bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends in extreme rainfall and their relationship to flooding episodes in Vhembe district, South Africa
Authors: Munzhedzi Lily , Mugari Ephias , Nethengwe Nthaduleni Samuel , Gumbo Anesu Dion
Published: September 2024

Extreme weather events, such as heavy rainfall, are being increased by climate change in various regions, and such events often cause floods. This study examined the trends and variability of extreme rainfall indices using daily rainfall data (1981–2023) from three study sites at different socio-economic development spectra in Vhembe District, Limpopo Province, South Africa. The analyses focus on indices such as the annual total rainfall from wet days (PRCPTOT), the maximum number of consecutive dry days (CDD) and wet days (CWD), annual maximum 1-day and 5-day rainfall (RX1 day and RX5 day), the Simple Daily Intensity Index (SDII), the number of days exceeding varying amounts of precipitation (R10, R20, R40) and the annual number of wet days with rainfall greater than the 95th and 99th percentile (R95p and R99p) of the 1981–2023 daily rainfall. We discuss the observed trends in extreme rainfall indices in light of the actual flood occurrences to establish linkages. Several statistically significant and marginal changes in extreme rainfall trends were identified and provided key insights into reported flooding events in the district—flooding episodes were mainly attributed to the significant increases in total precipitation (PRCPTOT) and rainfall exceeding the 99th percentile of daily rainfall (R99p). Other significant contributors were declining CDD and increasing RX1day at Duthuni, increasing R40 at Musina as well as increasing R1 and declining CDD at Sane. However, the low altitude, urbanization, poor waste management and inadequate drainage systems were among the key non-climatic drivers of flood risk across the study sites, but these warrant further investigation. The complex interplay between climatic and non-climatic drivers of flood risk underscores the importance of localized climate studies and the need for adaptive strategies to minimize loss and damage. Overall, this research provides valuable insights into localized extreme rainfall trends, which are essential for developing site-specific flood mitigation and adaptation strategies. However, such initiatives require placing vulnerable communities at the centre in order to develop solutions that are locally led and relevant.
Examining Your Instrument
Authors: Jahn Anthony F , Cho Youngnan Jenny
Published: September 2024

This chapter, unique in its purpose, offers a hands-on tour of the larynx and the neck. It guides the reader through a detailed self-examination tour of the anatomic structures involved in voice production. Through the familiarity gained through this chapter, singers will become more confident in examining themselves, the first step toward “owning” their vocal apparatus.
Hearing and Singing
Authors: Jahn Anthony F , Cho Youngnan Jenny
Published: September 2024

Hearing is an often neglected but vital topic for singers. Our ears are the afferent part of the feedback loop by which we monitor the voice. Even minor degrees of hearing loss may have an impact on vocal performance. This chapter describes how sound is heard, and addresses some common kinds of hearing loss. A simple self-test for distinguishing conductive versus sensory hearing loss is described, as well as advice regarding avoiding noise damage to the ears.
Common Disorders of the Larynx
Authors: Jahn Anthony F , Cho Youngnan Jenny
Published: September 2024

A handful of laryngeal disorders account for the majority of vocal complaints in singers. These are mostly benign and respond well to treatment. This chapter presents a description of these disorders, with illustrations, and an overview of the causes, symptoms, and management. The purpose is to familiarize singers with these problems and to reduce the anxiety provoked by diagnoses such as “vocal nodules” and “vocal fold hemorrhage.”
The Singer
Authors: Jahn Anthony F , Cho Youngnan Jenny
Published: September 2024

This chapter steps back a bit, to consider singing as an art form. The authors propose that singing is unique among all the arts, melding left brain and right brain input, and requiring the performer to be both artist and artisan. It is an appreciation of the skill, beauty, and unparalleled nature of vocal performance, and pays tribute to singers and the singing voice.
A Systematic Approach to Evaluating Instrumental Variable Assumptions: Applied Example of Glucose-lowering Medications and Risk for Hospitalized Heart Failure in Older Adults
Authors: Htoo Phyo T , Edwards Jessie K , Gokhale Mugdha , Pate Virginia , Buse John B , Jonsson-Funk Michele , Stürmer Til
Published: September 2024

One obstacle to adopting instrumental variable (IV) methods in pharmacoepidemiology is their reliance on strong, unverifiable assumptions. We can falsify IV assumptions by leveraging the causal structure, which can strengthen or refute their plausibility and increase the validity of effect estimates. We illustrate a systematic approach to evaluate calendar time IV assumptions in estimating the known effect of thiazolidinediones on hospitalized heart failure. Using cohort entry time before and after 09/2010, when the U.S. Food and Drug Administration issued a safety communication as a proposed IV, we estimated IV and propensity score-weighted 2-year risk differences (RDs) using Medicare data (2008-2014). We (i) performed inequality tests, (ii) identified the negative control IV/outcome using causal assumptions, (iii) estimated RDs after narrowing the calendar time range and excluding patients likely associated with unmeasured confounding, (iv) derived bounds for RDs, and (v) estimated the proportion of compliers and their characteristics. The findings revealed that IV assumptions were violated and RDs were extreme, but the assumptions became more plausible upon narrowing the calendar time range and restricting the cohort by excluding prevalent heart failure (the strongest measured predictor of outcome). Systematically evaluating IV assumptions could help detect bias in IV estimators and increase their validity.
The impact of media-based mental health campaigns on male help-seeking: a systematic review
Authors: Duthie Grant , Reavley Nicola , Wright Judith , Morgan Amy
Published: September 2024

More than half of all men do not seek professional help for depression, suicide and anxiety. Although media-based campaigns represent a promising health promotion intervention to improve male help-seeking, it is unclear what communication strategies in extant mental health media-based campaigns are effective for men. The aim of this systematic review was to synthesize information about the effectiveness of these campaigns on male help-seeking outcomes. A search was conducted of electronic databases and gray literature. Studies were eligible if they examined the effectiveness of a media-based campaign targeting male help-seeking attitudes, beliefs, intentions or behaviors in relation to mental disorders, distress, suicide or self-harm. Twenty-two studies of varying quality met the eligibility criteria. Most studies targeting mental health or depression were found to positively influence male help-seeking. There were mixed results for suicide prevention campaigns. Some evidence suggests that overall, brochure-based campaigns impact help-seeking. The use of male or mixed-gender campaign imagery produced similar results. The choice of message framing appeared to influence help-seeking outcomes. Despite substantial heterogeneity in campaign approaches and difficulties isolating the effects of campaign delivery from messaging, the review indicates that media-based campaigns can play a role in improving male help-seeking for mental health difficulties. Mounting evidence suggests that messaging and delivery should align with male communication preferences. However, high-quality, targeted research is required to evaluate the circumstances in which various campaign delivery and messaging components are effective in improving male help-seeking for poor mental health and suicidality.
Inflorescence development in female cannabis plants is mediated by photoperiod and gibberellin
Authors: Alter Hanan , Sade Yael , Sood Archit , Carmeli-Weissberg Mira , Shaya Felix , Kamenetsky-Goldstein Rina , Bernstein Nirit , Spitzer-Rimon Ben
Published: September 2024

In cannabis seedlings, the initiation of solitary flowers is photoperiod-independent. However, when cannabis reaches the adult stage, short-day photoperiod (SD) triggers branching of the shoot apex and a reduction in internode length, leading to development of a condensed inflorescence. We demonstrate that SD affects cannabis plants in two distinct phases: the first includes rapid elongation of the internodes and main stem, and occurring from Day 5 to Day 10 of plant cultivation under SD; in the second phase, elongation of newly developed internodes ceases, and a condensed inflorescence is formed. Exposure of plants to alternating photoperiods revealed that inflorescence onset requires at least three consecutive days of SD, and SD is consistently required throughout inflorescence maturation to support its typical condensed architecture. This photoperiod-dependent morphogenesis was associated with a decrease in gibberellin (GA4) and auxin levels in the shoot apex. Reverting the plants to a long-day photoperiod (LD) increased GA4 and auxin levels, leading to inflorescence disassembly, internode elongation, and subsequent resumption of LD growth patterns. Similar developmental patterns were observed under SD following the application of exogenous GA (and not auxin), which also impeded inflorescence development. Nevertheless, additional studies will help to further evaluate auxin’s role in these developmental changes. We propose a crucial role for GA in sexual reproduction and inflorescence development in female cannabis by mediating photoperiod signaling in the inflorescence tissues.
Impact of adequate empirical combination therapy on mortality in septic shock due to Pseudomonas aeruginosa bloodstream infections: a multicentre retrospective cohort study
Authors: Vena Antonio , Schenone Michela , Corcione Silvia , Giannella Maddalena , Pascale Renato , Giacobbe Daniele Roberto , Muccio Marco , Mornese Pinna Simone , Pari Bianca , Giovannenze Francesca , Geremia Nicholas , Mikulska Malgorzata , Taddei Eleonora , Sangiorgi Flavio , Bavaro Davide Fiore , Scaglione Vincenzo , Vassia Veronica , Merli Marco , Bartoletti Michele , Viale Pierluigi , De Rosa Francesco Giuseppe , Bassetti Matteo
Published: September 2024

Objectives

To determine the association of adequate empirical combination therapy (AECT) with 30-day all-cause mortality in patients with septic shock due to Pseudomonas aeruginosa bloodstream infections (BSI).

Methods

This multicentre, retrospective cohort study analysed data from 14 public hospitals in Italy, including all consecutive adult patients admitted during 2021–2022 with septic shock due to P. aeruginosa BSI. We compared the outcomes of patients receiving AECT to those on adequate empirical monotherapy (AEMT) using Cox regression analyses.

Results

Of the 98 patients who received adequate empirical antibiotic treatment for septic shock due to P. aeruginosa BSI, 24 underwent AECT and 74 were given AEMT. AECT was associated with a lower 30-day all-cause mortality (25%, six out of 24) compared to AEMT (56.8%, 42 out of 74; P = 0.007). Multivariate Cox regression analysis indicated AECT as the only factor significantly associated with improved survival (aHR 0.30; 95% CI 0.12–0.71; P = 0.006). By contrast, the use of monotherapy or combination therapy in the definitive regimen did not influence mortality (aHR 0.73; 95% CI 0.25–2.14; P = 0.568).

Conclusions

AECT may be associated with reduced mortality compared to monotherapy in septic shock patients due to P. aeruginosa BSI. However, the administration of definitive adequate monotherapy or combination therapy yields similar outcomes, suggesting that once susceptibility is documented, switching to a single active in vitro drug is safe and feasible. Further studies are recommended to validate these findings.
Activity of antibiotics against Burkholderia cepacia complex in artificial sputum medium
Authors: Shukla Anusha , Rodriguez Shade , Brennan-Krohn Thea
Published: September 2024

Background

Burkholderia cepacia complex (Bcc) is a collection of intrinsically drug-resistant Gram-negative bacteria that cause life-threatening disease in people with cystic fibrosis (CF). Standard antimicrobial susceptibility testing methods have poor predictive value for clinical outcomes in Bcc infections, probably due in part to differences between in vitro testing conditions and the environment in which Bcc grow in the lungs of people with CF.

Objectives

To compare the activity of commonly used antibiotics under standard in vitro testing conditions with activity in conditions mimicking those found in vivo.

Methods

Two Bcc strains were grown alone and with six different antibiotics (minocycline, ceftazidime, meropenem, tobramycin, levofloxacin, trimethoprim-sulfamethoxazole) in two different media: standard cation-adjusted Mueller–Hinton broth and an artificial sputum medium designed to simulate the environment in the lungs of people with CF through addition of components including mucin, free DNA and amino acids. Two different starting conditions were used for time–kill assays: a standard ∼5 × 106 cfu/mL inoculum, and a high-density inoculum in which bacteria were grown for 72 hours before addition of antibiotics. Growth detection was performed by colony enumeration and by detection of resazurin reduction.

Results

There were major discrepancies between standard susceptibility results and activity in our models. Some antibiotics, including ceftazidime, showed minimal activity in all time–kill assays despite low minimal inhibitory concentrations, while others, notably tobramycin, were more active in high-density growth conditions than in standard time–kill assays.

Conclusions

This work underscores the urgent need to develop more clinically relevant susceptibility testing approaches for Bcc.
Bacterial persistence to antibiotics activated by tRNA mutations
Authors: Park Jongwook , Lee Dongju , Yi Hyojeong , Yun Cheol-Won , Kim Heenam Stanley
Published: September 2024

Objectives

Bacterial persistence is a significant cause of the intractability of chronic and relapsing infections. Despite its importance, many of the underlying mechanisms are still not well understood.

Methods

Antibiotic-tolerant mutants of Burkholderia thailandensis were isolated through exposure to lethal doses of AMP or MEM, followed by whole-genome sequencing to identify mutations. Subsequently, these mutants underwent comprehensive characterization via killing curves, growth curves, and persistence-fraction plots. Northern blot analysis was employed to detect uncharged tRNA, while the generation of relA and spoT null mutations served to confirm the involvement of the stringent response in this persistence mechanism. Phenotypic reversion of the persistence mutation was demonstrated by incubating the mutants without antibiotics for 2 weeks.

Results

We have discovered a novel mechanism of persistence triggered by specific mutations at positions 32 or 38 within the anticodon loop of tRNAAsp. This leads to heightened persistence through a RelA-dependent stringent response. Notably, this persistence can be easily reverted to wild-type physiology by losing the mutant tRNA allele within the tRNA gene cluster when persistence is no longer essential for survival.

Conclusions

This distinct form of persistence underscores the novel function of tRNA mutations at positions 32 or 38 within the anticodon loop, as well as the significance of the tRNA gene cluster in conferring adaptability to regulate persistence for enhanced survival.
Foundation model-driven distributed learning for enhanced retinal age prediction
Authors: Nielsen Christopher , Souza Raissa , Wilms Matthias , Forkert Nils D
Published: September 2024

Objectives

The retinal age gap (RAG) is emerging as a potential biomarker for various diseases of the human body, yet its utility depends on machine learning models capable of accurately predicting biological retinal age from fundus images. However, training generalizable models is hindered by potential shortages of diverse training data. To overcome these obstacles, this work develops a novel and computationally efficient distributed learning framework for retinal age prediction.

Materials and Methods

The proposed framework employs a memory-efficient 8-bit quantized version of RETFound, a cutting-edge foundation model for retinal image analysis, to extract features from fundus images. These features are then used to train an efficient linear regression head model for predicting retinal age. The framework explores federated learning (FL) as well as traveling model (TM) approaches for distributed training of the linear regression head. To evaluate this framework, we simulate a client network using fundus image data from the UK Biobank. Additionally, data from patients with type 1 diabetes from the UK Biobank and the Brazilian Multilabel Ophthalmological Dataset (BRSET) were utilized to explore the clinical utility of the developed methods.

Results

Our findings reveal that the developed distributed learning framework achieves retinal age prediction performance on par with centralized methods, with FL and TM providing similar performance (mean absolute error of 3.57 ± 0.18 years for centralized learning, 3.60 ± 0.16 years for TM, and 3.63 ± 0.19 years for FL). Notably, the TM was found to converge with fewer local updates than FL. Moreover, patients with type 1 diabetes exhibited significantly higher RAG values than healthy controls in all models, for both the UK Biobank and BRSET datasets (P < .001).

Discussion

The high computational and memory efficiency of the developed distributed learning framework makes it well suited for resource-constrained environments.

Conclusion

The capacity of this framework to integrate data from underrepresented populations for training of retinal age prediction models could significantly enhance the accessibility of the RAG as an important disease biomarker.
Cost of medical care for malignant brain tumors at hospitals in the Japan Clinical Oncology Group brain-tumor study group
Authors: Motomura Kazuya , Sasaki Keita , Sugii Narushi , Yamaguchi Shigeru , Inoue Hirotaka , Oshima Akito , Tanaka Kazuhiro , Otani Yoshihiro , Shirahata Mitsuaki , Shibahara Ichiyo , Nagane Motoo , Tsuzuki Shunsuke , Matsutani Tomoo , Tsukamoto Yoshihiro , Kijima Noriyuki , Asano Kenichiro , Ohno Makoto , Inoue Akihiro , Mineharu Yohei , Miyake Keisuke , Mitobe Yuta , Hanihara Mitsuto , Kawanishi Yu , Deguchi Shoichi , Saito Masato , Matsuda Ryosuke , Ujifuku Kenta , Arita Hideyuki , Sato Yuichi , Yamashita Shinji , Yonezawa Ushio , Yamaguchi Junya , Momii Yasutomo , Ogawa Takahiro , Kambe Atsushi , Ohba Shigeo , Fukai Junya , Saito Norihiko , Kinoshita Masashi , Sumi Koichiro , Otani Ryohei , Uzuka Takeo , Takebe Noriyoshi , Koizumi Shinichiro , Saito Ryuta , Arakawa Yoshiki , Narita Yoshitaka ,   the Members of Japan Clinical Oncology Group Brain Tumor Study Group (JCOG-BTSG)
Published: September 2024

Background

This study aimed to investigate what treatment are selected for malignant brain tumors, particularly glioblastoma (GBM) and primary central nervous system lymphoma (PCNSL), in real-world Japan and the costs involved.

Methods

We conducted a questionnaire survey regarding treatment selections for newly diagnosed GBM and PCNSL treated between July 2021 and June 2022 among 47 institutions in the Japan Clinical Oncology Group-Brain Tumor Study Group. We calculated the total cost and cost per month of the initial therapy for newly diagnosed GBM or PCNSL.

Results

The most used regimen (46.8%) for GBM in patients aged ≤74 years was ‘Surgery + radiotherapy concomitant with temozolomide’. This regimen’s total cost was 7.50 million JPY (Japanese yen). Adding carmustine wafer implantation (used in 15.0%), TTFields (used in 14.1%), and bevacizumab (BEV) (used in 14.5%) to the standard treatment of GBM increased the cost by 1.24 million JPY for initial treatment, and 1.44 and 0.22 million JPY per month, respectively. Regarding PCNSL, ‘Surgery (biopsy) + rituximab, methotrexate, procarbazine, and vincristine (R-MPV) therapy’ was the most used regimen (42.5%) for patients of all ages. This regimen incurred 1.07 million JPY per month. The three PCNSL regimens based on R-MPV therapy were in ultra-high-cost medical care (exceeding 1 million JPY per month).

Conclusions

Treatment of malignant brain tumors is generally expensive, and cost-ineffective treatments such as BEV are frequently used. We believe that the results of this study can be used to design future economic health studies examining the cost-effectiveness of malignant brain tumors.
Real-world safety of nivolumab in patients with malignant pleural mesothelioma in Japan: post-marketing surveillance study
Authors: Fujimoto Nobukazu , Akamatsu Ayumi , Honda Chikara , Aoki Miki , Ohe Yuichiro
Published: September 2024

Objective

This post-marketing surveillance (PMS) was conducted to evaluate the incidence of adverse events with nivolumab in patients with unresectable, advanced or recurrent malignant pleural mesothelioma (MPM) that had progressed after first-line chemotherapy and to identify factors that potentially affected its safety in real-world clinical practice.

Methods

Patients who had not received nivolumab previously were registered between November 2018 and February 2021. Nivolumab was given intravenously 240 mg every 2 weeks or 480 mg every 4 weeks. Patients were followed up for 6 months after treatment initiation. Information on patient characteristics, treatment status, and adverse events was collected.

Results

This PMS enrolled 124 patients, involving 48 sites across Japan. At 6 months, nivolumab therapy was ongoing in 35.5% of patients (44/124) and had been discontinued in 64.5% (80/124). The overall incidence of treatment-related adverse events (TRAEs) was 40.3%; the incidence of Grade 3 or higher TRAEs was 12.9%. The pattern of TRAEs based on System Organ Class categories was generally consistent with those seen in the Japanese phase II MERIT study. The most common Grade 3 or higher TRAEs were interstitial lung disease (2.4%), lung disorder, and diarrhea (each 1.6%). The incidence of TRAEs was significantly higher in inpatients or patients who had good PS, high bodyweight, high body mass index, or autoimmune diseases than in those without these characteristics.

Conclusion

The post-marketing incidence of TRAEs with nivolumab in patients with MPM has been evaluated, and no new safety signals were identified compared to the phase II clinical trial in Japan.
Future Lives and Deaths with Purpose: Perspectives on Capacity, Character, and Intent
Authors: Maples Caitlin
Published: September 2024

The articles in this issue of the Journal of Medicine and Philosophy explore emerging technologies, medical innovations, and shifting moral norms, expanding present discussions around topics in bioethics both old and new. Some question whether novel definitions of death and harm change the moral permissibility of killing, particularly at the hands of a physician. Others question how increased or decreased abilities affect responsibility and achievement. Another illustrates how rhetorical appeals to character have been used to justify otherwise morally illicit actions within the clinic. Together, these articles shed new light on topics in the field of bioethics.
ID Consultant: Laboratory Monitoring During Long-Term Use of Oral Antimicrobials in Pediatric Patients
Authors: Downes Kevin J , Alemayehu Tinsae , Ashkenazi-Hoffnung Liat
Published: September 2024

Oral antimicrobials remain the mainstay of long-term treatment for many infections. Meanwhile, the use of oral agents is becoming commonplace for the treatment of several pediatric infections once managed exclusively with parenteral therapies. Unfortunately, antimicrobials are associated with several laboratory toxicities, particularly when high doses or combination therapies are used, but there is a paucity of data on optimal laboratory monitoring strategies. In this ID Consultant article, we offer a summary of the 3 most common laboratory-based toxicities seen with long-term use of oral antimicrobials—drug-induced kidney injury, liver injury, and hematological toxicities—and we provide our recommended approach to monitoring.
Linear β-1,2-glucans trigger immune hallmarks and enhance disease resistance in plants
Authors: Fuertes-Rabanal María , Largo-Gosens Asier , Fischer Alicia , Munzert Kristina S , Carrasco-López Cristian , Sánchez-Vallet Andrea , Engelsdorf Timo , Mélida Hugo
Published: September 2024

Immune responses in plants are triggered by molecular patterns or elicitors, recognized by plant pattern recognition receptors. Such molecular patterns are the consequence of host–pathogen interactions, and the response cascade activated after their perception is known as pattern-triggered immunity (PTI). Glucans have emerged as key players in PTI, but the ability of certain glucans to stimulate defensive responses in plants remains understudied. This work focused on identifying novel glucan oligosaccharides as molecular patterns. The ability of various microorganism-derived glucans to trigger PTI responses was tested, revealing that specific microbial-derived molecules, such as short linear β-1,2-glucans, trigger this response in plants by increasing the production of reactive oxygen species (ROS), mitogen-activated protein kinase phosphorylation, and differential expression of defence-related genes in Arabidopsis thaliana. Pre-treatments with β-1,2-glucan trisaccharide (B2G3) improved Arabidopsis defence against bacterial and fungal infections in a hypersusceptible genotype. The knowledge generated was then transferred to the monocotyledonous model species maize and wheat, demonstrating that these plants also respond to β-1,2-glucans, with increased ROS production and improved protection against fungal infections following B2G3 pre-treatments. In summary, as with other β-glucans, plants perceive β-1,2-glucans as warning signals which stimulate defence responses against phytopathogens.
Atmospheric ion escape and solar wind deposition as a function of planetary radius
Authors: Hinton P C , Brain D A , Schnepf N R , Jarvinen R , Ramstad R
Published: September 2024

We explore the ability of an unmagnetized planet to retain an atmosphere as a function of its radius. We use a particle-in-cell hybrid code to simulate the global plasma interaction of unmagnetized terrestrial planets at 1 au under average solar wind conditions. We vary the radius of the planet $(R_\mathrm{ p})$ from Mars-sized ($3390 \ \mathrm{km}$) to super-Earth-sized ($9390 \ \mathrm{km}$). We inject hydrogen and oxygen ion outflows from the ionosphere and quantify how the ion escape, recirculation, solar wind deposition, and net atmospheric mass flux vary as a function of planetary radius. We find that as the radius and the corresponding ionospheric outflow rate are varied, the fraction of outflowing $\mathrm{ H^+}$ that escapes remains at $15.5\pm 1.0{{\ \rm per\, cent}}$, while the rest recirculates back towards the planet. The fraction of produced $\mathrm{ O^+}$ that escapes from a Mars-sized planet is $27\pm 1{{\ \rm per\, cent}}$, and decreases to $7\pm 1{{\ \rm per\, cent}}$ for super-Earth, suggesting that smaller planets are less able to retain heavy ions. We find, however, that larger planets have lower solar wind deposition fractions because their bow shocks are at greater distances from the surface of the planet. The ionospheric outflow rate at which mass deposition is equal to mass escape is found to be proportional to $R_\mathrm{ p}^2$. Lastly, we propose that the bulk gyration of the solar wind at the induced magnetosphere can lead to differential escape trajectories of light and heavy ions.
Light-curve analysis and shape models of NEAs 7335, 7822, 154244, and 159402
Authors: Rodríguez Rodríguez Javier , Díez Alonso Enrique , Iglesias Álvarez Santiago , Pérez Fernández Saúl , Buendia Roca Alejandro , Fernández Díaz Julia , Licandro Javier , Alarcon Miguel R , Serra-Ricart Miquel , Pinilla-Alonso Noemi , de Cos Juez Francisco Javier
Published: September 2024

In an attempt to further characterize the near-Earth asteroid (NEA) population, we present 38 new light curves acquired between 2020 September and 2023 November for NEAs (7335) 1989 JA, (7822) 1991 CS, (154244) 2002 KL6, and (159402) 1999 AP10, obtained from observations taken at the Teide Observatory (Tenerife, Spain). With these new observations along with archival data, we computed their first shape models and spin solutions by applying the light-curve inversion method. The obtained rotation periods are in good agreement with those reported in previous works, with improved uncertainties. Additionally, besides the constant period models for (7335) 1989 JA, (7822) 1991 CS, and (159402) 1999 AP10, our results for (154244) 2002 KL6 suggest that it could be affected by a Yarkovsky–O’Keefe–Radzievskii–Paddack acceleration with a value of $\upsilon \simeq -7\times 10^{-9}$ rad d$^{-2}$. This would be one of the first detections of this effect slowing down an asteroid.
Eukaryotic initiation factor 4B is a multi-functional RNA binding protein that regulates histone mRNAs
Authors: Quintas Ana , Harvey Robert F , Horvilleur Emilie , Garland Gavin D , Schmidt Tobias , Kalmar Lajos , Dezi Veronica , Marini Alberto , Fulton Alexander M , Pöyry Tuija A A , Cole Cameron H , Turner Martin , Sawarkar Ritwick , Chapman Michael A , Bushell Martin , Willis Anne E
Published: September 2024

RNA binding proteins drive proliferation and tumorigenesis by regulating the translation and stability of specific subsets of messenger RNAs (mRNAs). We have investigated the role of eukaryotic initiation factor 4B (eIF4B) in this process and identify 10-fold more RNA binding sites for eIF4B in tumour cells from patients with diffuse large B-cell lymphoma compared to control B cells and, using individual-nucleotide resolution UV cross-linking and immunoprecipitation, find that eIF4B binds the entire length of mRNA transcripts. eIF4B stimulates the helicase activity of eIF4A, thereby promoting the unwinding of RNA structure within the 5′ untranslated regions of mRNAs. We have found that, in addition to its well-documented role in mRNA translation, eIF4B additionally interacts with proteins associated with RNA turnover, including UPF1 (up-frameshift protein 1), which plays a key role in histone mRNA degradation at the end of S phase. Consistent with these data, we locate an eIF4B binding site upstream of the stem–loop structure in histone mRNAs and show that decreased eIF4B expression alters histone mRNA turnover and delays cell cycle progression through S phase. Collectively, these data provide insight into how eIF4B promotes tumorigenesis.
The Effect of Chia Seed on Blood Pressure, Body Composition, and Glycemic Control: A GRADE-Assessed Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials
Authors: TaghipourSheshdeh Faranak , Behzadi Mehrdad , Bashiri Sara , Mohammadi-Sartang Mohsen
Published: September 2024

Context

Numerous studies have demonstrated the positive effects on metabolic factors of consuming chia seeds. However, the results of clinical trials have been inconsistent.

Objective

The aim of this study was to conduct a systematic review and meta-analysis of available randomized controlled trials to explore the effects of chia seed consumption on body weight (BW), body composition, blood pressure, and glycemic control.

Data Sources

A comprehensive search was conducted on the Scopus, PubMed, Medline via Ovid, ISI Web of Science, and Scholar Google databases up to August 2023.

Data Extraction

The outcomes of interest included systolic blood pressure (SBP), diastolic blood pressure (DBP), BW, body mass index (BMI), body fat percentage, waist circumference (WC), fasting blood glucose (FBG), and hemoglobin A1c (HbA1c).

Data Analysis

Weighted mean difference (WMD) and 95% CIs were used to determine the effect size.

Results

A total of 8 eligible studies were included in the analysis. The findings revealed a significant reduction in SBP (WMD: −7.19 mmHg; 95% CI, −10.63 to −3.73; P < .001) and DBP (WMD: −6.04 mmHg, 95% CI, −9.58 to −2.49; P = .001). However, no significant effects were observed on BW, body fat percentage, WC, BMI, FBG, and HbA1c. Subgroup analysis indicated that the effect of chia seed on SBP was significant in participants with a baseline SBP of less than 140 mmHg, but the effect was not dependent on the administered dose.

Conclusion

Chia seed consumption has positive effects on SBP and DBP but does not significantly impact BW, body composition, or glycemic parameters. However, the limited amount of data from included studies should be considered as a limitation while interpreting these findings.

Systematic Review Registration

PROSPERO registration no. CRD42023462575.
Phosphorylation of CRYAB Induces a Condensatopathy to Worsen Post-Myocardial Infarction Left Ventricular Remodeling
Authors: Islam Moydul , Rawnsley David R. , Ma Xiucui , Navid Walter , Zhao Chen , Foroughi Layla , Murphy John T. , Navid Honora , Weinheimer Carla J. , Kovacs Attila , Nigro Jessica , Diwan Aaradhya , Chang Ryan , Kumari Minu , Young Martin E. , Razani Babak , Margulies Kenneth B. , Abdellatif Mahmoud , Sedej Simon , Javaheri Ali , Covey Douglas F. , Mani Kartik , Diwan Abhinav
Published: September 2024

Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart failure syndromes remains mechanistically unexamined. We observed mis-localization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post-myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by R120G mutation in the cognate chaperone protein, CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine-59 to NP40-insoluble aggregate-rich biochemical fraction. While CRYAB undergoes phase separation to form condensates, the phospho-mimetic mutation of serine-59 to aspartate (S59D) in CRYAB mimics R120G-CRYAB mutants with reduced condensate fluidity, formation of protein aggregates and increased cell death. Conversely, changing serine to alanine (phosphorylation-deficient mutation) at position 59 (S59A) restored condensate fluidity, and reduced both R120G-CRYAB aggregates and cell death. In mice, S59D CRYAB knock-in was sufficient to induce desmin mis-localization and myocardial protein aggregates, while S59A CRYAB knock-in rescued left ventricular systolic dysfunction post-myocardial infarction and preserved desmin localization with reduced myocardial protein aggregates. 25-Hydroxycholesterol attenuated CRYAB serine-59 phosphorylation and rescued post-myocardial infarction adverse remodeling. Thus, targeting CRYAB phosphorylation-induced condensatopathy is an attractive strategy to counter ischemic cardiomyopathy.
Electrospun Fiber Surface Roughness Modulates Human Monocyte-Derived Macrophage Phenotype
Authors: Alemifar Aidan , Burnette KaLia , Jandres Bryan , Hurt Samuel , Tse Hubert M. , Robinson Jennifer L.
Published: September 2024

Injuries to fibrous connective tissues have very little capacity for self-renewal and exhibit poor healing after injury. Phenotypic shifts in macrophages play a vital role in mediating the healing response, creating an opportunity to design immunomodulatory biomaterials which control macrophage polarization and promote regeneration. In this study, electrospun poly(-caprolactone) fibers with increasing surface roughness (SR) were produced by increasing relative humidity and inducing vapor-induced phase separation during the electrospinning process. The impact of surface roughness on macrophage phenotype was assessed using human monocyte-derived macrophagesin vitroandin vivousing B6.Cg-Tg(Csf1r-EGFP)1Hume/J (MacGreen) mice.In vitroexperiments showed that macrophages cultured on mesh with increasing SR exhibited decreased release of both pro- and anti-inflammatory cytokines potentially driven by increased protein adsorption and biophysical impacts on the cells. Further, increasing SR led to an increase in the expression of the pro-regenerative cell surface marker CD206 relative to the pro-inflammatory marker CD80. Mesh with increasing SR were implanted subcutaneously in MacGreen mice, again showing an increase in the ratio of cells expressing CD206 to those expressing CD80 visualized by immunofluorescence. SR on implanted biomaterials is sufficient to drive macrophage polarization, demonstrating a simple feature to include in biomaterial design to control innate immunity.

GRAPHICAL ABSTRACT
Bibliometric Analysis of Circular RNA Cancer Vaccines and Their Emerging Impact
Authors: Das Uddalak , Banerjee Soupayan , Sarkar Meghna
Published: September 2024

Circular RNA (circRNA) vaccines are emerging as a revolutionary strategy in cancer immunotherapy, offering novel mechanisms for inducing robust and durable immune responses. Unlike traditional linear mRNA vaccines, circRNAs exhibit exceptional stability, enhanced translational efficiency, and resistance to exonuclease degradation, making them ideal candidates for vaccine development. Recent studies have shown that circRNA vaccines play an important and specialized role in cancer treatment. However, there are currently no relevant bibliometric studies. This study aimed to apply bibliometrics and scientometrics to summarize the knowledge structure and research hotspots regarding the role of circRNA vaccines in cancer. Publications related to circRNA vaccines in cancer were searched on the Scopus database. VOSviewer and Scopus were used to conduct the analyses. This study summarizes the research trends and development of circRNA vaccines for cancer and also a comparative analysis between mRNA cancer vaccine and circRNA cancer vaccine identifying potential areas of focus, innovation and growth. This information will provide a reference for researchers to studying circRNA vaccines against cancer due to its increasing trends over recent times.
Organoid Modeling and Single-Cell Profiling Uncover the Migration Mechanism of Smooth Muscle Cells in Moyamoya Disease
Authors: He Shihao , Zhang Junze , Wang Xilong , Qi Zhen , Zhou Zhenyu , Wang Yanru , Xu Shaoqi , Li Dandan , Ye Xun , Liu Ziqi , Hao Xiaokuan , Zhao Yuanli , Wang Rong
Published: September 2024

Moyamoya disease (MMD) is a chronic cerebrovascular disorder characterized by progressive occlusion of the intracranial arteries, resulting in severe ischemic or hemorrhagic stroke. The main characteristic of the affected vessels in MMD is arterial intimal thickening. However, there are no in vitro or in vivo models that can mimic its vascular characteristics. Moreover, the mechanisms underlying the intimal thickening remain unexplained. Here, we generated vascular organoids by differentiating human induced pluripotent stem cell derived from the peripheral blood of MMD patients, thereby creating an organoid model reflecting both the genetic background and characteristics of the affected vessels. Through single-cell sequencing, we found the increased vascular smooth muscle cell (VSMC) proportion and its functional abnormalities in MMD organoids. Proteomics and RNA sequencing identified abnormal TUBA4A and TUBB4B overexpression in both the organoids and patient serum. The following in vitro experiments demonstrated that TUBA4A and TUBB4B promote the contractile-to-synthetic phenotypic switching, migration and proliferation in VSMC. Further experiments identified the GJA1-mediated PI3K/AKT/KLF4 pathway as a key regulating pathway of these phenotypic changes in VSMCs. Our findings demonstrate that the abnormal expression of TUBA4A and TUBB4B in VSMC might be a significant contributor to the intimal thickening in the affected vessels of MMD.
Melastatin subfamily Transient Receptor Potential channels support spermatogenesis in planarian flatworms
Authors: Curry Haley Nicole , Huynh Roger , Rouhana Labib
Published: September 2024

The Transient Receptor Potential superfamily of proteins (TRPs) form cation channels that are abundant in animal sensory systems. Amongst TRPs, the Melastatin-related subfamily (TRPMs) is composed of members that respond to temperature, pH, sex hormones, and various other stimuli. Some TRPMs exhibit enriched expression in gonads of vertebrate and invertebrate species, but their contributions to germline development remain to be determined. We identified twenty-one potential TRPMs in the planarian flatwormSchmidtea mediterraneaand analyzed their anatomical distribution of expression by whole-mountin situhybridization. Enriched expression of two TRPMs (Smed-TRPM-candSmed-TRPM-l) was detected in testis, whereas eight TRPM genes had detectable expression in patterns representative of neuronal and/or sensory cell types. Functional analysis of TRPM homologs by RNA-interference (RNAi) revealed that disruption ofSmed-TRPM-cexpression results in reduced sperm development, indicating a role for this receptor in supporting spermatogenesis.Smed-TRPM-lRNAi did not result in a detectable phenotype, but it increased sperm development deficiencies when combined withSmed-TRPM-cRNAi. Fluorescencein situhybridization revealed expression ofSmed-TRPM-cin early spermatogenic cells within testes, suggesting cell-autonomous regulatory functions in germ cells for this gene. In addition,Smed-TRPM-cRNAi resulted in reduced numbers of presumptive germline stem cell clusters in asexual planarians, suggesting thatSmed-TRPM-csupports establishment, maintenance, and/or expansion of spermatogonial germline stem cells. While further research is needed to identify the factors that trigger Smed-TRPM-c activity, these findings reveal one of few known examples for TRPM function in direct regulation of sperm development.
A Novel Gene Synthesis Platform for Designing Functional Protein Polymers
Authors: Homma Toshimasa , Yamamoto Rie , Ang Lily Zuin Ping , Fehaid Alaa , Ebara Mitsuhiro
Published: September 2024

Recombinant protein polymers with repeat sequences of specific amino acids can be regarded as sustainable functional materials that can be designed using genetic engineering. However, synthesizing genes encoding these proteins is significantly time-consuming and labor-intensive owing to the difficulty of using common gene synthesis tools, such as restriction enzymes and PCR primers. To overcome these obstacles, we propose a novel method: seamless cloning of rolling-circle amplicons (SCRCA). This method involves one-pot preparation of repetitive-sequence genes with overlapping ends for cloning, facilitating the easy construction of the desired recombinants. Using SCRCA, we synthesized 10 genes encoding hydrophilic resilin-like and hydrophobic elastin-like repeat units that induce liquid–liquid phase separation. SCRCA shows higher transformation efficiency and better workability than conventional methods, and the time and budget required for SCRCA are comparable to those required for non-repetitive-sequence gene synthesis. Additionally, SCRCA allows the construction of a repeat unit library at a low cost. The library shows considerably higher diversity compared with that of the state-of-the-art method. By combining this library construction with the directed evolution concept, we can rapidly develop an elastin-like protein polymer with a desired function. SCRCA can greatly accelerate research on protein polymers.
Structural Adaptations of HepI Enzymes in Proteobacteria: Insights into Evolutionary Resilience and Functional Dynamics
Authors: Gupta Aayatti Mallick , Butelman June W. , Hassan Bakar A. , Arevalo Philip , Taylor Erika Anne
Published: September 2024

Since lipopolysaccharide molecules are highly variable in their structure while also being essential for bacterial cell survival, we hypothesized that enzymes involved in its biosynthesis may exhibit differences that could be used to predict the likelihood of survival in different ecological niches. We examined the sequence variability of orthologues of Heptosyltransferase I (HepI), which is found in all lipopolysaccharide (LPS) containing Gram-negative bacteria. We identified two different sequence motifs within the N-terminal domain of HepI, which correlated with differences in the Lipid A portion of the LPS. Further, we compared the protein structure of HepI fromEscherichia coliwith a structural model we generated that incorporated the alternate sequence motif. Molecular dynamics simulations of these two proteins, recapitulated our findings, that proteins with theE. coli-like sequence motif maintained a larger enzyme active site, while the mutated structural model undergoes rearrangements that lead to a smaller N-terminal active site pocket. This work revealed sequence-structure-function relationships that can be used to determine if a species incorporates a Heptose residue onto Lipid A chains containing one or two 3-deoxy-D-manno-oct-2-ulosonic acid (Kdo) residues. Since research suggests that the number of Kdo residues in LPS impacts the overall immune response to the LPS endotoxin, this work could aid in our understanding of the pathogenic effects of human-bacterial interactions. Understanding the sequence-structural adaptations of HepI enzymes across proteobacteria sheds light on their evolutionary resilience and functional versatility.

Highlights

Lipopolysaccharide (LPS) structure varies between organisms

Heptosytransferase I sequence motifs allow prediction of LPS structural features

Adaptations of HepI enzymes reveal evolutionary resilience and functional versatility