bluuebunny/crossref_metadata_2025 huggingface dataset:
The utilization of chitosan/Bletilla striata hydrogels to elevate anti-adhesion, anti-inflammatory and pro-angiogenesis properties of polypropylene mesh in abdominal wall repair
Authors: Di Yuntao , Wang Lu , He Wei , Liu Shuyan , He Yuqi , Liao Jie , Zhang Ruihong , Yin Lan , Xu Zhiwei , Li Xiaoming
Published: April 2024

Polypropylene (PP) mesh is commonly used in abdominal wall repair due to its ability to reduce the risk of organ damage, infections and other complications. However, the PP mesh often leads to adhesion formation and does not promote functional tissue repair. In this study, we synthesized one kind of aldehyde Bletilla striata polysaccharide (BSPA) modified chitosan (CS) hydrogel based on Schiff base reaction. The hydrogel exhibited a porous network structure, a highly hydrophilic surface and good biocompatibility. We wrapped the PP mesh inside the hydrogel and evaluated the performance of the resulting composites in a bilateral 1 × 1.5 cm abdominal wall defect model in rats. The results of gross observation, histological staining and immunohistochemical staining demonstrated the positive impact of the CS hydrogel on anti-adhesion and wound healing effects. Notably, the addition of BSPA to the CS hydrogel further improved the performance of the composites in vivo, promoting wound healing by enhancing collagen deposition and capillary rearrangement. This study suggested that the BSPA-modified CS hydrogel significantly promoted the anti-adhesion, anti-inflammatory and pro-angiogenesis properties of PP meshes during the healing process. Overall, this work offers a novel approach to the design of abdominal wall repair patches.
Striatal Functional Hypoconnectivity in Patients With Schizophrenia Suffering From Negative Symptoms, Longitudinal Findings
Authors: Geffen Tal , Hardikar Samyogita , Smallwood Jonathan , Kaliuzhna Mariia , Carruzzo Fabien , Böge Kerem , Zierhut Marco Matthäus , Gutwinski Stefan , Katthagen Teresa , Kaiser Stephan , Schlagenhauf Florian
Published: April 2024

Background

Negative symptoms in schizophrenia (SZ), such as apathy and diminished expression, have limited treatments and significantly impact daily life. Our study focuses on the functional division of the striatum: limbic—motivation and reward, associative—cognition, and sensorimotor—sensory and motor processing, aiming to identify potential biomarkers for negative symptoms.

Study Design

This longitudinal, 2-center resting-state-fMRI (rsfMRI) study examines striatal seeds-to-whole-brain functional connectivity. We examined connectivity aberrations in patients with schizophrenia (PwSZ), focusing on stable group differences across 2-time points using intra-class-correlation and associated these with negative symptoms and measures of cognition. Additionally, in PwSZ, we used negative symptoms to predict striatal connectivity aberrations at the baseline and used the striatal aberration to predict symptoms 9 months later.

Study Results

A total of 143 participants (77 PwSZ, 66 controls) from 2 centers (Berlin/Geneva) participated. We found sensorimotor-striatum and associative-striatum hypoconnectivity. We identified 4 stable hypoconnectivity findings over 3 months, revealing striatal-fronto-parietal-cerebellar hypoconnectivity in PwSZ. From those findings, we found hypoconnectivity in the bilateral associative striatum with the bilateral paracingulate-gyrus and the anterior cingulate cortex in PwSZ. Additionally, hypoconnectivity between the associative striatum and the superior frontal gyrus was associated with lower cognition scores in PwSZ, and weaker sensorimotor striatum connectivity with the superior parietal lobule correlated negatively with diminished expression and could predict symptom severity 9 months later.

Conclusions

Importantly, patterns of weaker sensorimotor striatum and superior parietal lobule connectivity fulfilled the biomarker criteria: clinical significance, reflecting underlying pathophysiology, and stability across time and centers.
Interindividual differences in mindfulness are linked to sleep-electroencephalographic characteristics
Authors: Wunderlin Marina , Studler Mirjam , Gianotti Lorena R R , Züst Marc A , Knoch Daria
Published: April 2024

Study Objectives

Mindfulness describes the ability to focus on the presence, including one’s thoughts and feelings. Trait mindfulness—a person’s inherent tendency to be mindful—has been connected to increased subjective sleep quality, but evidence from objective EEG-based sleep measures is lacking. Here, we investigate whether objective EEG-based sleep parameters explain interindividual differences in trait mindfulness.

Methods

Whole-night polysomnographic data were gathered from 52 healthy adults (27 females; agemean = 21.5 [SE = 0.28]) in their homes using a portable high-density EEG device. Trait mindfulness was assessed using the Five Facet Mindfulness Questionnaire short form (FFMQ-SF).

Results

Trait mindfulness was positively correlated at trend level with the percentage of rapid eye movement (REM), but not N1, N2, or slow wave sleep. Additionally, those exhibiting less REM beta/gamma power and NREM beta power displayed higher trait mindfulness and vice versa. Lastly, we replicated findings connecting higher trait mindfulness to better subjective sleep quality.

Conclusions

REM sleep is pivotal for emotional processing. Decreased REM high-frequency activity was suggested to reflect adrenergic reduction that defuses affective experiences. Increased NREM high-frequency activity is a marker for cognitive hyperarousal in insomnia. We speculate that differences in trait mindfulness might be explained by differences in REM- and NREM-sleep functions that promote ideal emotional regulation and prevent hyperarousal.
Anti-osteoporosis activity of casticin in ovariectomized rats
Authors: Zhang Dong , Li Jianmin , Li Xuejia , Liu Wanxin , Yu Ying , Sun Hao , Wu Jiajun , Ge Zhichao , Lv Kai , Shao Yanting , Wang Shuqiang , Ye Xiaojian
Published: April 2024

Background

Postmenopausal osteoporosis (PMPO) is the most familiar type of osteoporosis, a silent bone disease. Casticin, a natural flavonoid constituent, improves osteoporosis in animal model. Nevertheless, the potential mechanism remains to be further explored.

Methods

A model of PMPO was established in rats treated with ovariectomy (OVX) and RAW 264.7 cells induced with receptor activator of nuclear factor kappa-B ligand (RANKL). The effect and potential mechanism of casticin on PMPO were addressed by pathological staining, measurement of bone mineral density (BMD), three-point bending test, serum biochemical detection, filamentous-actin (F-actin) ring staining, TRAcP staining, reverse transcription quantitative polymerase chain reaction, western blot and examination of oxidative stress indicators.

Results

The casticin treatment increased the femoral trabecular area, bone maturity, BMD, elastic modulus, maximum load, the level of calcium and estrogen with the reduced concentrations of alkaline phosphatase (ALP) and tumor necrosis factor (TNF)-α in OVX rats. An enhancement in the F-actin ring formation, TRAcP staining and the relative mRNA expression of NFATc1 and TRAP was observed in RANKL-induced RAW 264.7 cells, which was declined by the treatment of casticin. Moreover, the casticin treatment reversed the reduced the relative protein expression of Nrf2 and HO-1 and the concentrations of superoxide dismutase and glutathione peroxidase, and the increased content of malondialdehyde both in vivo and in vitro.

Conclusion

Casticin improved bone density, bone biomechanics, the level of calcium and estrogen, the release of pro-inflammatory factor and oxidative stress to alleviate osteoporosis, which was associated with the upregulation of Nrf2/HO-1 pathway.
The response of physiological and xylem anatomical traits under cadmium stress in Pinus thunbergii seedlings
Authors: Li Shan , Li Huan , Wang Jing , Lu Sen , Liu Zepeng , Jia Honglei , Wei Ting , Guo Junkang
Published: April 2024

Studying the response of physiological and xylem anatomical traits under cadmium stress is helpful to understand plants’ response to heavy metal stress. Here, seedlings of Pinus thunbergii Parl. were treated with 50, 100 and 150 mg kg−1 Cd2+ for 28 days. Cadmium and nonstructural carbohydrate content of leaves, stems and roots, root Cd2+ flux, cadmium distribution pattern in stem xylem and phloem, stem xylem hydraulic traits, cell wall component fractions of stems and roots, phytohormonal content such as abscisic acid, gibberellic acid 3, molecule -indole-3-acetic acid, and jasmonic acid from both leaves and roots, as well as xylem anatomical traits from both stems and roots were measured. Root Cd2+ flux increased from 50 to 100 mmol L−1 Cd2+ stress, however it decreased at 150 mmol L−1 Cd2+. Cellulose and hemicellulose in leaves, stems and roots did not change significantly under cadmium stress, while pectin decreased significantly. The nonstructural carbohydrate content of both leaves and stems showed significant changes under cadmium stress while the root nonstructural carbohydrate content was not affected. In both leaves and roots, the abscisic acid content significantly increased under cadmium stress, while the gibberellic acid 3, indole-3-acetic acid and jasmonic acid methylester content significantly decreased. Both xylem specific hydraulic conductivity and xylem water potential decreased with cadmium stress, however tracheid diameter and double wall thickness of the stems and roots were not affected. High cadmium intensity was found in both the stem xylem and phloem in all cadmium stressed treatments. Our study highlighted the in situ observation of cadmium distribution in both the xylem and phloem, and demonstrated the instant response of physiological traits such as xylem water potential, xylem specific hydraulic conductivity, root Cd2+ flux, nonstructural carbohydrate content, as well as phytohormonal content under cadmium stress, and the less affected traits such as xylem anatomical traits, cellulose and hemicellulose.
The Role of Salicylic Acid in the Expression of RECEPTOR-LIKE PROTEIN 23 and Other Immunity-Related Genes
Authors: van Butselaar Tijmen , Silva Savani , Lapin Dmitry , Bañales Iñigo , Tonn Sebastian , van Schie Chris , Van den Ackerveken Guido
Published: April 2024

The hormone salicylic acid (SA) plays a crucial role in plant immunity by activating responses that arrest pathogen ingress. SA accumulation also penalizes growth, a phenomenon visible in mutants that hyperaccumulate SA, resulting in strong growth inhibition. An important question, therefore, is why healthy plants produce basal levels of this hormone when defense responses are not activated. Here, we show that basal SA levels in unchallenged plants are needed for the expression of a number of immunity-related genes and receptors, such as RECEPTOR-LIKE PROTEIN 23 ( RLP23). This was shown by depleting basal SA levels in transgenic Arabidopsis lines through the overexpression of the SA-inactivating hydroxylases DOWNY MILDEW-RESISTANT 6 (DMR6) or DMR6-LIKE OXYGENASE 1. RNAseq analysis revealed that the expression of a subset of immune receptor and signaling genes is strongly reduced in the absence of SA. The biological relevance of this was shown for RLP23: In SA-depleted and SA-insensitive plants, responses to the RLP23 ligand, the microbial pattern nlp24, were strongly reduced, whereas responses to flg22 remained unchanged. We hypothesize that low basal SA levels are needed for the expression of a subset of immune system components that enable early pathogen detection and activation of immunity.
Curricular Reform in Serious Illness Communication and Palliative Care: Using Medical Students’ Voices to Guide Change
Authors: Reidy Jennifer A. , Brizzi Kate , Chan Stephanie H. , Day Hollis , Epstein Scott K. , Fischer Melissa , Garg Priya S. , Gosline Anna , Jaramillo Carolina , Livne Emma , Mitchell Suzanne , Morgan Sarah , Olmsted Molly W. , Stebbins Patricia , Stumpf Isabella , Vesel Tamara , Yeh Irene M. , Young Megan E. , Goldman Roberta E.
Published: April 2024

Purpose

To gather and leverage the voices of students to drive creation of required, integrated palliative care curricula within undergraduate medical education in Massachusetts, which is lacking in a majority of U.S. medical schools.

Method

The study was conducted by the Massachusetts Medical Schools’ Collaborative, a working group committed to ensuring all medical students in Massachusetts receive foundational training in serious illness communication (SIC) and palliative care. Eight focus groups (2 per participating medical school) were conducted during January–May 2021 and included a total of 50 students from Boston University Chobanian & Avedisian School of Medicine, Harvard Medical School, Tufts University School of Medicine, and the UMass Chan Medical School. Data collected from focus groups were discussed and coded. Themes were identified using the immersion/crystallization qualitative data analysis approach.

Results

Six key themes emerged. Students viewed SIC as essential to high-quality medical practice regardless of specialty, and believed training in SIC skills and palliative care should be required in medical school curricula. Students preferred to learn and practice these skills using frameworks, particularly in real-world situations. Students recognized the expertise of palliative care specialists and described them as a scarce, often misunderstood resource in health care. Students reported it was mostly “luck” if they were included in family meetings and observed good role models. Finally, students desired practice in debriefing after difficult and emotional situations.

Conclusions

This study confirms long-standing themes on students’ experiences with SIC and palliative care topics, including feeling inadequately prepared to care for seriously ill patients as future physicians. Our study collected students’ perspectives as actionable data to develop recommendations for curricular change. Collaborative faculty also created recommendations based on the focus group data for immediate and ongoing SIC and palliative care curricular change in Massachusetts, which can apply to medical schools nationwide.
Sacroiliitis in inflammatory bowel disease
Authors: Malik Fardina , Weisman Michael H.
Published: April 2024

Purpose of review

This review summarizes the recent evidence regarding the epidemiology of inflammatory bowel disease (IBD) associated sacroiliitis, including the prevalence, pathogenesis, role of imaging, and therapeutic challenges.

Recent findings

Sacroiliitis is an underappreciated musculoskeletal manifestation of IBD, a chronic inflammatory condition of the gut affecting the younger population. Untreated sacroiliitis can lead to joint destruction and chronic pain, further adding to morbidity in IBD patients. Recent publications suggest sacroiliitis can be detected on abdominal imaging obtained in IBD patients to study bowel disease, but only a small fraction of these patients were seen by rheumatologists. Early detection of IBD-associated sacroiliitis could be achieved by utilization of clinical screening tools in IBD clinics, careful examination of existing computed tomography and MRI studies, and timely referral to rheumatologist for further evaluation and treatment. Current treatment approaches for IBD and sacroiliitis include several targeted biologic therapies, but IBD-associated sacroiliitis has limited options, as these therapies may not overlap in both conditions.

With the advances in imaging, sacroiliitis is an increasingly recognized comorbidity in IBD patients. Future studies focusing on this unique patient population will expand our understanding of complex pathophysiology of IBD-associated sacroiliitis and lead to identification of novel targeted therapies for this condition.
Utilizing immunotherapy towards achieving a functional cure for HIV-1
Authors: Sugiyama Fabrícia Heloisa Cavicchioli , Dietz Lisa Loksø , Søgaard Ole Schmeltz
Published: April 2024

Purpose of review

Advancements in antiretroviral therapy (ART) have positively impacted the life expectancy and possibility of living a normal life for people with HIV-1. However, lifelong daily medication is necessary to prevent disease progression. To this end, immunotherapeutic strategies are being tested with the aim of developing a functional cure in which the immune system effectively controls HIV-1 in the absence of ART.

Recent findings

The most promising advances in achieving sustained HIV-1 remission or cure include broadly neutralizing antibodies (bNAbs) that are administered alone or in combination with other agents. Newer and more innovative approaches redirecting T cells or natural killer cells to kill HIV-1 infected cells have also shown promising results. Finally, multiple ongoing trials focus on combining bNAbs with other immune-directed therapies to enhance both innate and adaptive immunity.

While immunotherapies as an alternative to conventional ART have generally proven to be well tolerated, these therapeutic approaches have largely been unsuccessful in inducing ART-free control of HIV-1. However, promising results from recent trials involving bNAbs that have reported durable HIV-1 control among a subset of participants, provide reason for cautious optimism that we with further optimization of these treatment strategies may be able to achieve functional cure for HIV-1.
Microbiological Profile of Culture-Positive Fungal Keratitis
Authors: Muni Ipsita , Behera Himanshu Sekhar , Sahu Srikant Kumar , Priyadarshini Smruti Rekha , Das Sujata
Published: April 2024

Purpose:

To examine the microbiological profile of cases of culture-positive fungal keratitis presenting to a tertiary eye care center in eastern India.

Methods:

Microbiology records of all culture-positive microbial keratitis patients presenting to L V Prasad Eye Institute, Bhubaneswar, between January 2020 and December 2021, were retrospectively reviewed. Collected data included smear results of culture-positive fungal or mixed infections, the species isolated, and the time taken for organisms to grow in each media.

Results:

Fungal keratitis formed 36% of all culture-positive microbial keratitis, whereas mixed infections (fungi and other organisms) formed 8.5%. The most common fungal species isolated was Fusarium spp. (25.8%). The most common bacteria involved in mixed infection with fungi was Staphylococcus spp. (54.8%). The positivity of potassium hydroxide+calcofluor white stain in detecting fungal filaments was 89.0% and that of Gram stain was 76.1%. Culture-positive cases of fungal keratitis showed most frequent growth on potato-dextrose agar (77.6%). A similar pattern was observed in culture-positive mixed infections (Sabouraud dextrose agar [SDA]: 84%). Most frequent growth of bacteria in mixed infections was seen in thioglycolate broth (54.7%). The shortest time to achieve significant fungal growth was observed in blood agar (BA) and chocolate agar (CA) (2.2/2.3 days, and 1.8/2 days for fungal keratitis and mixed infections, respectively). Filamentous hyaline fungi took the shortest time to achieve significant growth (2.8 days), whereas yeast forms took the longest (5 days).

Conclusion:

This study highlights the importance of combined use of both solid and liquid culture media, especially potato dextrose agar (PDA)/SDA and CA, to arrive at a definitive diagnosis of fungal keratitis and possible bacterial co-infection, which forms a significant proportion of cases with fungal keratitis. In resource-poor laboratories, two culture media, either SDA or PDA, along with BA, may be plated to detect mixed infections. Examination of stained smears of corneal samples provides an inexpensive method of rapid diagnosis of fungal keratitis when culture media is not available.
The role of cholesterol and its oxidation products in tuberculosis pathogenesis
Authors: Roth Andrew T. , Philips Jennifer A. , Chandra Pallavi
Published: April 2024

Mycobacterium tuberculosis causes tuberculosis (TB), one of the world’s most deadly infections. Lipids play an important role in M. tuberculosis pathogenesis. M. tuberculosis grows intracellularly within lipid-laden macrophages and extracellularly within the cholesterol-rich caseum of necrotic granulomas and pulmonary cavities. Evolved from soil saprophytes that are able to metabolize cholesterol from organic matter in the environment, M. tuberculosis inherited an extensive and highly conserved machinery to metabolize cholesterol. M. tuberculosis uses this machinery to degrade host cholesterol; the products of cholesterol degradation are incorporated into central carbon metabolism and used to generate cell envelope lipids, which play important roles in virulence. The host also modifies cholesterol by enzymatically oxidizing it to a variety of derivatives, collectively called oxysterols, which modulate cholesterol homeostasis and the immune response. Recently, we found that M. tuberculosis converts host cholesterol to an oxidized metabolite, cholestenone, that accumulates in the lungs of individuals with TB. M. tuberculosis encodes cholesterol-modifying enzymes, including a hydroxysteroid dehydrogenase, a putative cholesterol oxidase, and numerous cytochrome P450 monooxygenases. Here, we review what is known about cholesterol and its oxidation products in the pathogenesis of TB. We consider the possibility that the biological function of cholesterol metabolism by M. tuberculosis extends beyond a nutritional role.
Perceived Control, Functional Status, Depressive Symptoms, and Anxiety
Authors: Thapa Ashmita , Kang JungHee , Chung Misook L. , Wu Jia-Rong , Latimer Abigail , Lennie Terry A. , Lin Chin-Yen , Thompson Jessica Harman , Cha Geunyeong , Moser Debra K.
Published: April 2024

Background

Health-related quality of life (HRQoL) is poor in patients with heart failure. Psychological (ie, depressive symptoms [DS], anxiety, and perceived control) and physical (ie, functional status) factors are associated with HRQoL. The dynamic relationships among these variables and their impact on HRQoL remain unclear, limiting the ability to design effective interventions.

Purpose

Our aim was to evaluate a moderated mediation model, in which the association between perceived control and HRQoL was hypothesized to be mediated by DS and anxiety in the presence of a moderator, functional status.

Methods

Patients (N = 426) with heart failure completed the Control Attitudes Scale-Revised to measure perceived control, Duke Activity Status Index for functional status, Patient Health Questionnaire-9 for DS, Brief Symptom Inventory for anxiety, and Minnesota Living with Heart Failure Questionnaire for HRQoL. We performed a moderated parallel mediation analysis.

Results

Higher levels of perceived control were associated with better HRQoL through lower levels of anxiety and DS in the presence of functional status (index of moderated mediation for DS, b = 0.029; 95% confidence interval, 0.016–0.045; for anxiety: b = 0.009, 95% confidence interval, 0.002–0.018). The effect of perceived control on psychological symptoms was stronger at low and moderate functional statuses; however, this effect diminished with increasing functional status.

Conclusion

Functional status moderated the indirect effects of perceived control on HRQoL through DS and anxiety in patients with heart failure. Efforts to improve HRQoL by targeting perceived control may be more effective when considering DS and anxiety in patients with low to moderate levels of functional status.
Assessment of species distribution and virulence factors of oral fungal carriage among hospitalized patients with COVID-19: a case-control study
Authors: Ramezanalipour Zahra , Hashemi Seyed Jamal , Daie Ghazvini Roshanak , Shenagari Mohammad , Sharifdini Meysam , Salehiniya Hamid , Keivanlou Mohammad-Hossein , Ashrafi Keyhan , Roostaei Davoud , Mansour Ghanaei Fariborz , Sasani Elahe , Rafat Zahra
Published: April 2024

Background:

The COVID-19 pandemic highlighted the need to study oral fungal carriage and its potential impact. In oral fungal environments, factors like changes in respiratory epithelium, increased pathogen attachment, local inflammation, and virulence factors could influence COVID-19 severity. The authors conducted a study to explore oral fungal carriage in COVID-19 patients and compare it to a healthy control group.

Methods:

The authors executed a case-control investigation including 144 COVID-19 patients and an equivalent number of 144 healthy controls. The matching criteria encompassed age, sex, body mass index, and the history of antibiotic and antiviral medication intake. This research was performed over a span of 12 months from May 2021 to May 2022. The mouth area was sampled with a cotton-tipped swab. Subsequently, all the samples underwent fungal culture and PCR-sequencing procedures.

Results:

In COVID-19 patients, oral fungal carriage was three times higher compared to healthy controls. Candida was the exclusive genus found in both groups, with Candida albicans being the most frequently isolated species (90.79%). Among COVID-19 patients, Candida species showed significantly higher esterase, proteinase, and hemolysin activity compared to healthy individuals. Both groups exhibited elevated levels of C. albicans virulence factors compared to non-albicans species.

Conclusions:

It is crucial to understand the way that virulence factors of oral fungal carriage act in COVID-19 patients in order to come up with novel antifungal medications, identify the contributing factors to drug resistance, and manage clinical outcomes.
The effects of prehospital TXA on mortality and neurologic outcomes in patients with traumatic intracranial hemorrhage: A subgroup analysis from the prehospital TXA for TBI trial
Authors: Rowell Susan , Meier Eric N. , Hoyos Gomez Tatiana , Fleming Michael , Jui Jon , Morrison Laurie , Bulger Eileen , Sopko George , Weisfeldt Myron , Christenson Jim , Klotz Pat , McMullan Jason , Callum Jeannie , Sheehan Kellie , Tibbs Brian , Aufderheide Tom , Cotton Bryan , Gandhi Rajesh , Idris Ahamed , Frascone Ralph J. , Ferrara Michael , Richmond Neil , Kannas Delores , Schlamp Rob , Robinson Bryce , Dries David , Tallon John , Hendrickson Audrey , Gamber Mark , Garrett John , Simonson Robert , McKinley W. Ian , Schreiber Martin
Published: April 2024

BACKGROUND

In the prehospital tranexamic acid (TXA) for traumatic brain injury (TBI) trial, TXA administered within 2 hours of injury in the out-of-hospital setting did not reduce mortality in all patients with moderate/severe traumatic brain injury (TBI). We examined the association between TXA dosing arms, neurologic outcome, and mortality in patients with intracranial hemorrhage (ICH) on computed tomography (CT).

METHODS

This was a secondary analysis of the Prehospital Tranexamic Acid for TBI Trial (ClinicalTrials.gov [NCT01990768]) that randomized adults with moderate/severe TBI (Glasgow Coma Scale score < 13) and systolic blood pressure ≥ 90 mm Hg within 2 hours of injury to a 2-g out-of-hospital TXA bolus followed by an in-hospital saline infusion, a 1-g out-of-hospital TXA bolus/1-g in-hospital TXA infusion, or an out-of-hospital saline bolus/in-hospital saline infusion (placebo). This analysis included the subgroup with ICH on initial CT. Primary outcomes included 28-day mortality, 6-month Glasgow Outcome Scale-Extended (GOSE) ≤ 4, and 6-month Disability Rating Scale (DRS). Outcomes were modeled using linear regression with robust standard errors.

RESULTS

The primary trial included 966 patients. Among 541 participants with ICH, 28-day mortality was lower in the 2-g TXA bolus group (17%) compared with the other two groups (1-g bolus/1-g infusion 26%, placebo 27%). The estimated adjusted difference between the 2-g bolus and placebo groups was −8·5 percentage points (95% confidence interval [CI], −15.9 to −1.0) and between the 2-g bolus and 1-g bolus/1-g infusion groups was −10.2 percentage points (95% CI, −17.6 to −2.9). Disability Rating Scale at 6 months was lower in the 2-g TXA bolus group than the 1-g bolus/1-g infusion (estimated difference − 2.1 [95% CI, −4.2 to −0.02]) and placebo groups (−2.2 [95% CI, −4.3, −0.2]). Six-month GOSE did not differ among groups.

CONCLUSION

A 2-g out-of-hospital TXA bolus in patients with moderate/severe TBI and ICH resulted in lower 28-day mortality and lower 6-month DRS than placebo and standard TXA dosing.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level II.
Late-Onset Findings During Extended EEG Monitoring Are Rare in Critically Ill Children
Authors: Fung France W. , Parikh Darshana S. , Walsh Kathleen , Fitzgerald Mark P. , Massey Shavonne L. , Topjian Alexis A. , Abend Nicholas S.
Published: April 2024

Purpose:

Electrographic seizures (ES) are common in critically ill children undergoing continuous EEG (CEEG) monitoring, and previous studies have aimed to target limited CEEG resources to children at highest risk of ES. However, previous studies have relied on observational data in which the duration of CEEG was clinically determined. Thus, the incidence of late occurring ES is unknown. The authors aimed to assess the incidence of ES for 24 hours after discontinuation of clinically indicated CEEG.

Methods:

This was a single-center prospective study of nonconsecutive children with acute encephalopathy in the pediatric intensive care unit who underwent 24 hours of extended research EEG after the end of clinical CEEG. The authors assessed whether there were new findings that affected clinical management during the extended research EEG, including new-onset ES.

Results:

Sixty-three subjects underwent extended research EEG. The median duration of the extended research EEG was 24.3 hours (interquartile range 24.0–25.3). Three subjects (5%) had an EEG change during the extended research EEG that resulted in a change in clinical management, including an increase in ES frequency, differential diagnosis of an event, and new interictal epileptiform discharges. No subjects had new-onset ES during the extended research EEG.

Conclusions:

No subjects experienced new-onset ES during the 24-hour extended research EEG period. This finding supports observational data that patients with late-onset ES are rare and suggests that ES prediction models derived from observational data are likely not substantially underrepresenting the incidence of late-onset ES after discontinuation of clinically indicated CEEG.
Environmental and genetic influence on the rate and spectrum of spontaneous mutations in Escherichia coli
Authors: Gifford Danna R. , Bhattacharyya Anish , Geim Alexandra , Marshall Eleanor , Krašovec Rok , Knight Christopher G.
Published: April 2024

Spontaneous mutations are the ultimate source of novel genetic variation on which evolution operates. Although mutation rate is often discussed as a single parameter in evolution, it comprises multiple distinct types of changes at the level of DNA. Moreover, the rates of these distinct changes can be independently influenced by genomic background and environmental conditions. Using fluctuation tests, we characterized the spectrum of spontaneous mutations in Escherichia coli grown in low and high glucose environments. These conditions are known to affect the rate of spontaneous mutation in wild-type MG1655, but not in a ΔluxS deletant strain – a gene with roles in both quorum sensing and the recycling of methylation products used in E. coli’s DNA repair process. We find an increase in AT>GC transitions in the low glucose environment, suggesting that processes relating to the production or repair of this mutation could drive the response of overall mutation rate to glucose concentration. Interestingly, this increase in AT>GC transitions is maintained by the glucose non-responsive ΔluxS deletant. Instead, an elevated rate of GC>TA transversions, more common in a high glucose environment, leads to a net non-responsiveness of overall mutation rate for this strain. Our results show how relatively subtle changes, such as the concentration of a carbon substrate or loss of a regulatory gene, can substantially influence the amount and nature of genetic variation available to selection.
Noise Stress induces Cardiovascular Metabolic Shifts
Authors: Marques Jair G. , Kuntic Marin , Krishnankutty Roopesh , Blanco Giovanny Rodriguez , Malkov Mykyta , Frenis Katie , Wills Jimi , Shokry Engy , Mow Chee Frederic Li , Taylor Cormac T , Münzel Thomas , Daiber Andreas , von Kriegsheim Alex
Published: April 2024

Environmental stressors present in the modern world can fundamentally affect humans’ physiology and health. Exposure to stressors like air pollution, heat, and traffic noise has been linked to a pronounced increase in non-communicable diseases. Specifically, aircraft noise has been identified as a risk factor for cardiovascular and metabolic diseases, such as arteriosclerosis, heart failure, stroke, and diabetes. Noise stress leads to neuronal activation with subsequent stress hormone release that ultimately leads to activation of the renin-angiotensin-aldosterone system, increasing inflammation and oxidative stress, dramatically affecting the cardiovascular system. However, despite the epidemiological evidence of a link between noise stress and metabolic dysfunction, the consequences of exposure at the molecular, metabolic level of the cardiovascular system are largely unknown. Here we use a murine model system of aircraft noise exposure to show that noise stress profoundly alters heart metabolism. Within days of exposing animals to aircraft noise, the heart has a reduced potential for utilising fatty-acid beta-oxidation, the tricarboxylic acid cycle, and the electron transport chain for generating ATP. This is compensated by shifting energy production towards glycolysis. Intriguingly, the metabolic shift is reminiscent of what is observed in failing and ischaemic hearts. Our results demonstrate that within a relatively short exposure time, the cardiovascular system undergoes a fundamental metabolic shift that bears the hallmarks of cardiovascular disease.

Overall, aircraft noise induces rapid, detrimental metabolic shifts in the heart, resembling patterns seen in cardiovascular diseases. These findings underscore the urgent need to comprehend the molecular consequences of environmental stressors, paving the way for targeted interventions aiming at mitigating health risks associated with chronic noise exposure in our modern, noisy environments.
Fiora: Local neighborhood-based prediction of compound mass spectra from single fragmentation events
Authors: Nowatzky Yannek , Russo Francesco , Lisec Jan , Kister Alexander , Reinert Knut , Muth Thilo , Benner Philipp
Published: April 2024

Non-targeted metabolomics holds great promise for advancing precision medicine and facilitating the discovery of novel biomarkers. However, the identification of compounds from tandem mass spectra remains a non-trivial task due to the incomplete nature of spectral reference libraries. Augmenting these libraries with simulated mass spectra can provide the necessary reference to resolve unmatched mass spectra, but remains a difficult undertaking to this day. In this study, we introduce Fiora, an innovative open-source algorithm using graph neural networks to simulate tandem mass spectrain silico. Our objective is to improve fragment intensity prediction with an intricate graph model architecture that facilitates edge prediction, thereby modeling fragment ions as the result of singular bond breaks and their local molecular neighborhood. We evaluate the performance on test data from NIST (2017) and the curated MS-Dial spectral library, as well as compounds from the 2016 and 2022 CASMI challenges. Fiora not only surpasses state-of-the-art fragmentation algorithms, ICEBERG and CFM-ID, in terms of prediction quality, but also predicts additional features, such as retention time and collision cross section. In addition, Fiora demonstrates significant speed improvements through the use of GPUs. This enables rapid (re)scoring of putative compound identifications in non-targeted experiments and facilitates large-scale expansion of spectral reference libraries with accurate spectral predictions.

Abstract Figure
Neural activity for complex sounds in the marmoset medial prefrontal cortex
Authors: Gilliland Rebekah E. , Selvanayagam Janahan , Zanini Alessandro , Johnston Kevin D. , Everling Stefan
Published: April 2024

Vocalizations play an important role in the daily life of nonhuman primates and are likely precursors of human language. Recent functional imaging studies in the highly vocal common marmoset (Callithrix jacchus) have suggested that medial prefrontal cortex area 32 may be a part of a vocalization-processing network but the response properties of area 32 neurons to auditory stimuli remain unknown. Here, we performed electrophysiological recordings in area 32 with high-density Neuropixels probes and characterized neuronal responses to a variety of sounds including conspecific vocalizations. More than half of the neurons in area 32 responded to conspecific vocalizations and other complex auditory stimuli. These responses exhibited dynamics consisting of an initially non-selective reduction in neural activity, followed by an increase in activity that immediately conveyed sound selectivity. Our findings demonstrate that primate mPFC area 32 plays a critical role in processing species-specific and biologically relevant sounds.
Heterogeneous folding landscapes and predetermined breaking points within a protein family
Authors: Pechmann Sebastian
Published: April 2024

The accurate prediction of protein structures with artificial intelligence has been a spectacular success. Yet, how proteins fold into their native structures inside the cell remains incompletely understood. Of particular interest is to rationalize how proteins interact with the protein homeostasis network, an organism specific set of protein folding and quality control enzymes. Failure of protein homeostasis leads to widespread misfolding and aggregation, and thus neurodegeneration. Here, I present a comparative analysis of the folding across a protein family from a single organism, the Saccharomyces cerevisiae small GTPases. Using computational modelling to directly probe folding dynamics, this work shows how near identical structures from the same folding environment exhibit heterogeneous folding landscapes. Remarkably, yeast small GTPases are found to unfold along different pathways either via the N- or C-terminus initiated by structure-encoded predetermined breaking points. Moreover, degrons as recognition signals for ubiquitin-dependent degradation were systematically depleted from the initial unfolding sites, as if to protect from too rapid degradation upon spontaneous unfolding. In turn, Hsp70 Ssb chaperone binding correlated only with N-terminal hydrophobicity. The presented results highlight a direct coordination of folding pathway and protein homeostasis interaction signals across a protein family. A deeper understanding of the interdependence of proteins with their folding environment will help to rationalize and combat disease linked to protein misfolding and dysregulation. More generally, this work underlines the importance of understanding protein folding in the cellular context, and highlights valuable constraints towards a systems-level understanding of protein homeostasis.
Sampling Techniques and Genomic Analysis of Biological Material from Artworks
Authors: Roby Rhonda K. , Wiscovitch-Russo Rosana A. , Hart Rebecca , Appel Amanda E. , Kazmi Manija A. , Huber Thomas , Åberg Karina C. , Sakmar Thomas P. , Lorente José A. , Gonzalez-Juarbe Norberto
Published: April 2024

The genomic analysis of biological material obtained from artwork or cultural heritage artifacts can be used to guide curation, preservation and restoration. However, the recovery of biological samples from artworks is dependent on the sampling technique used and the media from which the biological materials are recovered. The ideal sampling method should be non-invasive, yet robust. Only rare examples of direct comparisons among sampling techniques have been reported. To develop a framework for the recovery of biological samples for subsequent microbial DNA analysis, we studied five artworks on paper and compared three sampling methods, each with increasing degrees of invasiveness. Minimally invasive swabbing techniques collect samples from the surface, whereas more aggressive techniques such as wet vacuuming were expected to yield more biological material from within the support media. We report a comparison of collection techniques to generate microbial DNA sequence data from artworks on paper. We observed that wet vacuuming resulted in higher DNA recovery than double swabbing and core punches; however, all three techniques yielded satisfactory microbial DNA sequences. Diverse microbial populations existed to varying degrees on the corners and centers of the five artworks studied, but the distribution of the total biomass was relatively even across the surfaces of the works sampled. Studies of peripheral regions, where sampling is less likely to cause alterations to the artwork, could thus yield useful results in microbiome studies. These results provide a framework for sampling artworks on paper to obtain biological material for microbial genomic analysis. The methods described may provide microbiome identification to facilitate restoration and preservation, and might also contribute to the determination of provenance.
Three dimensionally printed microstructured alginate scaffolds for neural tissue engineering
Authors: Li Jianfeng , Hietel Benjamin , Brunk Michael G.K. , Reimers Armin , Willems Christian , Groth Thomas , Cynis Holger , Adelung Rainer , Schütt Fabian , Sacher Wesley D. , Poon Joyce K.S.
Published: April 2024

The integration of scaffolds, signalling cues, and cellular components is essential in tissue engineering to create anin vivoequivalent environment that supports physiological function. Scaffolds provide mechanical reinforcement for cellular proliferation and differentiation while providing cues that instruct the development of cells during culture. Alginate (Alg) is a versatile biopolymer for scaffold engineering. However, due to a lack of intrinsic cell-binding sites, thus far, Alg must be functionalized for cellular adhesion. Here, we demonstrate proof-of-concept, bioactive additive-free, microstructured Alg (M-Alg) scaffolds for neuron culture. The M-Alg scaffold was formed by introducing tetrapod-shaped ZnO (t-ZnO) microparticles as structural templates in the Alg that were subsequently removed. These transparent, porous, additive-free Alg-based scaffolds with neuron affinity are promising for neuroregenerative and organoid- related research.

Highlights

Tetrapod-shaped ZnO (t-ZnO) microparticles are used as a template for the fabrication of open interconnected channels and textured surfaces in 3D printed microstructured alginate (M-Alg) scaffolds.

Primary mouse cortical neurons seeded on the 3D printed M-Alg scaffolds show improved adhesion and maturation with extensive neural projections forming inside the scaffolds.
Xanthomonas protegenssp. nov., a rice seed-associated probiotic and taxonomic outlier species ofXanthomonas sontii
Authors: Rana Rekha , Sharma Anushika , Madhavan Vishnu Narayanan , Sonti Ramesh V. , Patel Hitendra K. , Patil Prabhu B.
Published: April 2024

Rice seed microbiota play a vital role throughout their growth and developmental stages.Xanthomonas sontiiis known as an abundant, core-vertically transmitted rice seed endophyte with probiotic properties. Studies reveal a less explored world of non-pathogenicXanthomonas(NPX) species likeX. sontiiandX. indicathat are associated with healthy rice seeds. The present study reports the isolation, biochemical characterization, and in-depth taxonogenomic evidence for a third NPX species,X. protegens, from rice seeds, a taxonomic outlier ofX. sontii. It also highlights the importance of using multiple taxonogenomic indices to identify taxonomic outlier species. Similar to the other two NPX species, the new member species is also non-pathogenic and providesin vivoprotection to rice plants fromXanthomonas oryzaepv.oryzaeupon leaf clip inoculation. The pangenome investigation suggested a set of unique genes to the novel species that might be important in adaptation to rice plants and differentiate it from other NPX species. The study will allow the design of markers for the identification of these NPX members, targeted culturomics of a particular NPX species and in the discovery of other novel NPX species from healthy rice seed microbiome for further exploitation in rice health.
Rudhira-mediated microtubule stability controls TGFβ signaling during mouse vascular development
Authors: Joshi Divyesh , Jindal Preeti , Shetty Ronak , Inamdar Maneesha S.
Published: April 2024

The Transforming Growth Factor β (TGFβ) signaling pathway is critical for survival, proliferation, and cell migration, and is tightly regulated during cardiovascular development. Smads, key effectors of TGFβ signaling, are sequestered by microtubules (MTs) and need to be released for pathway function. Independently, TGFβ signaling also stabilizes MTs. Molecular details and thein vivorelevance of this cross-regulation remain unclear, understanding which is important in complex biological processes such as cardiovascular development. Here, we userudhira/Breast Carcinoma Amplified Sequence 3 (BCAS3), a MT-associated, endothelium-restricted and developmentally essential proto-oncogene, as a pivot to decipher cellular mechanisms in bridging TGFβ signaling and MT stability. We show that Rudhira regulates TGFβ signalingin vivo,during mouse cardiovascular development, and in endothelial cells in culture. Rudhira associates with MTs and is essential for the activation and release of Smad2/3 from MTs. Consequently, Rudhira depletion attenuates Smad2/3- dependent TGFβ signaling thereby impairing cell migration. Interestingly, Rudhira is also a transcriptional target of Smad2/3-dependent TGFβ signaling essential for TGFβ-induced MT stability. Our study identifies an immediate early physical role and a slower, transcription-dependent role for Rudhira in cytoskeleton-TGFβ signaling crosstalk. These two phases of control could facilitate temporally-and spatially restricted targeting of the cytoskeleton and/or TGFβ signaling in vascular development and disease.

Significance statement

The developmental TGFβ pathway is essential for cell migration, cell-cell communication, adhesion, apoptosis, and matrix remodeling. Dysregulation of TGFβ signaling leads to aberrant vascular patterning and angiogenesis during mouse embryogenesis. Pathway activation involves phosphorylation and nuclear transport of Smads. Microtubules sequester Smads in the cytoplasm, thereby inhibiting TGFβ signaling. Conversely, TGFβ signaling stabilizes microtubules. However, the molecular components involved, and biological relevance of this cross-regulation remain unclear. We show that the oncoprotein Rudhira/BCAS3 facilitates Smad-MT dissociation upon ligand-mediated TGFβ receptor activation. Interestingly, Smad-dependent TGFβ signaling activation enhances rudhira transcription, essential for microtubule stabilization during cardiovascular development. This dual regulation of TGFβ signaling and microtubule stability by Rudhira allows sustained temporal control essential for development, and its dysregulation has pathological outcomes.