bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of biomarkers related to sepsis diagnosis based on bioinformatics and machine learning and experimental verification
Authors: Wang Qianfei , Wang Chenxi , Zhang Weichao , Tao Yulei , Guo Junli , Liu Yuan , Liu Zhiliang , Liu Dong , Mei Jianqiang , Chen Fenqiao
Published: June 2023

Sepsis is a systemic inflammatory response syndrome caused by bacteria and other pathogenic microorganisms. Every year, approximately 31.5 million patients are diagnosed with sepsis, and approximately 5.3 million patients succumb to the disease. In this study, we identified biomarkers for diagnosing sepsis analyzed the relationships between genes and Immune cells that were differentially expressed in specimens from patients with sepsis compared to normal controls. Finally, We verified its effectiveness through animal experiments. Specifically, we analyzed datasets from four microarrays(GSE11755、GSE12624、GSE28750、GSE48080) that included 106 blood specimens from patients with sepsis and 69 normal human blood samples. SVM-RFE analysis and LASSO regression model were carried out to screen possible markers. The composition of 22 immune cell components in patients with sepsis were also determined using CIBERSORT. The expression level of the biomarkers in Sepsis was examined by the use of qRT-PCR and Western Blot (WB). We identified 50 differentially expressed genes between the cohorts, including 2 significantly upregulated and 48 significantly downregulated genes, and KEGG pathway analysis identified Salmonella infection, human T cell leukemia virus 1 infection, Epstein−Barr virus infection, hepatitis B, lysosome and other pathways that were significantly enriched in blood from patients with sepsis. Ultimately, we identified COMMD9, CSF3R, and NUB1 as genes that could potentially be used as biomarkers to predict sepsis, which we confirmed by ROC analysis. Further, we identified a correlation between the expression of these three genes and immune infiltrate composition. Immune cell infiltration analysis revealed that COMMD9 was correlated with T cells regulatory (Tregs), T cells follicular helper, T cells CD8, et al. CSF3R was correlated with T cells regulatory (Tregs), T cells follicular helper, T cells CD8, et al. NUB1 was correlated with T cells regulatory (Tregs), T cells gamma delta, T cells follicular helper, et al. Taken together, our findings identify potential new diagnostic markers for sepsis that shed light on novel mechanisms of disease pathogenesis and, therefore, may offer opportunities for therapeutic intervention.
Perspectives on oral chronic graft-versus-host disease from immunobiology to morbid diagnoses
Authors: Tollemar Victor , Garming Legert Karin , Sugars Rachael V.
Published: June 2023

Chronic Graft-versus-Host Disease (cGVHD) is a major long-term complication, associated with morbidity and mortality in patients following allogenic hematopoietic cell transplantation (HCT) for immune hematopoietic disorders. The mouth is one of the most frequently affected organs after HCT (45-83%) and oral cGVHD, which may appear as the first visible sign. Manifestations present with mucosal lichenoid lesions, salivary gland dysfunction and limited oral aperture. Diagnosis of oral cGVHD severity is based on mucosal lesions with symptoms of sensitivity and pain and reduced oral intake. However, diagnostic difficulties arise due to subjective definitions and low specificity to cover the spectrum of oral cGVHD. In recent years there have been significant improvements in our understanding of the underlying oral cGVHD disease mechanisms. Drawing upon the current knowledge on the pathophysiology and biological phases of oral cGVHD, we address oral mucosa lichenoid and Sjogren’s Syndrome-like sicca syndromes. We consider the response of alloreactive T-cells and macrophages to recipient tissues to drive the pathophysiological reactions and biological phases of acute inflammation (phase 1), chronic inflammation and dysregulated immunity (phase 2), and subsequent aberrant fibrotic healing (phase 3), which in time may be associated with an increased malignant transformation rate. When formulating treatment strategies, the pathophysiological spectrum of cGVHD is patient dependent and not every patient may progress chronologically through the biological stages. As such there remains a need to address and clarify personalized diagnostics and management to improve treatment descriptions. Within this review, we highlight the current state of the art knowledge on oral cGVHD pathophysiology and biological phases. We address knowledge gaps of oral cGVHD, with a view to facilitate clinical management and improve research quality on lichenoid biology and morbid forms of oral cGVHD.
Case Report: Real NPSLE? A patient with systemic sclerosis overlapping systemic lupus erythematosus presenting as epilepsy
Authors: Zhang Jialin , Wu Xiaodong , Xue Jing , Liu Lei
Published: June 2023

Neuropsychiatric systemic lupus erythematosus (NPSLE) is the diagnosis that rheumatologists most often need to consider when a patient with lupus presents with neurologic symptoms. However, neurological involvement is rare in systemic sclerosis (SSc), and high doses of steroids tend to trigger scleroderma renal crisis (SRC). When a patient with SSc overlapping SLE presents with epilepsy and renal crisis, the exact diagnosis and whether to initiate high-dose glucocorticoid therapy are questions to ponder. Here, we report a patient with overlap syndrome (SSc overlapping SLE), who developed CNS symptoms, and improved after treatment against SRC after excluding NPSLE. We report this case with the aim of arousing the attention of rheumatologists to SSc and SRC-related encephalopathy when SSc was overlapped with SLE.
Durability and extent of protection of SARS-CoV-2 antibodies among patients with COVID-19 in Metro Manila, Philippines
Authors: Gonzales Ma. Liza Antoinette M. , Dans Leonila F. , Tan-Lim Carol Stephanie C. , Uy Elenore , Cutiongco-dela Paz Eva , Sulit Maria Vanessa V. , Alejandria Marissa M. , Lansang Mary Ann D. , Dans Antonio L. , Dator Melissa A. , Cordero Cynthia P. , Pardilla Gina F.
Published: June 2023

Introduction

Information on the magnitude and durability of humoral immunity against COVID-19 among specific populations can guide policies on vaccination, return from isolation and physical distancing measures. The study determined the durability of SARS-CoV-2 antibodies after an initial infection among Filipinos in Metro Manila, Philippines, and the extent of protection SARS-CoV-2 antibodies confer against reinfection.

Methods

We conducted a cohort study to monitor the antibody levels of patients diagnosed with COVID-19. Receptor-binding domain (RBD)-specific antibodies were measured at Days 21, 90, 180, 270 and 360. Antibody levels were reported as geometric mean titers (GMT) with geometric standard deviation (GSD). Differences in GMT were tested using Friedman test and Kruskal Wallis test, with Bonferroni multiple comparisons procedure. Adjusted hazard ratios on the development of probable reinfection were estimated using Cox proportional models.

Results

There were 307 study participants included in the study, with 13 dropouts. Study participants received SARS-CoV-2 vaccines at varying times, with 278 participants (90.5%) fully vaccinated by the end of study. The GMT of the study cohort increased over time, from 19.7 U/mL (GSD 11) at Day 21; to 284.5 U/mL (GSD 9.6) at Day 90; 1,061 U/mL (GSD 5.3) at Day 180; 2,003 U/mL (GSD 6.7) at Day 270; and 8,403 U/mL (GSD 3.1) at Day 360. The increase was statistically significant from Day 21 to Day 90 (p<0.0001), Day 90 to Day 180 (p=0.0005), and Day 270 to Day 360 (p<0.0001). Participants with more severe initial infection demonstrated significantly higher antibody levels compared to those with milder infection at Day 21. Sixty-four patients had probable COVID-19 reinfection (incidence of 20.8%, 95% CI 16.4, 25.8%). The GMT of these 64 patients was 411.8 U/mL (GSD 6.9) prior to the occurrence of the probable reinfection. Majority (87.5%) were fully vaccinated. Antibody titers significantly affected the risk of developing reinfection, with adjusted hazard ratio of 0.994, 95% CI 0.992-0.996, p<0.001.

Conclusion

Antibody levels against SARS-CoV-2 increased over a one-year follow-up. Higher antibody levels were observed among those with more severe initial infection and those vaccinated. Higher antibody levels are associated with a lower risk of probable reinfection.
A meaningful exploration of ofatumumab in refractory NMOSD: a case report
Authors: Zhan Yibo , Zhao Min , Li Xiaojun , Ouyang Huiying , Du Chenghao , Chen Guixian , Lou Zhenzhen , Chen Haoxuan , Zhao Yuanqi , Xu Haoyou
Published: June 2023

Objective

To report the case of a patient with refractory neuromyelitis optica spectrum disorder (NMOSD), who, despite showing poor response or intolerance to multiple immunosuppressants, was successfully treated with Ofatumumab.

Case presentation

A 42-year-old female was diagnosed with NMOSD in the first episode of the disease. Despite treatment with intravenous methylprednisolone, immunoglobulin, rituximab and immunoadsorption, together with oral steroids, azathioprine, mycophenolate mofetil and tacrolimus, she underwent various adverse events, such as abnormal liver function, repeated infections, fever, rashes, hemorrhagic shock, etc., and experienced five relapses over the ensuing four years. Finally, clinicians decided to initiate Ofatumumab to control the disease. The patient received 9 doses of Ofatumumab over the next 10 months at customized intervals. Her symptoms were stable and there was no recurrence or any adverse events.

Conclusion

Ofatumumab might serve as an effective and safe alternative for NMOSD patients who are resistant to other current immunotherapies.
Negotiations to implement area-based management tools beyond national jurisdiction: the scientific community’s view
Authors: Caldeira Mariana , Teixeira Heliana , Hilário Ana
Published: June 2023

A new international legally-binding instrument, under the United Nations Convention on the Law of the Seas (UNCLOS), for the conservation and sustainable use of marine biodiversity in areas beyond national jurisdiction has recently been agreed on– the BBNJ agreement. Area-based management tools (ABMTs), including marine protected areas (MPAs) have an important role in maintaining biodiversity and ecosystem services in the current context of multiple threats to the ocean and are one of central elements of new instrument. In this work, we assessed the perspective of the scientific community, throughout the period of negotiations, on the potential of the BBNJ treaty to promote the creation of new area-based management tools, including MPAs, and fulfil acknowledged gaps in ocean governance. A systematic literature review was conducted, resulting in 80 publications then analysed in detail. From these, a total of 608 key messages were retrieved and classified into: 1) Strengths (S), Weaknesses (W), Opportunities (O) or Threats (T) for a SWOT analysis and 2) one of six categories that cover crucial aspects for the successful implementation of the ABMTs in areas beyond national jurisdiction. A Sentiment Analysis (SA) to these key messages shows that the instrument has been perceived by the scientific community as an opportunity for conserving and achieving sustainable use of biodiversity. However, the scientific community also feels that agreement needs stronger provisions to ensure effective measures, which is reflected by the small number of identified strengths. An overall decrease in sentiment score over the negotiations period, i.e. a growing pessimism, was also observed, which is supported by an increase of weaknesses and threats identified in the final stages of the negotiations. Our results suggest that despite its potential to promote conservation in areas beyond national jurisdiction, the instrument should include a unified definition of MPA, address fishing activities and clarify conflicting terms in its provisions, such as the term “not undermine”. Further, we show that sentiment analysis is a useful tool to evaluate opinion trends and facilitate the integration of different and subjective perspectives into final provisions of complex social-political-environmental agreements, identifying positive and negative attitudes that can enable better solutions to address existing governance challenges in international waters.
Wintertime sea surface temperature variability modulated by Arctic Oscillation in the northwestern part of the East/Japan Sea and its relationship with marine heatwaves
Authors: Song Se-Yong , Kim Yoo-Jun , Lee Eun-Joo , Yeh Sang-Wook , Park Jae-Hun , Park Young-Gyu
Published: June 2023

The northwestern part of the East/Japan Sea (EJS) is a region with large sea surface temperature (SST) variability and is known as a hotspot of marine heatwaves (MHW) stress for marine environments that peaked in boreal winter (January-February-March). This could have profound impacts on the marine ecosystems over the EJS. Here, we used a set of high-resolution satellite and reanalysis products to systematically analyze the spatiotemporal SST variations and examine their linkage to a large-scale mode of climate variability, such as the Arctic Oscillation (AO). The results show that AO-related wind forcing modulates the SST variability over the EJS via the oceanic dynamic adjustment processes. In particular, the abnormally warm SSTs in the northwestern part of the EJS are driven by the anomalous anticyclonic eddy-like circulation and Ekman downwelling during a positive AO phase. This physical linkage between a positive AO and the abnormally warm SST could be conducive to MHW occurrences in the EJS as in the extremely positive AO event during the winter of 2020. These results have implications that the MHW occurrences in the EJS could be amplified by natural climate variability along with long-term SST warming.
Baricitinib retention rate: ‘real-life’ data from a mono-centric cohort of patients affected by rheumatoid arthritis
Authors: Baldi Caterina , Berlengiero Virginia , Falsetti Paolo , Cartocci Alessandra , Conticini Edoardo , D’Alessandro Roberto , D’Ignazio Emilio , Bardelli Marco , Fabbroni Marta , Cantarini Luca , Frediani Bruno , Gentileschi Stefano
Published: June 2023

Objectives

The aim of this retrospective study was to evaluate baricitinib retention rate in patients affected by rheumatoid arthritis. Secondary aims were to compare the impact on treatment persistence of monotherapy and other variables such as systemic corticosteroid use, line of treatment, disease duration, sex, biomarkers positivity, and Herpes Zoster virus infection.

Materials and methods

Patients with Rheumatoid Arthritis undergoing baricitinib were consecutively enrolled. Rheumatoid Arthritis diagnosis was performed with 2010 ACR/EULAR classification criteria. The cohort’s demographic, clinical and therapeutical data were retrospectively collected. The whole follow-up duration was 104 weeks.

Results

Ninety-five patients affected by rheumatoid arthritis and treated with baricitinib were consecutively enrolled. At the end of follow-up, the overall retention rate was 69.3%. No statistically significant difference in retention rate was observed between patients treated with baricitinib in monotherapy or in combination with methotrexate (p = 0.638) while patients undergoing a steroidal treatment showed a significantly reduced treatment retention (p = 0.028). Contrarily, patients treated with baricitinib as a first-line b/tsDMARD showed higher drug retention (p = 0.002) compared to further treatment lines. Steroid employment, steroid dosage and previous treatment with bDMARDs correlated with risk of treatment discontinuation and at univariate analysis (p = 0.028, p < 0.001, and p = 0.002 respectively). Multivariate analysis confirmed significance for higher steroid dosage and previous treatment with bDMARDs (p = 0.002 and p = 0.046). No adverse events such as deep venous thrombosis, pulmonary embolism or tubercular infection/reactivation were reported during the study observation.

Conclusion

Our data show a good baricitinib retention rate after 12 and 24 months of observation (75.1 and 69.3%, respectively). In our cohort, concomitant treatment with methotrexate did not influence treatment persistence while retention was reduced in patients undergoing a steroidal treatment and/or in multi-failure subjects.
Monitoring lineages of growing and dividing bacteria reveals an inducible memory of mar operon expression
Authors: Guet Calin C. , Bruneaux Luke , Oikonomou Panos , Aldana Maximino , Cluzel Philippe
Published: June 2023

In Gram negative bacteria, the multiple antibiotic resistance or mar operon, is known to control the expression of multi-drug efflux genes that protect bacteria from a wide range of drugs. As many different chemical compounds can induce this operon, identifying the parameters that govern the dynamics of its induction is crucial to better characterize the processes of tolerance and resistance. Most experiments have assumed that the properties of the mar transcriptional network can be inferred from population measurements. However, measurements from an asynchronous population of cells can mask underlying phenotypic variations of single cells. We monitored the activity of the mar promoter in single Escherichia coli cells in linear micro-colonies and established that the response to a steady level of inducer was most heterogeneous within individual colonies for an intermediate value of inducer. Specifically, sub-lineages defined by contiguous daughter-cells exhibited similar promoter activity, whereas activity was greatly variable between different sub-lineages. Specific sub-trees of uniform promoter activity persisted over several generations. Statistical analyses of the lineages suggest that the presence of these sub-trees is the signature of an inducible memory of the promoter state that is transmitted from mother to daughter cells. This single-cell study reveals that the degree of epigenetic inheritance changes as a function of inducer concentration, suggesting that phenotypic inheritance may be an inducible phenotype.
Extremely chaotolerant and kosmotolerant Aspergillus atacamensis – a metabolically versatile fungus suitable for recalcitrant biosolid treatment
Authors: Moreno-Perlin Tonatiuh , Valdés-Muñoz Gisell , Jiménez-Gómez Irina , Gunde-Cimerman Nina , Yarzábal Rodríguez Luis Andrés , Sánchez-Carbente María del Rayo , Vargas-Fernández Alfaniris , Gutiérrez-Cepeda Adrián , Batista-García Ramón Alberto
Published: June 2023

Obligate halophily is extremely rare in fungi. Nevertheless, Aspergillus atacamensis (strain EXF-6660), isolated from a salt water-exposed cave in the Coastal Range hills of the hyperarid Atacama Desert in Chile, is an obligate halophile, with a broad optimum range from 1.5 to 3.4 M of NaCl. When we tested its ability to grow at varied concentrations of both kosmotropic (NaCl, KCl, and sorbitol) and chaotropic (MgCl2, LiCl, CaCl2, and glycerol) solutes, stereoscopy and laser scanning microscopy revealed the formation of phialides and conidia. A. atacamensis EXF-6660 grew up to saturating levels of NaCl and at 2.0 M concentration of the chaotropic salt MgCl2. Our findings confirmed that A. atacamensis is an obligate halophile that can grow at substantially higher MgCl2 concentrations than 1.26 M, previously considered as the maximum limit supporting prokaryotic life. To assess the fungus’ metabolic versatility, we used the phenotype microarray technology Biolog FF MicroPlates. In the presence of 2.0 M NaCl concentration, strain EXF-6660 metabolism was highly versatile. A vast repertoire of organic molecules (~95% of the substrates present in Biolog FF MicroPlates) was metabolized when supplied as sole carbon sources, including numerous polycyclic aromatic hydrocarbons, benzene derivatives, dyes, and several carbohydrates. Finally, the biotechnological potential of A. atacamensis for xenobiotic degradation and biosolid treatment was investigated. Interestingly, it could remove biphenyls, diphenyl ethers, different pharmaceuticals, phenols, and polyaromatic hydrocarbons. Our combined findings show that A. atacamensis EXF-6660 is a highly chaotolerant, kosmotolerant, and xerotolerant fungus, potentially useful for xenobiotic and biosolid treatments.
Prevalence and antimicrobial resistance profiles of Vibrio spp. and Enterococcus spp. in retail shrimp in Northern California
Authors: Hirshfeld Brady , Lavelle Kurtis , Lee Katie Yen , Atwill Edward Robert , Kiang David , Bolkenov Bakytzhan , Gaa Megan , Li Zhirong , Yu Alice , Li Xunde , Yang Xiang
Published: June 2023

Shrimp is one of the most consumed seafood products globally. Antimicrobial drugs play an integral role in disease mitigation in aquaculture settings, but their prevalent use raises public health concerns on the emergence and spread of antimicrobial resistant microorganisms. Vibrio spp., as the most common causative agents of seafood-borne infections in humans, and Enterococcus spp., as an indicator organism, are focal bacteria of interest for the monitoring of antimicrobial resistance (AMR) in seafood. In this study, 400 samples of retail shrimp were collected from randomly selected grocery stores in the Greater Sacramento, California, area between September 2019 and June 2020. The prevalence of Vibrio spp. and Enterococcus spp. was 60.25% (241/400) and 89.75% (359/400), respectively. Subsamples of Vibrio (n = 110) and Enterococcus (n = 110) isolates were subjected to antimicrobial susceptibility testing (AST). Vibrio isolates had high phenotypic resistance to ampicillin (52/110, 47.27%) and cefoxitin (39/110, 35.45%). Enterococcus were most frequently resistant to lincomycin (106/110, 96.36%), quinupristin-dalfopristin (96/110, 87.27%), ciprofloxacin (93/110, 84.55%), linezolid (86/110, 78.18%), and erythromycin (58/110, 52.73%). For both Vibrio and Enterococcus, no significant associations were observed between multidrug resistance (MDR, resistance to ≥3 drug classes) in isolates from farm raised and wild caught shrimp (p > 0.05) and in isolates of domestic and imported origin (p > 0.05). Whole genome sequencing (WGS) of a subset of Vibrio isolates (n = 42) speciated isolates as primarily V. metschnikovii (24/42; 57.14%) and V. parahaemolyticus (12/42; 28.57%), and detected 27 unique antimicrobial resistance genes (ARGs) across these isolates, most commonly qnrVC6 (19.05%, 8/42), dfrA31 (11.90%, 5/42), dfrA6 (9.5%, 4/42), qnrVC1 (9.5%, 4/42). Additionally, WGS predicted phenotypic resistance in Vibrio isolates with an overall sensitivity of 11.54% and specificity of 96.05%. This study provides insights on the prevalence and distribution of AMR in Vibrio spp. and Enterococcus spp. from retail shrimp in California which are important for food safety and public health and exemplifies the value of surveillance in monitoring the spread of AMR and its genetic determinants.
Antibody production and tolerance to the α-gal epitope as models for understanding and preventing the immune response to incompatible ABO carbohydrate antigens and for α-gal therapies
Authors: Galili Uri
Published: June 2023

This review describes the significance of the α-gal epitope (Galα-3Galβ1-4GlcNAc-R) as the core of human blood-group A and B antigens (A and B antigens), determines in mouse models the principles underlying the immune response to these antigens, and suggests future strategies for the induction of immune tolerance to incompatible A and B antigens in human allografts. Carbohydrate antigens, such as ABO antigens and the α-gal epitope, differ from protein antigens in that they do not interact with T cells, but B cells interacting with them require T-cell help for their activation. The α-gal epitope is the core of both A and B antigens and is the ligand of the natural anti-Gal antibody, which is abundant in all humans. In A and O individuals, anti-Gal clones (called anti-Gal/B) comprise >85% of the so-called anti-B activity and bind to the B antigen in facets that do not include fucose-linked α1–2 to the core α-gal. As many as 1% of B cells are anti-Gal B cells. Activation of quiescent anti-Gal B cells upon exposure to α-gal epitopes on xenografts and some protozoa can increase the titer of anti-Gal by 100-fold. α1,3-Galactosyltransferase knockout (GT-KO) mice lack α-gal epitopes and can produce anti-Gal. These mice simulate human recipients of ABO-incompatible human allografts. Exposure for 2–4 weeks of naïve and memory mouse anti-Gal B cells to α-gal epitopes in the heterotopically grafted wild-type (WT) mouse heart results in the elimination of these cells and immune tolerance to this epitope. Shorter exposures of 7 days of anti-Gal B cells to α-gal epitopes in the WT heart result in the production of accommodating anti-Gal antibodies that bind to α-gal epitopes but do not lyse cells or reject the graft. Tolerance to α-gal epitopes due to the elimination of naïve and memory anti-Gal B cells can be further induced by 2 weeks in vivo exposure to WT lymphocytes or autologous lymphocytes engineered to present α-gal epitopes by transduction of the α1,3-galactosyltransferase gene. These mouse studies suggest that autologous human lymphocytes similarly engineered to present the A or B antigen may induce corresponding tolerance in recipients of ABO-incompatible allografts. The review further summarizes experimental works demonstrating the efficacy of α-gal therapies in amplifying anti-viral and anti-tumor immune-protection and regeneration of injured tissues.
Referred pain: characteristics, possible mechanisms, and clinical management
Authors: Jin Qianjun , Chang Yuxin , Lu Chenmiao , Chen Lunhao , Wang Yue
Published: June 2023

Purpose of this review

Referred pain is a common but less understood symptom that originates from somatic tissues. A comprehensive recognition of referred pain is important for clinicians when dealing with it. The purpose of this study is to summarize the current understanding of referred pain, including its pathogenesis, characteristics, diagnosis, and treatment.

Recent findings

Referred pain arises not only from pathologies primarily involving local tissue but also from lesions in distant structures. Central sensitization of convergent neurons and peripheral reflexes of dichotomizing afferent fibers are two theories proposed to explain the pathological mechanism of referred pain. Because syndromes related to referred pain of different origins overlap each other, it is challenging to define referred pain and identify its originating lesions. Although various approaches have been used in the diagnosis and treatment of referred pain, including conservative treatment, blockade, radiofrequency, and surgery, management of referred pain remains a clinical challenge.

Unlike radicular pain and neuropathic pain, referred pain is a less studied area, despite being common in clinics. Referred pain can derive from various spinal structures, and blockage helps identify the primary pathology. Due to the heterogeneity of referred pain, treatment outcomes remain uncertain. Further studies are needed to improve our understanding of referred pain.
Staged use of ordinal and linear disability scales: a practical approach to granular assessment of acute stroke outcome
Authors: Chaisinanunkul Napasri , Starkman Sidney , Gornbein Jeffrey , Hamilton Scott , Chatfield Fiona , Conwit Robin , Saver Jeffrey L.
Published: June 2023

Background

The modified Rankin Scale (mRS) assessment of global disability is the most common primary endpoint in acute stroke trials but lacks granularity (7 broad levels) and is ordinal (scale levels unknown distances apart), which constrains study power. Disability scales that are linear and continuous may better discriminate outcomes, but computerized administration in stroke patients is challenging. We, therefore, undertook to develop a staged use of an ordinal followed by a linear scale practical to use in multicenter trials.

Methods

Consecutive patients undergoing 3-month final visits in the NIH FAST-MAG phase 3 trial were assessed with the mRS followed by 15 mRS level-specific yes–no items of the Academic Medical Center Linear Disability Score (ALDS), a linear disability scale derived using item response theory.

Results

Among 55 patients, aged 71.2 (SD ± 14.2), 67% were men and the entry NIHSS was 10.7 (SD ± 9.5). At 90 days, the median mRS score was 3 (IQR, 1–4), and the median ALDS score was 78.8 (IQR, 3.3–100). ALDS scores correlated strongly with 90 days outcome measures, including the Barthel Index (r = 0.92), NIHSS (r = 0.87), and mRS (r = 0.94). ALDS scores also correlated modestly with entry NIHSS (r = 0.38). At 90 days, the ALDS showed greater scale granularity than the mRS, with fewer patients with identical values, 1.9 (SD ± 3.2) vs. 8.0 (SD ± 3.6), p < 0.001. When treatment effect magnitudes were small to moderate, projected trial sample size requirements were 2–12-fold lower when the ALDS rather than the mRS was used as the primary trial endpoint.

Conclusion

Among patients enrolled in an acute neuroprotective stroke trial, the ALDS showed strong convergent validity and superior discrimination characteristics compared with the modified Rankin Scale and increased projected trial power to detect clinically meaningful treatment benefits.
Case report: Meningioma associated with meningioangiomatosis mimicking invasive meningioma
Authors: Ge Rong , Yang Jun , Yin Xiangang , Wang Jingya
Published: June 2023

Meningioangiomatosis (MA) is a rare malformation or hamartomatous lesion in the central nervous system, characterized by a plaque-like mass within the leptomeninges and cerebral cortex. An even rarer condition is MA complicated with meningiomas. We herein report a case of meningioma associated with MA that might be erroneously interpreted as a higher-grade lesion or an invasion by preoperative radiologic and postoperative histological examinations.
Do magnetic resonance imaging features differ between persons with multiple sclerosis of various races and ethnicities?
Authors: Nathoo Nabeela , Zeydan Burcu , Neyal Nur , Chelf Cynthia , Okuda Darin T. , Kantarci Orhun H.
Published: June 2023

Those of African American or Latin American descent have been demonstrated to have more severe clinical presentations of multiple sclerosis (MS) than non-Latin American White people with MS. Concurrently, radiological burden of disease on magnetic resonance imaging (MRI) in African Americans with MS has also been described as being more aggressive. Here, we review MRI studies in diverse racial and ethnic groups (adult and pediatric) investigating lesion burden, inflammation, neurodegeneration, and imaging response to disease modifying therapy. We also discuss why such disparities may exist beyond biology, and how future studies may provide greater insights into underlying differences.
TIMP3 promotes the maintenance of neural stem-progenitor cells in the mouse subventricular zone
Authors: Fang Lingyan , Kuniya Takaaki , Harada Yujin , Yasuda Osamu , Maeda Nobuyo , Suzuki Yutaka , Kawaguchi Daichi , Gotoh Yukiko
Published: June 2023

Adult neural stem cells (NSCs) in the mouse subventricular zone (SVZ) serve as a lifelong reservoir for newborn olfactory bulb neurons. Recent studies have identified a slowly dividing subpopulation of embryonic neural stem-progenitor cells (NPCs) as the embryonic origin of adult NSCs. Yet, little is known about how these slowly dividing embryonic NPCs are maintained until adulthood while other NPCs are extinguished by the completion of brain development. The extracellular matrix (ECM) is an essential component of stem cell niches and thus a key determinant of stem cell fate. Here we investigated tissue inhibitors of metalloproteinases (TIMPs)—regulators of ECM remodeling—for their potential roles in the establishment of adult NSCs. We found that Timp2, Timp3, and Timp4 were expressed at high levels in slowly dividing NPCs compared to rapidly dividing NPCs. Deletion of TIMP3 reduced the number of adult NSCs and neuroblasts in the lateral SVZ. In addition, overexpression of TIMP3 in the embryonic NPCs suppressed neuronal differentiation and upregulated the expression levels of Notch signaling relating genes. These results thus suggest that TIMP3 keeps the undifferentiated state of embryonic NPCs, leading to the establishment and maintenance of adult NSCs.
Single-cell RNA-sequencing identifies various proportions of excitatory and inhibitory neurons in cultured human fetal brain cortical tissues
Authors: Liu Rong , Dong Wei , Xiong Dan , Hu Lanqi , Zhang Haoran , Yuan Xiaoping , Tang Zhonghui , Fu Fang , Yang Xin , Wu Xia
Published: June 2023

Introduction

Cortical neural progenitor cells possess the capacity to differentiate into both excitatory and inhibitory neurons. However, the precise proportions in which these progenitor cells differentiate remain unclear.

Methods

Human fetal prefrontal cortical tissues were collected at various fetal stages and cultured in vitro. Bulk and single-cell RNA sequencing techniques were employed to analyze the resulting neuronal cell types, cell proportions, and the expression levels of cell-type marker genes.

Results

The culture of fetal prefrontal cortex tissues obtained at gestation weeks 11 and 20 predominantly consisted of excitatory and inhibitory neurons, respectively. This abrupt transition in cell proportions was primarily driven by the differential lineage specificity of neural progenitors in the fetal cortical tissues at distinct stages of fetal brain development. Additionally, it was observed that the transcriptional profiles of cultured fetal cortical tissues were strongly influenced by the presence of FGF2.

Discussion

This study presents a novel strategy to obtain excitatory and inhibitory neuronal cells from the culture of fetal cortical tissues. The findings shed light on the mechanisms underlying neurogenesis and provide an approach that might contribute to future research investigating the pathophysiology of various neural disorders.
The link between SARS-CoV-2 related microglial reactivity and astrocyte pathology in the inferior olivary nucleus
Authors: Madden Nacoya , Mei Ying Zi Jessy , Jakubiak Kelly , Li Juncheng , Hargus Gunnar , Goldman James E. , Al-Dalahmah Osama
Published: June 2023

The pathological involvement of the central nervous system in SARS-CoV2 (COVID-19) patients is established. The burden of pathology is most pronounced in the brain stem including the medulla oblongata. Hypoxic/ischemic damage is the most frequent neuropathologic abnormality. Other neuropathologic features include neuronophagia, microglial nodules, and hallmarks of neurodegenerative diseases: astrogliosis and microglial reactivity. It is still unknown if these pathologies are secondary to hypoxia versus a combination of inflammatory response combined with hypoxia. It is also unknown how astrocytes react to neuroinflammation in COVID-19, especially considering evidence supporting the neurotoxicity of certain astrocytic phenotypes. This study aims to define the link between astrocytic and microglial pathology in COVID-19 victims in the inferior olivary nucleus, which is one of the most severely affected brain regions in COVID-19, and establish whether COVID-19 pathology is driven by hypoxic damage. Here, we conducted neuropathologic assessments and multiplex-immunofluorescence studies on the medulla oblongata of 18 COVID-19, 10 pre-pandemic patients who died of acute respiratory distress syndrome (ARDS), and 7–8 control patients with no ARDS or COVID-19. The comparison of ARDS and COVID-19 allows us to identify whether the pathology in COVID-19 can be explained by hypoxia alone, which is common to both conditions. Our results showed increased olivary astrogliosis in ARDS and COVID-19. However, microglial density and microglial reactivity were increased only in COVID-19, in a region-specific manner. Also, olivary hilar astrocytes increased YKL-40 (CHI3L1) in COVID-19, but to a lesser extent than ARDS astrocytes. COVID-19 astrocytes also showed lower levels of Aquaporin-4 (AQP4), and Metallothionein-3 in subsets of COVID-19 brain regions. Cluster analysis on immunohistochemical attributes of astrocytes and microglia identified ARDS and COVID-19 clusters with correlations to clinical history and disease course. Our results indicate that olivary glial pathology and neuroinflammation in the COVID-19 cannot be explained solely by hypoxia and suggest that failure of astrocytes to upregulate the anti-inflammatory YKL-40 may contribute to the neuroinflammation. Notwithstanding the limitations of retrospective studies in establishing causality, our experimental design cannot adequately control for factors external to our design. Perturbative studies are needed to confirm the role of the above-described astrocytic phenotypes in neuroinflammation.
Modeling Alzheimer’s disease related phenotypes in the Ts65Dn mouse: impact of age on Aβ, Tau, pTau, NfL, and behavior
Authors: Overk Cassia , Fiorini Emma , Babolin Chiara , Vukicevic Marija , Morici Catherine , Madani Rime , Eligert Valerie , Kosco-Vilbois Marie , Roberts Amanda , Becker Ann , Pfeifer Andrea , Mobley William C.
Published: June 2023

Introduction

People with DS are highly predisposed to Alzheimer’s disease (AD) and demonstrate very similar clinical and pathological features. Ts65Dn mice are widely used and serve as the best-characterized animal model of DS.

Methods

We undertook studies to characterize age-related changes for AD-relevant markers linked to Aβ, Tau, and phospho-Tau, axonal structure, inflammation, and behavior.

Results

We found age related changes in both Ts65Dn and 2N mice. Relative to 2N mice, Ts65Dn mice showed consistent increases in Aβ40, insoluble phospho-Tau, and neurofilament light protein. These changes were correlated with deficits in learning and memory.

Discussion

These data have implications for planning future experiments aimed at preventing disease-related phenotypes and biomarkers. Interventions should be planned to address specific manifestations using treatments and treatment durations adequate to engage targets to prevent the emergence of phenotypes.
Rethinking the network determinants of motor disability in Parkinson’s disease
Authors: Surmeier Dalton James , Zhai Shenyu , Cui Qiaoling , Simmons DeNard V.
Published: June 2023

For roughly the last 30 years, the notion that striatal dopamine (DA) depletion was the critical determinant of network pathophysiology underlying the motor symptoms of Parkinson’s disease (PD) has dominated the field. While the basal ganglia circuit model underpinning this hypothesis has been of great heuristic value, the hypothesis itself has never been directly tested. Moreover, studies in the last couple of decades have made it clear that the network model underlying this hypothesis fails to incorporate key features of the basal ganglia, including the fact that DA acts throughout the basal ganglia, not just in the striatum. Underscoring this point, recent work using a progressive mouse model of PD has shown that striatal DA depletion alone is not sufficient to induce parkinsonism and that restoration of extra-striatal DA signaling attenuates parkinsonian motor deficits once they appear. Given the broad array of discoveries in the field, it is time for a new model of the network determinants of motor disability in PD.
Case report: biallelic DNMT3A mutations in acute myeloid leukemia
Authors: Cumbo Cosimo , Orsini Paola , Anelli Luisa , Zagaria Antonella , Iannò Maria Federica , De Cecco Loris , Minervini Crescenzio Francesco , Coccaro Nicoletta , Tota Giuseppina , Parciante Elisa , Conserva Maria Rosa , Redavid Immacolata , Tarantini Francesco , Minervini Angela , Carluccio Paola , De Grassi Anna , Pierri Ciro Leonardo , Specchia Giorgina , Musto Pellegrino , Albano Francesco
Published: June 2023

DNMT3A gene mutations, detected in 20-25% of de novo acute myeloid leukemia (AML) patients, are typically heterozygous. Biallelic variants are uncommon, affecting ~3% of cases and identifying a worse prognosis. Indeed, two concomitant DNMT3A mutations were recently associated with shorter event-free survival and overall survival in AML. We present an AML case bearing an unusual DNMT3A molecular status, strongly affecting its function and strangely impacting the global genomic methylation profile. A 56-year-old Caucasian male with a diagnosis of AML not otherwise specified (NOS) presented a complex DNMT3A molecular profile consisting of four different somatic variants mapping on different alleles (in trans). 3D modelling analysis predicted the effect of the DNMT3A mutational status, showing that all the investigated mutations decreased or abolished DNMT3A activity. Although unexpected, DNMT3A’s severe loss of function resulted in a global genomic hypermethylation in genes generally involved in cell differentiation. The mechanisms through which DNMT3A contributes to AML remain elusive. We present a unique AML case bearing multiple biallelic DNMT3A variants abolishing its activity and resulting in an unexpected global hypermethylation. The unusual DNMT3A behavior described requires a reflection on its role in AML development and persistence, highlighting the heterogeneity of its deregulation.
In silico assessment of histotripsy-induced changes in catheter-directed thrombolytic delivery
Authors: Bader Kenneth B. , Flores Basterrechea Katia , Hendley Samuel A.
Published: June 2023

Introduction: For venous thrombosis patients, catheter-directed thrombolytic therapy is the standard-of-care to recanalize the occluded vessel. Limitations with thrombolytic drugs make the development of adjuvant treatments an active area of research. One potential adjuvant is histotripsy, a focused ultrasound therapy that lyses red blood cells within thrombus via the spontaneous generation of bubbles. Histotripsy has also been shown to improve the efficacy of thrombolytic drugs, though the precise mechanism of enhancement has not been elucidated. In this study, in silico calculations were performed to determine the contribution of histotripsy-induced changes in thrombus diffusivity to alter catheter-directed therapy.

Methods: An established and validated Monte Carlo calculation was used to predict the extent of histotripsy bubble activity. The distribution of thrombolytic drug was computed with a finite-difference time domain (FDTD) solution of the perfusion-diffusion equation. The FDTD calculation included changes in thrombus diffusivity based on outcomes of the Monte Carlo calculation. Fibrin degradation was determined using the known reaction rate of thrombolytic drug.

Results: In the absence of histotripsy, thrombolytic delivery was restricted in close proximity to the catheter. Thrombolytic perfused throughout the focal region for calculations that included the effects of histotripsy, resulting in an increased degree of fibrinolysis.

Discussion: These results were consistent with the outcomes of in vitro studies, suggesting histotripsy-induced changes in the thrombus diffusivity are a primary mechanism for enhancement of thrombolytic drugs.
Hormonal regulation of ethylene response factors in tomato during storage and distribution
Authors: Park Me-Hea , Yang Hae-Jo , Malka Siva Kumar
Published: June 2023

Introduction

Ethylene response factors (ERFs) play a critical role in regulating hormone interactions that affect the shelf life of tomatoes. Understanding their regulation during storage and distribution can be highly beneficial.

Methods

This study examined the effects of treatment with ethylene (ET), brassinosteroid (BR), auxin (AUX), and gibberellin (GA) on fruit ripening and the expression of 18 ripening-associated ERFs in tomato stored at 20°C (room temperature) for 10 d or 4°C (cold storage) for 14 d followed by 2 d at 20°C (retailer conditions).

Results

The results showed that ripening was accelerated by ET and BR but was delayed by AUX and GA at room temperature. Cold storage delayed ripening in all groups, with ET and GA treatments showing the highest and lowest a* values, respectively. The effects of hormone treatment were consistent with room temperature when the fruits were transferred from cold storage to retail conditions. At room temperature, ERFs responsive to ET (ERF.B1, B2, B6, E2, and F1) and BR (ERF.E5, F2, and F3) were inhibited by AUX. ET-induced genes (ERF.C1, E1, F4, and H7) could be co-regulated by other hormones at cold storage. When the fruits were transferred from cold storage to retailer conditions, ERFs responsive to ET and BR were inhibited by GA. Additionally, ET-responsive ERFs could be inhibited by BR at room temperature, whereas ET could inhibit BR-responsive ERFs at retailer conditions. The same ERFs that were regulated by ET at room temperature were instead regulated by BR under retailer conditions, and vice versa.

Discussion

These findings can help provide a better understanding of the complex hormone interactions regulating the postharvest physiology of tomato and in maintaining its quality and shelf life during storage and distribution.
Phenomics based prediction of plant biomass and leaf area in wheat using machine learning approaches
Authors: Singh Biswabiplab , Kumar Sudhir , Elangovan Allimuthu , Vasht Devendra , Arya Sunny , Duc Nguyen Trung , Swami Pooja , Pawar Godawari Shivaji , Raju Dhandapani , Krishna Hari , Sathee Lekshmy , Dalal Monika , Sahoo Rabi Narayan , Chinnusamy Viswanathan
Published: June 2023

Introduction

Phenomics has emerged as important tool to bridge the genotype-phenotype gap. To dissect complex traits such as highly dynamic plant growth, and quantification of its component traits over a different growth phase of plant will immensely help dissect genetic basis of biomass production. Based on RGB images, models have been developed to predict biomass recently. However, it is very challenging to find a model performing stable across experiments. In this study, we recorded RGB and NIR images of wheat germplasm and Recombinant Inbred Lines (RILs) of Raj3765xHD2329, and examined the use of multimodal images from RGB, NIR sensors and machine learning models to predict biomass and leaf area non-invasively.

Results

The image-based traits (i-Traits) containing geometric features, RGB based indices, RGB colour classes and NIR features were categorized into architectural traits and physiological traits. Total 77 i-Traits were selected for prediction of biomass and leaf area consisting of 35 architectural and 42 physiological traits. We have shown that different biomass related traits such as fresh weight, dry weight and shoot area can be predicted accurately from RGB and NIR images using 16 machine learning models. We applied the models on two consecutive years of experiments and found that measurement accuracies were similar suggesting the generalized nature of models. Results showed that all biomass-related traits could be estimated with about 90% accuracy but the performance of model BLASSO was relatively stable and high in all the traits and experiments. The R2 of BLASSO for fresh weight prediction was 0.96 (both year experiments), for dry weight prediction was 0.90 (Experiment 1) and 0.93 (Experiment 2) and for shoot area prediction 0.96 (Experiment 1) and 0.93 (Experiment 2). Also, the RMSRE of BLASSO for fresh weight prediction was 0.53 (Experiment 1) and 0.24 (Experiment 2), for dry weight prediction was 0.85 (Experiment 1) and 0.25 (Experiment 2) and for shoot area prediction 0.59 (Experiment 1) and 0.53 (Experiment 2).

Discussion

Based on the quantification power analysis of i-Traits, the determinants of biomass accumulation were found which contains both architectural and physiological traits. The best predictor i-Trait for fresh weight and dry weight prediction was Area_SV and for shoot area prediction was projected shoot area. These results will be helpful for identification and genetic basis dissection of major determinants of biomass accumulation and also non-invasive high throughput estimation of plant growth during different phenological stages can identify hitherto uncovered genes for biomass production and its deployment in crop improvement for breaking the yield plateau.