bluuebunny/crossref_metadata_2025_split huggingface dataset:
Saccharomyces cerevisiae
biofactory to produce naringenin using a systems biology approach and a bicistronic vector expression strategy in flavonoid production
Authors: Mejía-Manzano Luis Alberto , Ortiz-Alcaráz César Iván , Parra Daza Laura E. , Suarez Medina Lina , Vargas-Cortez Teresa , Fernández-Niño Miguel , González Barrios Andrés Fernando , González-Valdez José 
Published: December 2023

ABSTRACT

Naringenin is the central flavonoid in the biosynthesis of several bioactive compounds and presents a growing demand for its nutraceutical properties. Naringenin extraction from plants is non-viable due to low yields, and microbial platforms could represent a controlled and sustained alternative to produce it using several metabolic engineering tools. This study shows the naringenin production in
Saccharomyces cerevisiae
from glucose through a combined approach of systems biology, enzyme criteria selection, and a molecular engineering strategy.
In silico
prediction using a mixed integer linear programming (MILP) algorithm showed that the phenylpropanoid pathway was the shortest and most viable metabolic pathway. Two biscistronic constructs were generated using the PTV-1 2A peptide sequence, and a naringenin biofactory was assembled with the phenylalanine ammonia-lyase/tyrosine ammonia-lyase genes encoding phenylalanine/tyrosine ammonia-lyase (
Rhodobacter capsulatus
), 4-coumaroyl (4 Cl) encoding a
p
-coumaroyl-CoA ligase (
Solanum lycopersicum
), CHS encoding chalcone synthase (
Hypericum androsaemum
), and CHI encoding a chalcone isomerase (
Glycine max
). Naringenin productivity in batch fermentation was about 40.67 ± 3.47 µg/Lh with a 6.10 ± 0.52 mg/L titer (22.41 ± 1.91 µM) and a 3.26 ± 1.36 mg/g yield (
Y

P
/
S

) with the detection of additional flavonoids. The obtained concentration is better than other related works in diverse engineered microorganisms. The results suggest a successful and optimizable alternative for the heterologous flavanone production in yeast combined with bicistronic expression mediated by a 2A peptide sequence for the first time. This strategy supports the production of extensive routes for other nutraceutical compounds.

IMPORTANCE

Flavonoids are a group of compounds generally produced by plants with proven biological activity, which have recently beeen recommended for the treatment and prevention of diseases and ailments with diverse causes. In this study, naringenin was produced in adequate amounts in yeast after
in silico
design. The four genes of the involved enzymes from several organisms (bacteria and plants) were multi-expressed in two vectors carrying each two genes linked by a short viral peptide sequence. The batch kinetic behavior of the product, substrate, and biomass was described at lab scale. The engineered strain might be used in a more affordable and viable bioprocess for industrial naringenin procurement.
Ectopic BH3-Only Protein Bim Associates with Hsp70 to Regulate Yeast Mitophagy
Authors: Yuan Linjie , Wang Yuying , Margulis B. A. , Song Ting , Wang Ziqian , Zhang Zhichao 
Published: December 2023

Abstract
Mitophagy, a form of selective autophagy, plays an essential role to maintain a population of healthy and functional mitochondria for normal cellular metabolism. Acting mainly as one of the B-cell lymphoma 2 (Bcl-2) family pro-apoptotic members, Bim (also known as BCL2L11) was identified to be a co-chaperone of Hsp70 to promote mitophagy in mammalian cells. Herein, with the help of a specific Hsp70/Bim disruptor and Om45-GFP processing assay, we illustrated that ectopic BimEL is able to promote mitophagy through Hsp70/Bim interaction in yeast, where Bax/Bak is absent. The Hsp70/Bim-mediated mitophagy is conserved in eukaryotes, from yeast to humans.
A Dysfunctional T-cell Gene Signature for Predicting Nonresponse to PD-1 Blockade in Non–small Cell Lung Cancer That Is Suitable for Routine Clinical Diagnostics
Authors: Hummelink Karlijn , Tissier Renaud , Bosch Linda J.W. , Krijgsman Oscar , van den Heuvel Michel M. , Theelen Willemijn S.M.E. , Damotte Diane , Goldwasser François , Leroy Karen , Smit Egbert F. , Meijer Gerrit A. , Thommen Daniela S. , Monkhorst Kim 
Published: December 2023

Abstract

Purpose:
Because PD-1 blockade is only effective in a minority of patients with advanced-stage non–small cell lung cancer (NSCLC), biomarkers are needed to guide treatment decisions. Tumor infiltration by PD-1T tumor-infiltrating lymphocytes (TIL), a dysfunctional TIL pool with tumor-reactive capacity, can be detected by digital quantitative IHC and has been established as a novel predictive biomarker in NSCLC. To facilitate translation of this biomarker to the clinic, we aimed to develop a robust RNA signature reflecting a tumor's PD-1T TIL status.

Experimental Design:
mRNA expression analysis using the NanoString nCounter platform was performed in baseline tumor samples from 41 patients with advanced-stage NSCLC treated with nivolumab that were selected on the basis of PD-1T TIL infiltration by IHC. Samples were included as a training cohort (n = 41) to develop a predictive gene signature. This signature was independently validated in a second cohort (n = 42). Primary outcome was disease control at 12 months (DC 12 m), and secondary outcome was progression-free and overall survival.

Results:
Regularized regression analysis yielded a signature using 12 out of 56 differentially expressed genes between PD-1T IHC-high tumors from patients with DC 12 m and PD-1T IHC-low tumors from patients with progressive disease (PD). In the validation cohort, 6/6 (100%) patients with DC 12 m and 23/36 (64%) with PD were correctly classified with a negative predictive value (NPV) of 100% and a positive predictive value of 32%.

Conclusions:
The PD-1T mRNA signature showed a similar high sensitivity and high NPV as the digital IHC quantification of PD-1T TIL. This finding provides a straightforward approach allowing for easy implementation in a routine diagnostic clinical setting.
Daily Physical Activity Measured by Wearable Smartwatch for Patients Undergoing Transcatheter Aortic Valve Replacement: Insights From the SMART TAVR Study
Authors: Fan Jiaqi , Liu Qiong , Dai Hanyi , Zhou Dao , Guo Yuchao , Xu Jianguo , Wang Lihan , Hu Po , Jiang Jubo , Lin Xinping , Li Cheng , Liu Xianbao , Wang Jian’an 
Published: December 2023

BACKGROUND:
This study aims to evaluate limited data about daily physical activity patterns, influential factors, and their association with 1-year mortality or rehospitalization after transcatheter aortic valve replacement (TAVR) through smartwatches.

METHODS:
Consecutive severe aortic stenosis patients undergoing elective transfemoral TAVR in a Chinese tertiary hospital were enrolled from July 2021 to May 2022 and received a Huawei smartwatch at least 1 day before TAVR. The primary outcome was a composite of all-cause mortality or hospital readmission within 1 year. Linear mixed-effects models were applied to determine influential factors of daily step counts, and Cox proportional hazard regression models were to estimate the association between baseline step counts within 1 month since discharge and composite outcome from months 2 to 12. The dose-response association was assessed using restricted cubic spline curves.

RESULTS:

A total of 222 participants and 59 469 valid monitoring person-day records were included (mean age, 72.7 years; 61% women). Step counts increased rapidly within the first 2 months (
P
<0.001), followed by a slower increase for those without composite outcomes (
P
=0.029) and a gradual decrease for those who developed composite outcomes (
P
<0.001). In multivariate linear mixed models, a 1-m increase in baseline 6-minute walk test and a 1-month delay after discharge were associated with 4 (95% CI, 1–7) and 170 (95% CI, 145–194) additional step counts, respectively. In restricted cubic spline analysis, the hazard ratio declined progressively until ≈5000 steps per day, after which they leveled. Below 5000 steps, the adjusted hazard ratio of composite outcome associated with each 1000-step count increase was 0.67 (0.50–0.89;
P
=0.007). However, above 5000 steps, step counts were not significantly associated with the composite outcome (
P
=0.645), with a hazard ratio of 1.12 (0.70–1.79).

CONCLUSIONS:
Daily step counts rapidly increased within the first 2 months post-TAVR. Increased physical activity was associated with a lower risk of 1-year mortality or rehospitalization after TAVR for patients with daily step counts below 5000.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT04454177.
Health equity, care access and quality in headache – part 2
Authors: Raffaelli Bianca , Rubio-Beltrán Eloísa , Cho Soo-Jin , De Icco Roberto , Labastida-Ramirez Alejandro , Onan Dilara , Ornello Raffaele , Ruscheweyh Ruth , Waliszewska-Prosół Marta , Messina Roberta , Puledda Francesca 
Published: December 2023

Abstract
Background
Headache disorders are a global public health concern affecting diverse populations. This review examines headache service organizations in low-, middle-, and high-income countries. It addresses global challenges in pharmacological headache treatment, with a focus on safety, tolerability, reproductive and child health, and outlines disparities in accessing innovative treatments worldwide.

Main body
Organized headache services are essential due to the wide prevalence and varying severity of headache disorders. The tiered headache service model is globally recognized, although its implementation varies based on financial and workforce considerations. Headache burden affects well-being, causing disability, economic challenges, and work limitations, irrespective of location or income. All nations still require improved diagnosis and treatment, and the majority of countries face obstacles including limited access, awareness, economic barriers, and inadequate health policies. Provided adequate internet availability, telemedicine could help improve health equity by expanding access to headache care, since it can offer patients access to services without lengthy waiting times or extensive travel and can provide healthcare unavailable in underserved areas due to staff shortages.
Numerous health disparities restrict global access to many headache medications, especially impacting individuals historically excluded from randomized controlled trials, such as those with cardiovascular and cerebrovascular conditions, as well as pregnant women. Furthermore, despite advancements in researching migraine treatments for young patients, the options for treatment remain limited.
Access to headache treatment relies on factors like medication availability, approval, financial coverage, and healthcare provider expertise. Inadequate public awareness leads to neglect by policymakers and undertreatment by patients and healthcare providers. Global access discrepancies are exacerbated by the introduction of novel disease-specific medications, particularly impacting Asian, African, and Latin American nations excluded from clinical trials. While North America and Europe experience broad availability of migraine treatments, the majority of countries worldwide lack access to these therapies.

Conclusions
Healthcare disparities, treatment access, and medication availability are concerning issues in headache medicine. Variations in national healthcare systems impact headache management, and costly innovative drugs are widening these gaps. Healthcare practitioners and experts should acknowledge these challenges and work towards minimizing access barriers for equitable global headache care in the future.
WLP3 Encodes the Ribosomal Protein L18 and Regulates Chloroplast Development in Rice
Authors: Lu Tao , Yin Wenjin , Zhang Yinuo , Zhu Chaoyu , Zhong Qianqian , Li Sanfeng , Wang Nuo , Chen Zhengai , Ye Hanfei , Fang Yuan , Mu Dan , Wang Yuexing , Rao Yuchun 
Published: December 2023

AbstractPlastid ribosomal proteins play a crucial role in the growth and development of plants, mainly in the gene expression and translation of key genes in chloroplasts. While some information is known about the regulatory processes of plastid ribosomal proteins in various plant species, there is limited knowledge about the underlying mechanisms in rice. In this study, ethyl methanesulfonate (EMS) mutagenesis was used to generate a new mutant called wlp3 (white leaf and panicle3), characterized by white or albino leaves and panicles, which exhibited this phenotype from the second leaf stage until tillering. Furthermore, after a certain period, the newly emerging leaves developed the same phenotype as the rice variety ZH11, while the albino leaves of wlp3 showed an incomplete chloroplast structure and significantly low chlorophyll content. A transition mutation (T to C) at position 380 was identified in the coding region of the LOC_Os03g61260 gene, resulting in the substitution of isoleucine by threonine during translation. WLP3 encodes the ribosomal L18 subunit, which is localized in the chloroplast. Complementation experiments confirmed that LOC_Os03g61260 was responsible for the albino phenotype in rice. WLP3 has high expression in the coleoptile, leaves at the three-leaf stage, and panicles at the heading stage. Compared to the wild-type (WT), wlp3 exhibited reduced chlorophyll synthesis and significantly decreased expression levels of genes associated with plastid development. Yeast two-hybrid (Y2H) analysis revealed that WLP3 interacts with other ribosomal subunits, to influence chloroplast development. These results contribute to a better understanding of the underlying molecular mechanisms of chloroplast development and plastid gene translation.
Small Papillae Regulated by SPD25 are Critical for Balancing Photosynthetic CO2 Assimilation and Water Loss in Rice
Authors: Zhu Lin , Zeng Faliang , Liang Yinpei , Wang Qi , Chen Hongwei , Feng Pulin , Fan Mingqian , Cheng Yanshuang , Wang Jiayu 
Published: December 2023

Abstract
Background
The leaf epidermis plays an important role in the transmission of light and the regulation of water and gas exchange, which influences the photosynthesis of mesophyll cells. Small papillae (SP) are one of the important structural elements of the leaf epidermis. The mechanism of the effect that small papillae have on rice leaf photosynthetic performance remains unclear.

Results
In this study, a small papilla deficient 25 (spd25) mutant was isolated from japonica rice Longjin1. Small papillae were absent on the adaxial and abaxial leaf surfaces of the spd25 mutant and the silicon and cuticular wax content in the spd25 mutant leaves decreased. Map-based cloning and functional analysis revealed that SPD25, encoding a guanine nucleotide exchange factor for Rop, is a novel allele of OsRopGEF10. The spd25 mutant showed an increased water loss rate and reduced relative water content. The lower stomatal conductance in the spd25 mutant prevented water loss but decreased the intercellular CO2 concentration and net assimilation rate. The fluorescence parameters showed that the inhibited CO2 assimilation reaction feedback regulated the photochemical electron-transfer reaction, but the performance of Photosystem II was stable. Further analysis indicated that the excess light energy absorbed by the spd25 mutant was dissipated in the form of non-photochemical quenching to avoid photodamage through the optical properties of small papillae.

Conclusions
SPD25 regulates the development of small papillae on the surface of rice leaves, which play an important role in balancing photosynthetic gas exchange and water loss. This study deepens our understanding of the physiological mechanisms by which small papillae affect photosynthetic performance.
Comorbidities in congenital heart disease: different patterns in childhood and adulthood
Authors: Ding Zhibao , Zhu Jingai , Ding Ye , Zhu Chun 
Published: December 2023

Abstract
Background
Existing studies were no exploration of the association between congenital heart disease (CHD) in children and comorbidities. This study was to assess the prevalence and number of comorbidities in CHD among children and adults, and to compare the comorbidity patterns by children and adults using association rule analysis.

Methods
Patients identified by the International Classification of Diseases, Ninth Revision (ICD‐9) code in the Medical Information Mart for Intensive Care III (MIMIC-III) 2001–2012 and MIMIC-IV 2008–2018 were included in this cross-sectional study. Association rule analysis was used to explore associations between CHD and comorbidities in children and adults using values of support (%), confidence (%), and lift.

Results
Among 60,400 eligible patients, 1.54% of adults had CHD and 0.83% of adults had CHD with at least one comorbidity, 13.79% had CHD and 12.37% had CHD with at least one comorbidity in children. The most common comorbidities were circulatory system diseases (53.78%), endocrine diseases (35.76%), and respiratory system diseases (23.46%) in adults with CHD, and the most common comorbidities were perinatal diseases (87.50%) in children with CHD. The comorbidity rate was 90.19% and 56.68% in children and adults, respectively. In children, perinatal diseases, circulatory system diseases, and endocrine diseases had the highest prevalence. The incidence of circulatory system diseases, perinatal diseases and endocrine diseases in CHD adults was confidence = 31.56%, 36.11%, and 23.23%, respectively. Perinatal diseases were common comorbidities among all CHD severity groups in children and adults.

Conclusion
The prevalence of comorbidities in children with CHD was higher than that in adults with CHD. The most common comorbidities were perinatal diseases and endocrine diseases among children and adults with CHD, respectively. Our study provided insights into comorbidity patterns in children and adults with CHD.
COVID-19- related work, managerial factors and exhaustion among general practitioners in Sweden: a cross-sectional study
Authors: Månsson Sandberg Helena , Landstad Bodil J. , Tjulin Åsa , Brulin Emma 
Published: December 2023

Abstract
Introduction
A significant number of international studies show that general practitioners (GPs) suffered from burnout when working during the COVID-19 pandemic. A Swedish study found that more than 16% of GPs had exhaustion in spring 2021. Exhaustion can be regarded as an initial stage of burnout. A knowledge gap remains on GPs´ working conditions, the impact of management during the pandemic and how it was associated with exhaustion. This study aims to explore the association between severe symptoms of exhaustion and COVID-19 pandemic-related work and managerial factors among Swedish GPs and whether managerial factors have an impact on the association between exhaustion and COVID-19-related work factors.

Methods
Cross-sectional data was drawn from the Longitudinal Occupational Health survey in Health Care Sweden (LOHHCS), which included a representative sample of practicing doctors in Sweden. The sample consisted of 6699 doctors with a response rate of 41.2%. This study constitutes a sample of doctors who reported working in primary care facilities at the time of data collection, i.e. 1013 GPs. The Burnout Assessment Tool (BAT) was used to assess severe symptoms of exhaustion. Questions were also asked about pandemic-related work and managerial factors. The data was analysed using descriptive statistics and multivariate logistic regression to identify the association between exhaustion, work and managerial factors.

Results
The multivariate analysis showed that GPs who managed COVID-19 patients were about twice as likely to report severe symptoms of exhaustion. Further, GPs who reported that management was unsupportive, provided unsatisfactory working conditions and unsatisfactory policies for patient prioritisation were between two and four times more likely to report severe symptoms of exhaustion.

Conclusions
COVID-19-related work and managerial factors had a significant impact on the mental health of GPs. Furthermore, the potentially protective effect that satisfactory management actions had on mental health was limited. In the aftermath of the COVID-19 pandemic and in preparation for future major crises that have a high impact on healthcare, there is a need to investigate the measures that can be taken to enable GPs to carry out their work, while maintaining their wellbeing.
Impact of community health workers on improving identification and primary care of hypertension among the urban poor – findings from Chhattisgarh state of India
Authors: Garg Samir , Dewangan Mukesh , Nanda Prabodh , Sahu Ashu , Xalxo Lalita , Bebarta Kirtti Kumar , Gupta Vishnu , Quereishi Mohammad Jawed , Sahu Anand Kumar , Tandan Pradeep 
Published: December 2023

Abstract
Background
Hypertension is a major health problem globally and in India. Around 60% of people with hypertension in India are not aware that they have the condition. Less than 30% of individuals with hypertension are on treatment. Existing studies have indicated that community health workers (CHWs) can play a useful role in expanding the care for hypertension. Evaluations are needed to study the impact when an intervention is implemented by the government in its existing large-scale CHW programme to improve the identification, regular follow-up and medication adherence for hypertension.

Methods
Chhattisgarh state implemented a pilot intervention to improve screening and follow-up for hypertension by equipping Mitanin-CHWs to measure blood pressure (BP). The study design involved an intervention-group and a comparison-group of urban slum population. The survey covered 5974 individuals (30–79 years age) in intervention-group and 5131 in comparison-group. Multivariate analysis was conducted to find out the effect of intervention on the desired outcomes.

Results
In intervention-group, 80.2% of the individuals (30–79 years age) had been screened for hypertension whereas the proportion was 37.9% in comparison-group. For 47.0% of individuals in intervention-group, Mitanin CHW was the provider who measured BP for the first time. Around 16.3% of individuals in intervention-group and 9.5% in comparison-group had been diagnosed with hypertension. Around 85.9% of hypertension cases in intervention-group and 77.0% in comparison-group were on treatment. BP had been measured in preceding 30 days for 81.8% of hypertension-cases in intervention-group and 64.3% in comparison-group. Around 70.3% of hypertension-cases in intervention-group and 55.1% in comparison-group had taken their complete medication for last seven days. Multivariate analysis showed that CHW intervention was associated significantly with improvements in all the desired outcomes.

Conclusion
Equipping the CHWs to measure BP was effective in increasing the screening and identification of hypertension, regular measurement of BP of individuals with hypertension and the adherence to medication. This shows the potential if the one-million strong work-force of Accredited-Social-Health-Activists (ASHA) CHWs in India gets equipped for this role. Governments need to provide a stronger policy push to get this materialised.