and including December 2022, for articles published in the English language, in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The quality of RCT was assessed using the Physiotherapy Evidence Database (PEDro) scale, and level of evidence was assigned using a modified Sackett scale.

Results:

Forty-six RCTs examining interventions and outcome measures related to behavioral issues post-MSTBI were included. These studies collectively enrolled 3,267 participants. The majority of RCTs were conducted in the United States (n = 27; 58.7%) and 28 (60.9%) were conducted after 2010. Of these, 27 RCTs examined non-pharmacological interventions and 19 examined pharmacological interventions. Effective pharmacological treatments included amantadine and dexmedetomidine. Effective non-pharmacological interventions included sensory stimulation in the acute phase, anger self-management programs, peer mentoring, problem-solving, and emotional regulation. Psychotherapy showed conflicting evidence.

Conclusion:

This evidence-based review provides a comprehensive overview of the research landscape of RCTs addressing behavior post-MSTBI. The findings from these RCTs may be valuable for health care professionals, researchers, and policymakers involved in the field of TBI and behavior.
Racial, ethnic, and sex bias in large language model opioid recommendations for pain management
Authors: Young Cameron C. , Enichen Elizabeth , Rao Arya , Succi Marc D.
Published: September 2024

Understanding how large language model (LLM) recommendations vary with patient race/ethnicity provides insight into how LLMs may counter or compound bias in opioid prescription. Forty real-world patient cases were sourced from the MIMIC-IV Note dataset with chief complaints of abdominal pain, back pain, headache, or musculoskeletal pain and amended to include all combinations of race/ethnicity and sex. Large language models were instructed to provide a subjective pain rating and comprehensive pain management recommendation. Univariate analyses were performed to evaluate the association between racial/ethnic group or sex and the specified outcome measures—subjective pain rating, opioid name, order, and dosage recommendations—suggested by 2 LLMs (GPT-4 and Gemini). Four hundred eighty real-world patient cases were provided to each LLM, and responses included pharmacologic and nonpharmacologic interventions. Tramadol was the most recommended weak opioid in 55.4% of cases, while oxycodone was the most frequently recommended strong opioid in 33.2% of cases. Relative to GPT-4, Gemini was more likely to rate a patient's pain as “severe” (OR: 0.57 95% CI: [0.54, 0.60]; P < 0.001), recommend strong opioids (OR: 2.05 95% CI: [1.59, 2.66]; P < 0.001), and recommend opioids later (OR: 1.41 95% CI: [1.22, 1.62]; P < 0.001). Race/ethnicity and sex did not influence LLM recommendations. This study suggests that LLMs do not preferentially recommend opioid treatment for one group over another. Given that prior research shows race-based disparities in pain perception and treatment by healthcare providers, LLMs may offer physicians a helpful tool to guide their pain management and ensure equitable treatment across patient groups.
Predictors of Prolonged Hospital Stay After Microsurgery for Vestibular Schwannoma: Analysis of a Decade of Data
Authors: Aboueisha Mohamed A. , Manayan Regan , Tie Kevin , Issa Peter P. , Al-Hamtary Mohamed A. , Huang Victoria , Naples James G.
Published: September 2024

Importance

Microsurgical resection is one of the treatments for vestibular schwannomas (VS). While several factors have been linked to increased length of stay (LOS) for VS patients undergoing microsurgery, a better understanding of these factors is important to provide prognostic information for patients.

Objective

Determine predictors of increased LOS for VS patients undergoing microsurgical resection.

Design

Retrospective analysis using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from 2010 to 2020.

Setting

Database review

Participants

All patients who underwent microsurgery (CPT codes 61520, 61526/61596) for the management of vestibular schwannoma (ICD9 and ICD10 codes 225.1, D33.3) were included.

Main Outcomes and Measures

Analyzing perioperative factors that can predict prolonged hospital stay

Results

A total of 2096 cases were identified and 1,188 (57%) of these patients were female. The mean age was 51.0 ± 14.0 years. Factors contributing to prolonged LOS included African American race (OR = 2.11, 95% CI: 1.32–3.36, p = 0.002), insulin-dependent diabetes mellitus (OR = 2.12, 95% CI: 1.09–4.4.11, p = 0.026), hypertension (OR = 1.26, 95% CI: 1–1.58, p = 0.046), functional dependency (OR = 5.22, 95% CI: 2.31–11.79, p = 0.001), prior steroid use (OR = 1.96, 95% CI: 1.18–3.15, p = 0.009), ASA class III (OR = 2.06, 95% CI: 1.18–3.6, p < 0.011), ASA class IV (OR = 6.34, 95% CI: 2.62–15.33, p < 0.001), and prolonged operative time (OR = 2.14, 95% CI: 1.76–2.61). Microsurgery by a translabyrinthine (TL) approach compared to a retrosigmoid (RSG) approach had lower odds of prolonged LOS (OR = 0.67, 95% CI: 0.54–0.82, p < 0.001). In a separate analysis regarding patients receiving reoperation, operative time was the only predictor of prolonged LOS (OR = 2.77, 95% CI: 1.39–5.53, p = 0.004.)

Conclusions and Relevance

Our analysis offers an analysis of the factors associated with a prolonged LOS for the surgical management of VS. By identifying healthcare disparities, targeting modifiable factors, and applying risk stratification based on demographics and comorbidities, we can work toward reducing disparities in LOS and enhancing patient outcomes.
Global emergency medicine research priorities: a mapping review
Authors: Kim Erin , Mahajan Prashant , Barousse Chris , Kumar Vijaya A. , Chong Shu-ling , Belle Apoorva , Roth Dominik
Published: September 2024

Recognizing and prioritizing research areas in emergency care is crucial for generating evidence and advancing research programs, aiming to enhance health outcomes for both individuals and populations. The objective of this review is to document global clinical and nonclinical research priorities. The Emergency Medicine Education and Research by Global Experts network, consisting of 22 sites across six continents, conducted a mapping review of publications on emergency medicine research priorities (2000–2022) across seven databases. We included studies with replicable methodologies for determining research priorities, excluding those limited to individual diseases. Three reviewers independently screened, selected, and categorized results into clinical and nonclinical topics. Discrepancies were resolved by an independent investigator and consensus. Outcomes measures and analysis include descriptive analysis of research priorities grouped into clinical and nonclinical topics, characteristics of publications including countries represented in the author list, target audience (such as researchers or policy makers), participants (e.g. patients), and methods (e.g. Delphi) of priority setting. Among 968 screened papers, 57 publications from all WHO regions were included. Most (36, 63%) had authors from only a single country, primarily in North America and Europe. Patient representatives were included in only 10 (18%). Clinical research priorities clustered into resuscitation, cardiology, central nervous system, emergency medical services, infectious disease, mental health, respiratory disease, and trauma. Distribution was broad in North America and Europe but focused on infectious diseases and resuscitation in Africa and Asia. Eleven nonclinical topics included access to care, health policy, screening/triage, social determinants of health, staffing, technology/simulation, shared decision making, cross-sectoral collaboration, education, patient-centered care, and research networks. Nonclinical topics were broad in Europe and America, focused on access to care and health screening in Africa, and mostly absent in other WHO regions. Published research priorities in emergency medicine are heterogeneous and geographically limited, mostly containing groups of authors from the same country. The majority of publications in global research priority setting stem from Western countries, covering a broad spectrum of clinical and nonclinical topics. Research priorities from Africa and Asia tend to focus on specific issues more prevalent in those regions of the world.
Association of smoking with neurocognition, inflammatory and myeloid cell activation profiles in people with HIV on antiretroviral therapy
Authors: Yadav Anjana , Gionet Gabrielle , Karaj Antoneta , Kossenkov Andrew V. , Kannan Toshitha , Putt Mary E. , Stephens Shields Alisa J. , Ashare Rebecca L. , Collman Ronald G.
Published: September 2024

Objective:

People with HIV (PWH) experience excess comorbidities, including neurocognitive disorders, which are linked to inflammation, particularly monocyte–macrophage activation. Smoking contributes to morbidity and mortality in well treated PWH. We investigated associations between smoking, neurocognitive function, and inflammation in PWH on antiretroviral therapy (ART).

Design:

We used baseline data on cognition and inflammation from a longitudinal study of virologically suppressed PWH who do and do not smoke.

Methods:

Participants completed four neurocognitive tests (seven measures), with a composite score as the primary measure. Inflammatory markers were plasma sCD14, sCD163, and CCL2/MCP-1; %CD14+ monocytes expressing CD16, CD163, and CCR2; and %CD8+ T cells co-expressing CD38/HLA-DR. Exploratory analyses included a plasma cytokine/chemokine panel, neurofilament light chain (NFL), hsCRP, and monocyte transcriptomes by RNAseq.

Results:

We recruited 58 PWH [26 current smoking (PWH/S), 32 no current smoking (PWH/NS)]. Mean composite and individual neurocognitive scores did not differ significantly by smoking status except for the color shape task; PWH/S exhibited worse cognitive flexibility, with adjusted mean times 317.2 [95% confidence interval (CI) 1.4–632.9] ms longer than PWH/NS. PWH/S had higher plasma sCD14 than PWH/NS [median (IQR) 1820 (1678–2105) vs. 1551 (1284–1760) ng/ml, P = 0.009]. Other inflammatory markers were not significantly different between PWH/S and PWH/NS. Monocyte transcriptomes showed several functions, regulators, and gene-sets that differed by smoking status.

Conclusion:

sCD14, a marker of monocyte activation, is elevated in PWH who smoke. Although neurocognitive measures and other inflammatory markers did not generally differ, these data implicate smoking-related myeloid activation and monocyte gene dysregulation in the HIV/smoking synergy driving HIV-associated comorbidities.
Cell division cycle fluctuation of Pal concentration in Escherichia coli
Authors: Mertens Laureen , Liu Xinwei , Verheul Jolanda , Egan Alexander J.F. , Vollmer Waldemar , den Blaauwen Tanneke
Published: September 2024

The Tol-Pal proteins stabilise the outer membrane during cell division in many gram-negative bacteria, including Escherichia coli. Pal is an outer membrane lipoprotein that can bind peptidoglycan. It accumulates at the septum during division by a mobilisation-and-capture mechanism. This work further substantiates and extends knowledge of Pal's localisation in E. coli using immunolabeling, this method enables the detection of endogenous proteins. The midcell localisation of Pal and TolB, as seen with fluorescent protein fusions, during cell division, was confirmed. The retention of Pal in newly formed cell poles seemed to persist longer than observed with fluorescent Pal fusions. The concentration of endogenous Pal during the cell division cycle fluctuated: it decreased initially (to half the fluorescence concentration (32.1 au.µm-3) of the maximum (64.1 au.µm-3) reached during the cell cycle) and then increased during the second half of the cell division cycle. We probed for possible regulators and proposed two new putative regulators of Pal. Deleting the periplasmic protease, Prc decreased the total Pal abundance (to approximately 65% of the fluorescence concentration in wildtype cells) and affected its concentration fluctuation during the cell cycle. This suggests that Prc controls a cell division stage-specific regulator of Pal. Immunolabeling also supported the prediction that the small RNA MicA suppresses Pal expression (the fluorescence concentration of Pal in cells without MicA is double that of Pal in wildtype cells). However, the regulation by MicA occurred in a cell-cycle-independent manner. All these findings urge further research on the tight regulation of the dividing cell envelope stability.
Detection of Hepatitis B Virus Genotypes in a Group of Hepatitis B Virus Infected Patients in Central and Northern Sri Lanka
Authors: Pattiyakumbura T T , Malkanthi K.G.K , Manamperi A. , Dheerasekara W.K.H , Muthugala M.A.R.V.
Published: September 2024

Introduction

Hepatitis B infection causes a spectrum of clinical diseases varying from asymptomatic infection to severe or fulminant acute hepatitis, chronic liver disease, cirrhosis, and hepatocellular carcinoma. Hepatitis B virus genotypes appear to influence transmission dynamics, clinical outcomes, and responses to antiviral therapy. However, hepatitis B genotyping is a poorly investigated topic in Sri Lanka. This study intended to determine hepatitis B genotypes in a group of HBV-infected persons in central and northern Sri Lanka.

Methodology

The study was a laboratory-based descriptive cross-sectional study. Initial detection of HBV DNA in EDTA blood samples was done by a commercially validated quantitative real-time polymerase chain reaction kit (qPCR). Hepatitis B genotyping was performed by in-house conventional semi-nested multiplex PCR using genotype-specific primers (for genotypes A, B, C, D, E, F). The serological profile was determined using a commercially validated ELISA/ CLIA assay. The results were evaluated for the genotype prevalence, viral load association, and HBeAg expression in the study population.

Results and Conclusion

The study detected that genotype C is most prevalent and infections with multiple genotypes (52%) were commoner than mono-genotype (23%) infections. In 25% of patients, had no detectable genotype among genotype A-F. The mean viral load in asymptomatic patients with a single genotype was 3.28 log 10 copies/mL and in multiple genotypes was 4.18 log 10 copies/mL before treatment. Statistical significance was not detected in mean viral loads and HBeAg expression in these two groups. In the future, chronic HBV infection may be effectively treated and managed according to the infected genotype.
Tunable picoliter-scale dropicle formation using amphiphilic microparticles with patterned hydrophilic patches
Authors: Song Xinpei , Udani Shreya , Ouyang Mengxing , Sahin Mehmet Akif , Di Carlo Dino , Destgeer Ghulam
Published: September 2024

Microparticle-templated droplets or dropicles have recently gained interest in the fields of diagnostic immunoassays, single-cell analysis, and digital molecular biology. Amphiphilic particles have been shown to spontaneously capture aqueous droplets within their cavities upon mixing with an immiscible oil phase, where each particle templates a single droplet. Here, we fabricated an amphiphilic microparticle with four discrete hydrophilic patches embedded at the inner corners of a square-shaped hydrophobic outer ring of the particle (4C particle). 3D computational fluid dynamics simulations predicted droplet formation dynamics and differing equilibrium conditions depending on the patterning configuration. Experiments recapitulated equilibrium conditions enabling tunable dropicle configurations with reproducible volumes down to ~200pL templated by the amphiphilic particles. The dropicle configurations depended predominantly on the size of the hydrophilic patches of the 4C particles. This validated modeling approach can inform the design of dropicles with varying volumes and numbers per particle, which can be harnessed in new amplified bioassays for greater sensitivity, dynamic range, and statistical confidence.
Proposing a methodology for axon-centric analysis of IOP-induced mechanical insult
Authors: Bansal Manik , Wang Bingrui , Waxman Susannah , Zhong Fugiang , Hua Yi , Lu Yuankai , Reynaud Juan , Fortune Brad , Sigal Ian A
Published: September 2024

Purpose. IOP-induced mechanical insult on retinal ganglion cell axons within the optic nerve head (ONH) is believed to be a key factor in axonal damage and glaucoma. However, most studies focus on tissue-level mechanical deformations, overlooking that axons are long and thin, and that their susceptibility to damage likely depends on the insult's type (e.g. stretch/compression) and orientation (longitudinal/transverse). We propose an axon-centric approach to quantify IOP-induced mechanical insult from an axon perspective. Methods. We used optical coherence tomography (OCT) scans from a healthy monkey eye along with histological images of cryosections to reconstruct the axon-occupied volume including detailed lamina cribrosa (LC) pores. Tissue-level strains were determined experimentally using digital volume correlation from OCT scans at baseline and elevated IOPs, then transformed into axonal strains using axon paths estimated by a fluid mechanics simulation. Results. Axons in the LC and post-LC regions predominantly experienced longitudinal compression and transverse stretch, whereas those in the pre-LC and ONH rim mainly suffered longitudinal stretch and transverse compression. No clear patterns were observed for tissue-level strains. Conclusions. Our approach allowed discerning axonal longitudinal and transverse mechanical insults, which are likely associated with different mechanisms of axonal damage. The technique also enabled quantifying insult along individual axon paths, providing a novel link relating the retinal nerve fiber layer and the optic nerve through the LC via individual axons. This is a promising approach to establish a clearer connection between IOP-induced insult and glaucoma. Further studies should evaluate a larger cohort.
In vivoquantification of creatine kinase kinetics in mouse brain using31P-MRS at 7 Tesla
Authors: Tachrount Mohamed , Smart Sean , Lerch Jason , Cherix Antoine
Published: September 2024

31P-MRS is a method of choice for studying neuroenergeticsin vivo, but its application in the mouse brain have been limited, often restricted to ultra-high field (>7 Tesla) MRI scanners. Establishing its feasibility on more readily available preclinical 7 Tesla (T) scanners would create new opportunities to study metabolism and physiology in murine models of brain disorders. Here, we demonstrate that the apparent forward rate constant (kf) of creatine kinase (CK) can be accurately quantified using a progressive saturation-transfer approach in the mouse brain at 7T. We also find that a reduction of approximately 20% in the breathing rate of anesthetized mice can lead to a 36% increase in kfattributable to a drop in intracellular pH and mitochondrial ATP production. To achieve this, we used a test-retest analysis to assess the reliability and repeatability of31P-MRS acquisition, analysis and experimental design protocols. We report that most31P-containing metabolites can be reliably measured using a localized 3D-ISIS sequence, which showed highest SNR amplitude, SNR consistency and minimal T2relaxation signal loss. Using this protocol, our study identifies, for the first time, key physiological factors influencing mouse brain energy homeostasisin vivoand provides a methodological basis that will guide future studies interested in implementing31P-MRS on preclinical 7T scanners.
Structure – silencing duration relationships in RNAi medicines in rapidly dividing cells
Authors: Kremer Anastasia , Ryaykenen Tatyana , Segarra-Visent Xavier , Sauer Melanie , Tang Qi , Cooper David A , Echeverria Dimas , Philouze Clothilde , Bayon Emilie , Georgess Dan , Haraszti Reka A
Published: September 2024

RNA interference (RNAi)-based medicines offer precise targeting of virtually any transcript, making them an appealing new drug class for addressing unmet needs in immune-oncological applications. While RNAi therapies show exceptional duration of effect in non-dividing cells, their efficacy in rapidly dividing cells, crucial for immune-oncology, remains largely unexplored. Unlike in non-dividing cells, full chemical modification in rapidly dividing cells has not consistently extended silencing duration, according to limited data available.

In this study, we investigated key factors affecting the duration of effect for three main types of RNAi-based therapeutics (siRNA, miRNA mimics, and miRNA inhibitors) in rapidly dividing cancer and immune cells. Saturation of intracellular depots by multiple loading doses, a common strategy to prolong silencing duration in non-dividing hepatocytes, had minimal impact on siRNA duration of effect in rapidly dividing cells. However, modifying the antisense strand with a 5’-(E)-vinylphosphonate (5’-VP) to protect siRNAs from exonucleases and enhance AGO2 binding significantly extended siRNA silencing duration to over 30 days bothin vitroandin vivo. For miRNA mimics, extensive stabilization of the antisense strand with phosphorothioates was not effective and led to reduced potency and silencing duration. Interestingly, a shorter duplex region commonly seen in therapeutic siRNAs partially rescued duration of silencing in miRNA mimics with extended phosphorothioate modifications. On the other hand, miRNA inhibitors demonstrated robust reversal of miRNA activity for an impressive 25 days in cancer cell lines.

Our findings enable the rational design of the chemical architecture and administration regimens of RNAi-based therapies in oncology and immunology.
The new phycobilisome linker protein ApcI regulates high light adaptation inSynechocystissp. PCC 6803
Authors: Espinoza-Corral Roberto , Zavřel Tomáš , Sutter Markus , Leslie Chase H. , Yang Kunwei , Beck Warren F. , Červený Jan , Kerfeld Cheryl A.
Published: September 2024

Phycobilisomes are versatile cyanobacterial antenna complexes that harvest light energy to drive photosynthesis. These complexes can also adapt to various light conditions, dismantling under high light to prevent photo-oxidation and arranging in rows under low light to increase light harvesting efficiency. Light quality also influences phycobilisome structure and function, as observed under far-red light exposure. Here we describe a new, phycobilisome linker protein, ApcI (previously hypothetical protein sll1911), expressed specifically under red light. We characterized ApcI inSynechocystissp. PCC 6803 using mutant strain analyses, phycobilisome binding experiments, and protein interaction studies. Mutation ofapcIconferred high light tolerance toSynechocystissp. PCC 6803 compared to wild type with reduced energy transfer from phycobilisomes to the photosystems. Binding experiments revealed that ApcI replaces the linker protein ApcG at the membrane-facing side of the phycobilisome core using a paralogous C-terminal domain. Additionally, the N-terminal extension of ApcI was found to interact with photosystem II. Our findings highlight the importance of phycobilisome remodeling for adaptation under different light conditions. The characterization of ApcI provides new insights into the mechanisms by which cyanobacteria optimize light-harvesting in response to varying light environments.
Material Composition and Implantation Site Affect in vivo Device Degradation Rate
Authors: Pawelec K. M. , Hix J. M.L. , Troia A. , Kiupel M. , Shapiro E. M.
Published: September 2024

Successful tissue engineering requires biomedical devices that initially stabilize wounds, then degrade as tissue is regenerated. However, the material degradation rates reported in literature are often conflicting. Incorporation of in situ monitoring functionality into implanted devices would allow real time assessment of degradation and potential failure. This necessitates introduction of contrast agent as most biomedical devices are composed of polymeric materials with no inherent contrast in medical imaging modalities. In the present study, computed tomography (CT)-visible radiopaque composites were created by adding 5-20wt% tantalum oxide (TaOx) nanoparticles into polymers with distinct degradation profiles: polycaprolactone (PCL), poly(lactide-co-glycolide) (PLGA) 85:15 and PLGA 50:50, representing slow, medium and fast degrading materials respectively. Radiopaque phantoms, mimicking porous tissue engineering devices, were implanted into mice intramuscularly or intraperitoneally, and monitored via CT over 20 weeks. Changes in phantom volume, including collapse and swelling, were visualized over time. Phantom degradation profile was determined by polymer matrix, regardless of nanoparticle addition and foreign body response was dictated by the implant site. In addition, degradation kinetics were significantly affected in mid-degrading materials, transitioning from linear degradation intramuscularly to exponential degradation intraperitoneally, due to differences in inflammatory responses and fluid flow. Nanoparticle excretion from degraded phantoms lagged behind polymer, and future studies will modulate nanoparticle clearance. Utilizing in situ monitoring, this study seeks to unify literature and facilitate better tissue engineering devices, by highlighting the relative effect of composition and implant site on important materials properties.
A Comparison of Tokenization Impact in Attention Based and State Space Genomic Language Models
Authors: Lindsey LeAnn M. , Pershing Nicole L. , Habib Anisa , Stephens W. Zac , Blaschke Anne J. , Sundar Hari
Published: September 2024

Genomic language models have recently emerged as powerful tools to decode and interpret genetic sequences. Existing genomic language models have utilized various tokenization methods including character tokenization, overlapping and non-overlapping k-mer tokenization, and byte-pair encoding, a method widely used in natural language models. Genomic models have significant differences from natural language and protein language models because of their low character variability, complex and overlapping features, and inconsistent directionality. These differences make sub-word tokenization in genomic language models significantly different from traditional language models.

This study explores the impact of tokenization in attention-based and state-space genomic language models by evaluating their downstream performance on various fine-tuning tasks. We propose new definitions forfertility, the token per word ratio, in the context of genomic language models, and introduceto-kenization parity, which measures how consistently a tokenizer parses homologous sequences. We also perform an ablation study on the state-space model, Mamba, to evaluate the impact of character-based tokenization compared to byte-pair encoding. Our results indicate that the choice of tokenizer significantly impacts model performance and that when experiments control for input sequence length, character tokenization is the best choice in state-space models for all evaluated task categories except epigenetic mark prediction.
Cognitive-and lifestyle-related microstructural variation in the ageing human hippocampus
Authors: Agyekum Tyler , García Cindy L. , Fay Felix , Parent Olivier , Bussy Aurélie , Devenyi Gabriel A. , Chakravarty M. Mallar
Published: September 2024

Ageing is a biological process associated with the natural degeneration of various regions of the brain. Alteration of neural tissue in the hippocampus with ageing typically results in cognitive decline that may serve as a risk factor for dementia and other neurodegenerative diseases. Modifiable lifestyle factors may help preserve hippocampal neural tissue (microstructure) and slow down neurodegeneration and thus promote healthy cognition in old age. In this study, we sought to identify potential modifiable lifestyle factors that may help preserve microstructure in the hippocampus. We used data from 494 subjects (36-100 years old) without clinical cognitive impairment from the Human Connectome Project-Aging study. We estimated hippocampal microstructure using myelin-sensitive (T1w/T2w ratio), inflammation-sensitive (MD) and fibre-sensitive (FA) MRI markers. Non-negative matrix factorization was used to integrate the signals of these images into a multivariate spatial signature of microstructure covariance across the hippocampus. The associations between hippocampal microstructural patterns and lifestyle factors & cognition were identified using partial least squares analysis. Our results reveal that the preservation of axon density and myelin in regions corresponding to subicular regions and CA1 to CA3 regions of the hippocampi of younger adults is associated with improved performance in executive function tasks, however, this is also associated with a decreased performance in memory tasks. We also show that microstructure is preserved across the hippocampus when there is normal hearing levels, physical fitness and normal insulin levels in younger adults of our study even in the presence of cardiovascular risk factors like high body mass index, blood pressure, triglycerides and blood glucose known to be associated with hippocampal neurodegeneration. This preservation is not observed in older adults when there are no normal levels of insulin, physical fitness and hearing. Taken together, our results suggest that certain lifestyle factors like normal hearing, physical fitness and normal insulin levels may help preserve hippocampal microstructure which may be useful in maintaining optimum performance on executive function tasks and potentially other modes of cognition.
Unsupervised, piecewise linear decoding enables an accurate prediction of muscle activity in a multi-task brain computer interface
Authors: Ma Xuan , Rizzoglio Fabio , Bodkin Kevin L. , Miller Lee E.
Published: September 2024

Objective

Creating an intracortical brain-computer interface (iBCI) capable of seamless transitions between tasks and contexts would greatly enhance user experience. However, the nonlinearity in neural activity presents challenges to computing a global iBCI decoder. We aimed to develop a method that differs from a globally optimized decoder to address this issue.

Approach

We devised an unsupervised approach that relies on the structure of a low-dimensional neural manifold to implement a piecewise linear decoder. We created a distinctive dataset in which monkeys performed a diverse set of tasks, some trained, others innate, while we recorded neural signals from the motor cortex (M1) and electromyographs (EMGs) from upper limb muscles. We used both linear and nonlinear dimensionality reduction techniques to discover neural manifolds and applied unsupervised algorithms to identify clusters within those spaces. Finally, we fit a linear decoder of EMG for each cluster. A specific decoder was activated corresponding to the cluster each new neural data point belonged to.

Main results

We found clusters in the neural manifolds corresponding with the different tasks or task sub-phases. The performance of piecewise decoding improved as the number of clusters increased and plateaued gradually. With only two clusters it already outperformed a global linear decoder, and unexpectedly, it outperformed even a global recurrent neural network (RNN) decoder with 10-12 clusters.

Significance

This study introduced a computationally lightweight solution for creating iBCI decoders that can function effectively across a broad range of tasks. EMG decoding is particularly challenging, as muscle activity is used, under varying contexts, to control interaction forces and limb stiffness, as well as motion. The results suggest that a piecewise linear decoder can provide a good approximation to the nonlinearity between neural activity and motor outputs, a result of our increased understanding of the structure of neural manifolds in motor cortex.
Glassy Surfactants Enable Ultra-High Concentration Biologic Therapeutics
Authors: Jons Carolyn K. , Prossnitz Alexander N. , Eckman Noah , Dong Changxin , Utz Ashley , Appel Eric A.
Published: September 2024

Protein therapeutics, like peptides and antibodies, have become critical to healthcare. Despite their exceptional potency and specificity, biopharmaceuticals are prone to aggregation, often necessitating low formulation concentrations as well as cold storage and distribution to maintain stability. Yet, high doses are required to treat many diseases. To achieve these doses, most approved protein drug products are administered intravenously, imposing excessive burdens on patients and the healthcare system. New approaches are needed to formulate proteins at high concentrations to enable less burdensome subcutaneous injection, preferably in an autoinjector format. To address this challenge, we report a subcutaneously injectable biotherapeutic delivery platform composed of spray-dried protein microparticles suspended in a non-solvent liquid carrier. These microparticles contain only active biopharmaceutical agent and a high glass transition temperature polyacrylamide-derived copolymer excipient affording several key benefits over traditional excipients, including: (i) improved stabilization of biopharmaceuticals through the spray drying process, and (ii) improved morphology and properties of the spray-dried particles, enhancing suspension injectability. Experiments with albumin and antibodies demonstrate that this technology enables ultra-high-concentration protein formulations (exceeding 500 mg/mL) that are injectable through standard needles with clinically relevant injection forces. Additionally, experiments in mice with two clinically relevant antibody drugs show these ultra-high- concentration formulations reduce required injection volumes without altering pharmacokinetics or efficacy. This approach could nearly triple the number of commercial protein drugs amenable to subcutaneous administration, dramatically reducing burden and improving access to these critical biopharmaceuticals.

One Sentence Summary

Here we leverage a unique copolymer excipient to enable ultra-high concentration protein formulations with improved stability and amenable to subcutaneous injection that can reduce patient burden, lower costs, and improve access to critical drugs.