bluuebunny/crossref_metadata_2025 huggingface dataset:
Engineering Saccharomyces cerevisiae for targeted hydrolysis and fermentation of glucuronoxylan through CRISPR/Cas9 genome editing
Authors: Ravn Jonas L. , Manfrão-Netto João H.C. , Schaubeder Jana B. , Torello Pianale Luca , Spirk Stefan , Ciklic Iván F. , Geijer Cecilia
Published: March 2024

Background

The abundance of glucuronoxylan (GX) in agricultural and forestry residual side streams positions it as a promising feedstock for microbial conversion into valuable compounds. By engineering strains of the widely employed cell factory Saccharomyces cerevisiae with the ability to directly hydrolyze and ferment GX polymers, we can avoid the need for harsh chemical pretreatments and costly enzymatic hydrolysis steps prior to fermentation. However, for an economically viable bioproduction process, the engineered strains must efficiently express and secrete enzymes that act in synergy to hydrolyze the targeted polymers.

Results

The aim of this study was to equip the xylose-fermenting S. cerevisiae strain CEN.PK XXX with xylanolytic enzymes targeting beechwood GX. Using a targeted enzyme approach, we matched hydrolytic enzyme activities to the chemical features of the GX substrate and determined that besides endo-1,4-β-xylanase and β-xylosidase activities, α-methyl-glucuronidase activity was of great importance for GX hydrolysis and yeast growth. We also created a library of strains expressing different combinations of enzymes, and screened for yeast strains that could express and secrete the enzymes and metabolize the GX hydrolysis products efficiently. While strains engineered with BmXyn11A xylanase and XylA β-xylosidase could grow relatively well in beechwood GX, strains further engineered with Agu115 α-methyl-glucuronidase did not display an additional growth benefit, likely due to inefficient expression and secretion of this enzyme. Co-cultures of strains expressing complementary enzymes as well as external enzyme supplementation boosted yeast growth and ethanol fermentation of GX, and ethanol titers reached a maximum of 1.33 g L− 1 after 48 h under oxygen limited condition in bioreactor fermentations.

Conclusion

This work underscored the importance of identifying an optimal enzyme combination for successful engineering of S. cerevisiae strains that can hydrolyze and assimilate GX. The enzymes must exhibit high and balanced activities, be compatible with the yeast’s expression and secretion system, and the nature of the hydrolysis products must be such that they can be taken up and metabolized by the yeast. The engineered strains, particularly when co-cultivated, display robust growth and fermentation of GX, and represent a significant step forward towards a sustainable and cost-effective bioprocessing of GX-rich biomass. They also provide valuable insights for future strain and process development targets.
Affinity fine-tuning anti-CAIX CAR-T cells mitigate on-target off-tumor side effects
Authors: Wang Yufei , Buck Alicia , Piel Brandon , Zerefa Luann , Murugan Nithyassree , Coherd Christian D. , Miklosi Andras G. , Johal Haraman , Bastos Ricardo Nunes , Huang Kun , Ficial Miriam , Laimon Yasmin Nabil , Signoretti Sabina , Zhong Zhou , Hoang Song-My , Kastrunes Gabriella M. , Grimaud Marion , Fayed Atef , Yuan Hsien-Chi , Nguyen Quang-De , Thai Tran , Ivanova Elena V. , Paweletz Cloud P. , Wu Ming-Ru , Choueiri Toni K. , Wee Jon O. , Freeman Gordon J. , Barbie David A. , Marasco Wayne A.
Published: March 2024

One of the major hurdles that has hindered the success of chimeric antigen receptor (CAR) T cell therapies against solid tumors is on-target off-tumor (OTOT) toxicity due to sharing of the same epitopes on normal tissues. To elevate the safety profile of CAR-T cells, an affinity/avidity fine-tuned CAR was designed enabling CAR-T cell activation only in the presence of a highly expressed tumor associated antigen (TAA) but not when recognizing the same antigen at a physiological level on healthy cells. Using direct stochastic optical reconstruction microscopy (dSTORM) which provides single-molecule resolution, and flow cytometry, we identified high carbonic anhydrase IX (CAIX) density on clear cell renal cell carcinoma (ccRCC) patient samples and low-density expression on healthy bile duct tissues. A Tet-On doxycycline-inducible CAIX expressing cell line was established to mimic various CAIX densities, providing coverage from CAIX-high skrc-59 tumor cells to CAIX-low MMNK-1 cholangiocytes. Assessing the killing of CAR-T cells, we demonstrated that low-affinity/high-avidity fine-tuned G9 CAR-T has a wider therapeutic window compared to high-affinity/high-avidity G250 that was used in the first anti-CAIX CAR-T clinical trial but displayed serious OTOT effects. To assess the therapeutic effect of G9 on patient samples, we generated ccRCC patient derived organotypic tumor spheroid (PDOTS) ex vivo cultures and demonstrated that G9 CAR-T cells exhibited superior efficacy, migration and cytokine release in these miniature tumors. Moreover, in an RCC orthotopic mouse model, G9 CAR-T cells showed enhanced tumor control compared to G250. In summary, G9 has successfully mitigated OTOT side effects and in doing so has made CAIX a druggable immunotherapeutic target.
Nanoscale engineering of gold nanostars for enhanced photoacoustic imaging
Authors: Zhang Rui , Thoröe-Boveleth Sven , Chigrin Dmitry N. , Kiessling Fabian , Lammers Twan , Pallares Roger M.
Published: March 2024

Photoacoustic (PA) imaging is a diagnostic modality that combines the high contrast resolution of optical imaging with the high tissue penetration of ultrasound. While certain endogenous chromophores can be visualized via PA imaging, many diagnostic assessments require the administration of external probes. Anisotropic gold nanoparticles are particularly valued as contrast agents, since they produce strong PA signals and do not photobleach. However, the synthesis of anisotropic nanoparticles typically requires cytotoxic reagents, which can hinder their biological application. In this work, we developed new PA probes based on nanostar cores and polymeric shells. These AuNS were obtained through one-pot synthesis with biocompatible Good’s buffers, and were subsequently functionalized with polyethylene glycol, chitosan or melanin, three coatings widely used in (pre)clinical research. Notably, the structural features of the nanostar cores strongly affected the PA signal. For instance, despite displaying similar sizes (i.e. 45 nm), AuNS obtained with MOPS buffer generated between 2 and 3-fold greater signal intensities in the region between 700 and 800 nm than nanostars obtained with HEPES and EPPS buffers, and up to 25-fold stronger signals than spherical gold nanoparticles. A point source analytical model demonstrated that AuNS synthesized with MOPS displayed greater absorption coefficients than the other particles, corroborating the stronger PA responses. Furthermore, the AuNS shell not only improved the biocompatibility of the nanoconstructs but also affected their performance, with melanin coating enhancing the signal more than 4-fold, due to its own PA capacity, as demonstrated by both in vitro and ex vivo imaging. Taken together, these results highlight the strengths of gold nanoconstructs as PA probes and offer insights into the design rules for the nanoengineering of new nanodiagnostic agents.
Radiation therapy for retroperitoneal sarcoma: practice patterns in North America
Authors: Ruff Samantha M. , Heh Victor , Konieczkowski David J. , Onuma Amblessed , Dunlop Hayley M. , Kim Alex C. , Grignol Valerie P. , Contreras Carlo M. , Pawlik Timothy M. , Pollock Raphael , Beane Joal D.
Published: March 2024

Background

The addition of radiation therapy (RT) to surgery in retroperitoneal sarcoma (RPS) remains controversial. We examined practice patterns in the use of RT for patients with RPS over time in a large, national cohort.

Methods

Patients in the National Cancer Database (2004–2017) who underwent resection of RPS were included. Trends over time for proportions were calculated using contingency tables with Cochran-Armitage Trend test.

Results

Of 7,485 patients who underwent resection, 1,821 (24.3%) received RT (adjuvant: 59.9%, neoadjuvant: 40.1%). The use of RT decreased annually by < 1% (p = 0.0178). There was an average annual increase of neoadjuvant RT by 13% compared to an average annual decrease of adjuvant RT by 6% (p < 0.0001). Treatment at high-volume centers (OR 14.795, p < 0.0001) and tumor > 10 cm (OR 2.009, p = 0.001) were associated with neoadjuvant RT. In contrast liposarcomas (OR 0.574, p = 0.001) were associated with adjuvant RT. There was no statistically significant difference in overall survival between patients treated with surgery alone versus surgery and RT (p = 0.07).

Conclusion

In the United States, the use of RT for RPS has decreased over time, with a shift towards neoadjuvant RT. However, a large percentage of patients are still receiving adjuvant RT and this mostly occurs at low-volume hospitals.
A retrospective study: exploring preoperative hyponatremia in elderly patients with hip fractures
Authors: Shi Li-Tao , Feng Zhen , Zhu Cui-Min
Published: March 2024

Background

This research aims to examine the frequency, age-related distribution, and intensity of preoperative hyponatremia among elderly individuals with hip fractures. This study aims to provide valuable insights into the diagnosis of preoperative hyponatremia in this patient population.

Methods

This research involved the analysis of clinical data obtained from 419 elderly individuals with hip fractures (referred to as the fracture group) and 166 elderly individuals undergoing routine health examinations (designated as the control group). A comprehensive comparison was conducted, examining baseline characteristics such as age, gender, and comorbidities between these two groups. We further investigated variations in the incidence rate of hyponatremia, age distribution, and the severity of hyponatremia. Additionally, a subgroup analysis compared patients with femoral neck fractures to those with intertrochanteric femur fractures, specifically examining the incidence rate and severity of hyponatremia in these distinct fracture types.

Results

The incidence of cerebrovascular disease was found to be higher in the fracture group as compared to the control group in our research. Nevertheless, no significant differences in general health and other comorbidities were observed between the two groups. Notably, the fracture group exhibited a greater preoperative prevalence of hyponatremia, with its severity increasing with age. Furthermore, among elderly patients with intertrochanteric femur fractures, the incidence of preoperative hyponatremia was not only higher but also more severe when compared to those with femoral neck fractures.

Conclusion

Elderly individuals experiencing hip fractures exhibit a notable prevalence of preoperative hyponatremia, predominantly mild to moderate, with an escalating occurrence linked to advancing age. This phenomenon is especially conspicuous among patients with intertrochanteric fractures, warranting dedicated clinical scrutiny. The administration of sodium supplementation is advisable for the geriatric demographic as deemed necessary. Addressing hyponatremia becomes crucial, as it may play a role in the etiology of hip fractures in the elderly, and rectifying this electrolyte imbalance could potentially serve as a preventive measure against such fractures.
Navigation versus fluoroscopy in minimalinvasive iliosacral screw placement
Authors: Prost Max , Taday Roman , Beyersdorf Carl Christoph Paul , Latz David , Windolf Joachim , Scheyerer Max Joseph , Konieczny Markus Rafael
Published: March 2024

Introduction

When needed operative treatment of sacral fractures is mostly performed with percutaneous iliosacral screw fixation. The advantage of navigation in insertion of pedicle screws already could be shown by former investigations. The aim of this investigation was now to analyze which influence iliosacral screw placement guided by navigation has on duration of surgery, radiation exposure and accuracy of screw placement compared to the technique guided by fluoroscopy.

Methods

68 Consecutive patients with sacral fractures who have been treated by iliosacral screws were inclouded. Overall, 85 screws have been implanted in these patients. Beside of demographic data the duration of surgery, duration of radiation, dose of radiation and accuracy of screw placement were analyzed.

Results

When iliosacral screw placement was guided by navigation instead of fluoroscopy the dose of radiation per inserted screw (155.0 cGy*cm2 vs. 469.4 cGy*cm2p < 0.0001) as well as the duration of radiation use (84.8 s vs. 147.5 s p < 0.0001) were significantly lower. The use of navigation lead to a significant reduction of duration of surgery (39.0 min vs. 60.1 min p < 0.01). The placement of the screws showed a significantly higher accuracy when performed by navigation (0 misplaced screws vs 6 misplaced screws—p < 0.0001).

Conclusion

Based on these results minimal invasive iliosacral screw placement guided by navigation seems to be a safe procedure, which leads to a reduced exposure to radiation for the patient and the surgeon, a reduced duration of surgery as well as a higher accuracy of screw placement.
Blood-based biomarkers in patients with non-small cell lung cancer treated with immune checkpoint blockade
Authors: Tsai Yo-Ting , Schlom Jeffrey , Donahue Renee N.
Published: March 2024

The paradigm of non-small cell lung cancer (NSCLC) treatment has been profoundly influenced by the development of immune checkpoint inhibitors (ICI), but the range of clinical responses observed among patients poses significant challenges. To date, analyses of tumor biopsies are the only parameter used to guide prognosis to ICI therapy. Tumor biopsies, however, are often difficult to obtain and tissue-based biomarkers are limited by intratumoral heterogeneity and temporal variability. In response, there has been a growing emphasis on the development of “liquid biopsy”‒ derived biomarkers, which offer a minimally invasive means to dynamically monitor the immune status of NSCLC patients either before and/or during the course of treatment. Here we review studies in which multiple blood-based biomarkers encompassing circulating soluble analytes, immune cell subsets, circulating tumor DNA, blood-based tumor mutational burden, and circulating tumor cells have shown promising associations with the clinical response of NSCLC patients to ICI therapy. These investigations have unveiled compelling correlations between the peripheral immune status of patients both before and during ICI therapy and patient outcomes, which include response rates, progression-free survival, and overall survival. There is need for rigorous validation and standardization of these blood-based assays for broader clinical application. Integration of multiple blood-based biomarkers into comprehensive panels or algorithms also has the potential to enhance predictive accuracy. Further research aimed at longitudinal monitoring of circulating biomarkers is also crucial to comprehend immune dynamics and resistance mechanisms and should be used alongside tissue-based methods that interrogate the tumor microenvironment to guide treatment decisions and may inform on the development of novel therapeutic strategies. The data reviewed here reinforce the opportunity to refine patient stratification, optimize treatments, and improve outcomes not only in NSCLC but also in the wider spectrum of solid tumors undergoing immunotherapy.
Identification and validation of IRF6 related to ovarian cancer and biological function and prognostic value
Authors: Hong Shihao , Fu Ni , Sang Shanliang , Ma Xudong , Sun Fangying , Zhang Xiao
Published: March 2024

Background

Ovarian cancer (OC) is a severe gynecological malignancy with significant diagnostic and therapeutic challenges. The discovery of reliable cancer biomarkers can be used to adjust diagnosis and improve patient care. However, serous OC lacks effective biomarkers. We aimed to identify novel biomarkers for OC and their pathogenic causes.

Methods

The present study used the differentially expressed genes (DEGs) obtained from the “Limma” package and WGCNA modules for intersection analysis to obtain DEGs in OC. Three hub genes were identified—claudin 3 (CLDN3), interferon regulatory factor 6 (IRF6), and prostasin (PRSS8)—by searching for hub genes through the PPI network and verifying them in GSE14407, GSE18520, GSE66957, and TCGA + GTEx databases. The correlation between IRF6 and the prognosis of OC patients was further confirmed in Kaplan-Miller Plotter. RT-qPCR and IHC confirmed the RNA and protein levels of IRF6 in the OC samples. The effect of IRF6 on OC was explored using transwell invasion and scratch wound assays. Finally, we constructed a ceRNA network of hub genes and used bioinformatics tools to predict drug sensitivity.

Results

The joint analysis results of TCGA, GTEx, and GEO databases indicated that IRF6 RNA and protein levels were significantly upregulated in serous OC and were associated with OS and PFS. Cell function experiments revealed that IRF6 knockdown inhibited SKOV3 cell proliferation, migration and invasion.

Conclusion

IRF6 is closely correlated with OC development and progression and could be considered a novel biomarker and therapeutic target for OC patients.
Simultaneous determination of bromoxynil and MCPA in commercial samples and raw materials using reversed phase high performance liquid chromatography
Authors: Yar Ahmed , Ansari Tariq Mahmood , Rehman Faariah , Raza Asad , Riaz Umair , Iqbal Rashid , Al-Mohaimeed Amal M. , Al-onazi Wedad A. , Rizwan Muhammad
Published: March 2024

This study encompasses a quick, efficient, repeatable and reproducible analytical method for simultaneous determination of Bromoxynil (3, 5-Dibromo-4-hydroxybenzonitrile) and MCPA (2-methyl-4-chlorophenoxyacetic acid) using RP-HPLC with UV-Detector. Bromoxynil + MCPA is one of the most selective post emergent herbicide formulations for the control of important broad leaf weeds infesting small grains (wheat, barley, oats, rye), conservation reserve program areas and grass grown for seed. Optimum weed control is achieved when Bromoxynil + MCPA is applied to actively growing weed seedlings. So, a simple, repeatable, reproducible and efficient simultaneous analytical method was developed for Bromoxynil + MCPA. The developed method was applied for the detection and quantitation of these pesticides in formulations and raw materials with excellent recoveries. It was validated according to ICH Guidelines with excellent linearity R2 = 0.992 for Bromoxynil and 0.998 for MCPA. For Bromoxynil, LOD = 1.57 mg/L and LOQ = 5.22 mg/L while for MCPA the LOD = 1.08 mg/L and LOQ = 3.62 mg/L was found. The proposed method has shown high precision (RSD %) 0.06% and 0.11% for Bromoxynil and MCPA respectively while the trueness has been calculated in terms of recovery percentage obtained as “mean value of Bromoxynil 99.53% and MCPA 100.10%” which is excellent under optimized conditions. For repeatability and reproducibility, five replicate readings of standard and sample were taken and had found within acceptable limits of relative standard deviation (RSD ≤  ± 2%). Finally, the robustness of the developed method was determined by changing flow rate and mobile phase ratios that has found within the permissible limits (% RSD NMT 1.5). So, the proposed analytical method has found to be more precise, valid and accurate at commercial scale.

Graphical Abstract
Multi-omics analysis reveals novel loci and a candidate regulatory gene of unsaturated fatty acids in soybean (Glycine max (L.) Merr)
Authors: Zhao Xunchao , Zhan Yuhang , Li Kaiming , Zhang Yan , Zhou Changjun , Yuan Ming , Liu Miao , Li Yongguang , Zuo Peng , Han Yingpeng , Zhao Xue
Published: March 2024

Background

Soybean is a major oil crop; the nutritional components of soybean oil are mainly controlled by unsaturated fatty acids (FA). Unsaturated FAs mainly include oleic acid (OA, 18:1), linoleic acid (LLA, 18:2), and linolenic acid (LNA, 18:3). The genetic architecture of unsaturated FAs in soybean seeds has not been fully elucidated, although many independent studies have been conducted. A 3 V multi-locus random single nucleotide polymorphism (SNP)-effect mixed linear model (3VmrMLM) was established to identify quantitative trait loci (QTLs) and QTL-by-environment interactions (QEIs) for complex traits.

Results

In this study, 194 soybean accessions with 36,981 SNPs were calculated using the 3VmrMLM model. As a result, 94 quantitative trait nucleotides (QTNs) and 19 QEIs were detected using single-environment (QTN) and multi-environment (QEI) methods. Three significant QEIs, namely rs4633292, rs39216169, and rs14264702, overlapped with a significant single-environment QTN.

Conclusions

For QTNs and QEIs, further haplotype analysis of candidate genes revealed that the Glyma.03G040400 and Glyma.17G236700 genes were beneficial haplotypes that may be associated with unsaturated FAs. This result provides ideas for the identification of soybean lipid-related genes and provides insights for breeding high oil soybean varieties in the future.
Sensitive B-cell receptor repertoire analysis shows repopulation correlates with clinical response to rituximab in rheumatoid arthritis
Authors: Pollastro Sabrina , Musters Anne , Balzaretti Giulia , Niewold Ilse , van Schaik Barbera , Hässler Signe , Verhoef Catharina M. , Pallardy Marc , van Kampen Antoine , Mariette Xavier , de Vries Niek ,   on behalf of the ABIRISK Consortium, Szely Natacha , Gleizes Aude , Abina Salima Hacein-Bey , Richez Christophe , Soubrier Martin , Avouac Jérome , Brocq Olivier , Sellam Jérémie , Huizinga Tom , Jury Elizabeth , Manson Jessica , Mauri Claudia , Matucci Andrea
Published: March 2024

Background

Although B-cell depleting therapy in rheumatoid arthritis (RA) is clearly effective, response is variable and does not correlate with B cell depletion itself.

Methods

The B-cell receptor (BCR) repertoire was prospectively analyzed in peripheral blood samples of twenty-eight RA patients undergoing rituximab therapy. Timepoints of achieved BCR-depletion and -repopulation were defined based on the percentage of unmutated BCRs in the repertoire. The predictive value of early BCR-depletion (within one-month post-treatment) and early BCR-repopulation (within 6 months post-treatment) on clinical response was assessed.

Results

We observed changes in the peripheral blood BCR repertoire after rituximab treatment, i.e., increased clonal expansion, decreased clonal diversification and increased mutation load which persisted up to 12 months after treatment, but started to revert at month 6. Early BCR depletion was not associated with early clinical response but late depleters did show early response. Patients with early repopulation with unmutated BCRs showed a significant decrease in disease activity in the interval 6 to 12 months. Development of anti-drug antibodies non-significantly correlated with more BCR repopulation.

Conclusion

Our findings indicate that rather than BCR-depletion it is repopulation with unmutated BCRs, possibly from naïve B cells, which induces remission. This suggests that (pre-existing) differences in B-cell turnover between patients explain the interindividual differences in early clinical effect.
Increased stress hyperglycemia ratio at hospital admission in stroke patients are associated with increased in-hospital mortality and length of stay
Authors: Shen Di , Cai Xintian , Zhu Qing , Heizhati Mulalibieke , Hu Junli , Song Shuaiwei , Yang Wenbo , Hong Jing , Li Nanfang
Published: March 2024

Objective

Recently, the stress hyperglycemia ratio (SHR) has been introduced as a metric to signify relative hyperglycemia. This study aimed to investigate the relationship between SHR and in-hospital mortality and length of stay occurring during hospitalization in stroke patients.

Methods

The retrospective cohort study comprised a total of 4,018 patients diagnosed with acute stroke. The SHR is expressed by the formula: SHR = ABG (mmol/L) / [1.59 × HbA1c (%) − 2.59]. Outcomes included in-hospital mortality and length of stay. Multivariable logistic and linear regression analyses were conducted. Receiver operating characteristic (ROC) analysis was performed to distinguish between the variables, and the area under the ROC curve (AUC) was compared.

Results

In this analysis, a total of 4,018 individuals participated, including 2,814 male patients, accounting for 70.0%. Overall, in-hospital mortality and length of stay tended to rise as SHR increased. A higher prevalence of in-hospital mortality was observed with each standard deviation (SD) increase of the SHR (odds ratio [OR]: 1.26, 95% confidence interval [CI]: 1.05–1.52). Moreover, after considering the confounders, a significant positive association between SHR levels and length of stay was observed (β = 0.70, 95% CI: 0.40-1.00). ROC analysis showed that among stroke patients, SHR (AUC = 0.693) was more effective than admission blood glucose (ABG) (AUC = 0.646) and glycosylated hemoglobin (HbA1c) (AUC = 0.523), which were more predictive of in-hospital mortality.

Conclusions

Elevated SHR levels are associated with increased in-hospital mortality and prolonged length of stay in stroke patients.
Integrative multi-omics characterization reveals sex differences in glioblastoma
Authors: Jang Byunghyun , Yoon Dayoung , Lee Ji Yoon , Kim Jiwon , Hong Jisoo , Koo Harim , Sa Jason K.
Published: March 2024

Background

Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults, with limited treatment modalities and poor prognosis. Recent studies have highlighted the importance of considering sex differences in cancer incidence, prognosis, molecular disparities, and treatment outcomes across various tumor types, including colorectal adenocarcinoma, lung adenocarcinoma, and GBM.

Methods

We performed comprehensive analyses of large-scale multi-omics data (genomic, transcriptomic, and proteomic data) from TCGA, GLASS, and CPTAC to investigate the genetic and molecular determinants that contribute to the unique clinical properties of male and female GBM patients.

Results

Our results revealed several key differences, including enrichments of MGMT promoter methylation, which correlated with increased overall and post-recurrence survival and improved response to chemotherapy in female patients. Moreover, female GBM exhibited a higher degree of genomic instability, including aneuploidy and tumor mutational burden. Integrative proteomic and phosphor-proteomic characterization uncovered sex-specific protein abundance and phosphorylation activities, including EGFR activation in males and SPP1 hyperphosphorylation in female patients. Lastly, the identified sex-specific biomarkers demonstrated prognostic significance, suggesting their potential as therapeutic targets.

Conclusions

Collectively, our study provides unprecedented insights into the fundamental modulators of tumor progression and clinical outcomes between male and female GBM patients and facilitates sex-specific treatment interventions.

Highlights

Female GBM patients were characterized by increased MGMT promoter methylation and favorable clinical outcomes compared to male patients.

Female GBMs exhibited higher levels of genomic instability, including aneuploidy and TMB.

Each sex-specific GBM is characterized by unique pathway dysregulations and molecular subtypes.

EGFR activation is prevalent in male patients, while female patients are marked by SPP1 hyperphosphorylation.
Impact of reimbursement systems on patient care – a systematic review of systematic reviews
Authors: Wagenschieber Eva , Blunck Dominik
Published: March 2024

Background

There is not yet sufficient scientific evidence to answer the question of the extent to which different reimbursement systems influence patient care and treatment quality. Due to the asymmetry of information between physicians, health insurers and patients, market-based mechanisms are necessary to ensure the best possible patient care. The aim of this study is to investigate how reimbursement systems influence multiple areas of patient care in form of structure, process and outcome indicators.

Methods

For this purpose, a systematic literature review of systematic reviews is conducted in the databases PubMed, Web of Science and the Cochrane Library. The reimbursement systems of salary, bundled payment, fee-for-service and value-based reimbursement are examined. Patient care is divided according to the three dimensions of structure, process, and outcome and evaluated in eight subcategories.

Results

A total of 34 reviews of 971 underlying primary studies are included in this article. International studies identified the greatest effects in categories resource utilization and quality/health outcomes. Pay-for-performance and bundled payments were the most commonly studied models. Among the systems examined, fee-for-service and value-based reimbursement systems have the most positive impact on patient care.

Conclusion

Patient care can be influenced by the choice of reimbursement system. The factors for successful implementation need to be further explored in future research.
The economic effect of financial compensation in China’s healthcare system: comprehensive insights regarding supply and demand factors
Authors: Guo Yi , Hong Xuezhi , Li Dongmei , An Qiannan , Fan Wenwen , Yang Minghe , Xiao Luyang
Published: March 2024

Objectives

We aim to analyse the effects of government subsidies on residents’ health and healthcare expenditure from the perspectives of supply and demand.

Data and methods

According to the regional division adopted in the data query system of the National Bureau of Statistics, this study divides 31 provinces and cities into three regions: eastern, central, and western. The data used are from public databases, such as the “China Statistical Yearbook,” “China Health Statistical Yearbook,” and “Government Final Account Report”. In this study, mathematical model derivation is used to construct a fixed effects model, and an empirical study based on cross-sectional data and general linear regression is conducted. To prevent endogeneity issues, this study introduces instrumental variables and uses 2SLS regression to further analyse the output results.

Results

For every 1% increase in supplementary funding on the supply side, the perinatal mortality rate decreases by 1.765%, while for every 1% increase in financial compensation on the demand side, per capita outpatient expenses increase by 0.225% and per capita hospitalization expenses increase by 0.196%. Regarding medical resources, for every 1% increase in the number of beds per 1,000 people, per capita hospitalization expenses decrease by 0.099%. In the central and eastern regions, where economic levels are higher, supply-side government funding is more effective than demand-side funding. In contrast, demand-side funding is more effective in the western region.

Conclusions

The roles of multiple influencing factors and significant regional heterogeneity are clarified. Increasing financial compensation to providers positively impacts perinatal mortality but leads to higher per capita outpatient and hospital expenditures. Finally, this study provides targeted policy recommendations and solid theoretical support for policymakers.
RNA editing enzymes: structure, biological functions and applications
Authors: Zhang Dejiu , Zhu Lei , Gao Yanyan , Wang Yin , Li Peifeng
Published: March 2024

With the advancement of sequencing technologies and bioinformatics, over than 170 different RNA modifications have been identified. However, only a few of these modifications can lead to base pair changes, which are called RNA editing. RNA editing is a ubiquitous modification in mammalian transcriptomes and is an important co/posttranscriptional modification that plays a crucial role in various cellular processes. There are two main types of RNA editing events: adenosine to inosine (A-to-I) editing, catalyzed by ADARs on double-stranded RNA or ADATs on tRNA, and cytosine to uridine (C-to-U) editing catalyzed by APOBECs. This article provides an overview of the structure, function, and applications of RNA editing enzymes. We discuss the structural characteristics of three RNA editing enzyme families and their catalytic mechanisms in RNA editing. We also explain the biological role of RNA editing, particularly in innate immunity, cancer biogenesis, and antiviral activity. Additionally, this article describes RNA editing tools for manipulating RNA to correct disease-causing mutations, as well as the potential applications of RNA editing enzymes in the field of biotechnology and therapy.
Treatment setting and buprenorphine discontinuation: an analysis of multi-state insurance claims
Authors: Xu Kevin Y. , Gertner Alex K. , Greenfield Shelly F. , Williams Arthur Robin , Grucza Richard A.
Published: March 2024

Background

Potential differences in buprenorphine treatment outcomes across various treatment settings are poorly characterized in multi-state administrative data. We thus evaluated the association of opioid use disorder (OUD) treatment setting and insurance type with risk of buprenorphine discontinuation among commercial insurance and Medicaid enrollees initiated on buprenorphine.

Methods

In this observational, retrospective cohort study using the Merative MarketScan databases (2006–2016), we analyzed buprenorphine retention in 58,200 US adults with OUD. Predictor variables included insurance status (Medicaid vs commercial) and treatment setting, operationalized as substance use disorder (SUD) specialty treatment facility versus outpatient primary care physicians (PCPs) versus outpatient psychiatry, ascertained by linking physician visit codes to buprenorphine prescriptions. Treatment setting was inferred based on timing of prescriber visit claims preceding prescription fills. We estimated time to buprenorphine discontinuation using multivariable cox regression.

Results

Among enrollees with OUD receiving buprenorphine, 26,168 (45.0%) had prescriptions from SUD facilities without outpatient buprenorphine treatment, with the remaining treated by outpatient PCPs (n = 23,899, 41.1%) and psychiatrists (n = 8133, 13.9%). Overall, 50.6% and 73.3% discontinued treatment at 180 and 365 days respectively. Buprenorphine discontinuation was higher among enrollees receiving prescriptions from SUD facilities (aHR = 1.03[1.01–1.06]) and PCPs (aHR = 1.07[1.05–1.10]). Medicaid enrollees had lower buprenorphine retention than those with commercial insurance, particularly those receiving buprenorphine from SUD facilities and PCPs (aHR = 1.24[1.20–1.29] and aHR = 1.39[1.34–1.45] respectively, relative to comparator group of commercial insurance enrollees receiving buprenorphine from outpatient psychiatry).

Conclusion

Buprenorphine discontinuation is high across outpatient PCP, psychiatry, and SUD treatment facility settings, with potentially lower treatment retention among Medicaid enrollees receiving care from SUD facilities and PCPs.
Classification of soybeans from different habitats based on metabolomic–transcriptomic integration
Authors: Wang Jinghui , Zheng Qiyou , Wang Chenxu , Zhou Ao
Published: March 2024

Soybeans are a significant agricultural product in China, with certain geographical locations often yielding higher quality, and thus more expensive, soybean crops. In this study, metabolomics and transcriptomics analyses were conducted on soybean samples from nine regions in Heilongjiang and Liaoning Provinces using untargeted liquid chromatography–mass spectrometry (LC–MS) and Illumina sequencing technologies. The primary objective was to devise an effective and unbiased method for determining the geographical origin of each soybean variety to mitigate potential fraudulent practices. Through multidimensional and unidimensional analyses, successful identification of differentially expressed metabolites (DEMs) and differentially expressed genes (DEGs) was achieved, yielding statistically significant outcomes. Integration of the metabolomics and transcriptomics datasets facilitated the construction of a correlation network model capable of distinguishing soybeans originating from different geographical locations, leading to the identification of significant biomarkers exemplifying noteworthy distinctions. To validate the feasibility of this method in practical applications, partial least squares discriminant analysis was employed to differentiate soybean samples from the nine regions. The results convincingly showcased the applicability and reliability of this approach in accurately pinpointing the geographical origin of soybeans. Distinguishing itself from prior research in soybean traceability, this study incorporates an integrated analysis of metabolomics and transcriptomics data, thereby unveiling biomarkers that offer a more precise differentiation of soybean traits across distinct regions, thereby bridging a critical research gap within the soybean traceability domain. This innovative dual-data integration analysis methodology is poised to enhance the accuracy of soybean traceability tools and lay a new foundation for future agricultural product identification research.
Global prevalence of organohalide-respiring bacteria dechlorinating polychlorinated biphenyls in sewage sludge
Authors: Xu Guofang , Zhao Siyan , Rogers Matthew J. , Chen Chen , He Jianzhong
Published: March 2024

Background

Massive amounts of sewage sludge are generated during biological sewage treatment and are commonly subjected to anaerobic digestion, land application, and landfill disposal. Concurrently, persistent organic pollutants (POPs) are frequently found in sludge treatment and disposal systems, posing significant risks to both human health and wildlife. Metabolically versatile microorganisms originating from sewage sludge are inevitably introduced to sludge treatment and disposal systems, potentially affecting the fate of POPs. However, there is currently a dearth of comprehensive assessments regarding the capability of sewage sludge microbiota from geographically disparate regions to attenuate POPs and the underpinning microbiomes.

Results

Here we report the global prevalence of organohalide-respiring bacteria (OHRB) known for their capacity to attenuate POPs in sewage sludge, with an occurrence frequency of ~50% in the investigated samples (605 of 1186). Subsequent laboratory tests revealed microbial reductive dechlorination of polychlorinated biphenyls (PCBs), one of the most notorious categories of POPs, in 80 out of 84 sludge microcosms via various pathways. Most chlorines were removed from the para- and meta-positions of PCBs; nevertheless, ortho-dechlorination of PCBs also occurred widely, although to lower extents. Abundances of several well-characterized OHRB genera (Dehalococcoides, Dehalogenimonas, and Dehalobacter) and uncultivated Dehalococcoidia lineages increased during incubation and were positively correlated with PCB dechlorination, suggesting their involvement in dechlorinating PCBs. The previously identified PCB reductive dehalogenase (RDase) genes pcbA4 and pcbA5 tended to coexist in most sludge microcosms, but the low ratios of these RDase genes to OHRB abundance also indicated the existence of currently undescribed RDases in sewage sludge. Microbial community analyses revealed a positive correlation between biodiversity and PCB dechlorination activity although there was an apparent threshold of community co-occurrence network complexity beyond which dechlorination activity decreased.

Conclusions

Our findings that sludge microbiota exhibited nearly ubiquitous dechlorination of PCBs indicate widespread and nonnegligible impacts of sludge microbiota on the fate of POPs in sludge treatment and disposal systems. The existence of diverse OHRB also suggests sewage sludge as an alternative source to obtain POP-attenuating consortia and calls for further exploration of OHRB populations in sewage sludge.
Global abundance patterns, diversity, and ecology of Patescibacteria in wastewater treatment plants
Authors: Hu Huifeng , Kristensen Jannie Munk , Herbold Craig William , Pjevac Petra , Kitzinger Katharina , Hausmann Bela , Dueholm Morten Kam Dahl , Nielsen Per Halkjaer , Wagner Michael
Published: March 2024

Background

Microorganisms are responsible for nutrient removal and resource recovery in wastewater treatment plants (WWTPs), and their diversity is often studied by 16S rRNA gene amplicon sequencing. However, this approach underestimates the abundance and diversity of Patescibacteria due to the low coverage of commonly used PCR primers for this highly divergent bacterial phylum. Therefore, our current understanding of the global diversity, distribution, and ecological role of Patescibacteria in WWTPs is very incomplete. This is particularly relevant as Patescibacteria are considered to be associated with microbial host cells and can therefore influence the abundance and temporal variability of other microbial groups that are important for WWTP functioning.

Results

Here, we evaluated the in silico coverage of widely used 16S rRNA gene-targeted primer pairs and redesigned a primer pair targeting the V4 region of bacterial and archaeal 16S rRNA genes to expand its coverage for Patescibacteria. We then experimentally evaluated and compared the performance of the original and modified V4-targeted primers on 565 WWTP samples from the MiDAS global sample collection. Using the modified primer pair, the percentage of ASVs classified as Patescibacteria increased from 5.9 to 23.8%, and the number of detected patescibacterial genera increased from 560 to 1576, while the detected diversity of the remaining microbial community remained similar. Due to this significantly improved coverage of Patescibacteria, we identified 23 core genera of Patescibacteria in WWTPs and described the global distribution pattern of these unusual microbes in these systems. Finally, correlation network analysis revealed potential host organisms that might be associated with Patescibacteria in WWTPs. Interestingly, strong indications were found for an association between Patescibacteria of the Saccharimonadia and globally abundant polyphosphate-accumulating organisms of the genus Ca. Phosphoribacter.

Conclusions

Our study (i) provides an improved 16S rRNA gene V4 region-targeted amplicon primer pair inclusive of Patescibacteria with little impact on the detection of other taxa, (ii) reveals the diversity and distribution patterns of Patescibacteria in WWTPs on a global scale, and (iii) provides new insights into the ecological role and potential hosts of Patescibacteria in WWTPs﻿.
Exploring the roles of academic expectation stress, adaptive coping, and academic resilience on perceived English proficiency
Authors: Kao Po-Chi
Published: March 2024

This study aims to examine and analyze a research model comprising three latent variables (academic expectation stress, adaptive coping, and academic resilience) to gain insights into the perceived English proficiency of EFL (English as a foreign language) learners. These variables have been overlooked in previous literature despite their importance in understanding learning outcomes. A total of 395 undergraduate students from a Taiwanese university participated in this study. Through the use of structural equation modeling, the hypotheses in the research model were tested. The findings of this research are as follows: (1) Academic expectation stress has a significant and negative impact on EFL learners’ perceived English proficiency; (2) Academic resilience positively predicts EFL learners’ perceived English proficiency; (3) Academic resilience mediates the relationship between academic expectation stress and perceived English proficiency; (4) Adaptive coping mediates the relationship between academic expectation stress and academic resilience. These results add valuable insights to the existing literature in EFL teaching and learning, shedding light on the dynamics of these variables.
Recent advances in the biosynthesis and industrial biotechnology of Gamma-amino butyric acid
Authors: Milon Ripon Baroi , Hu Pengchen , Zhang Xueqiong , Hu Xuechao , Ren Lujing
Published: March 2024

GABA (Gamma-aminobutyric acid), a crucial neurotransmitter in the central nervous system, has gained significant attention in recent years due to its extensive benefits for human health. The review focused on recent advances in the biosynthesis and production of GABA. To begin with, the investigation evaluates GABA-producing strains and metabolic pathways, focusing on microbial sources such as Lactic Acid Bacteria, Escherichia coli, and Corynebacterium glutamicum. The metabolic pathways of GABA are elaborated upon, including the GABA shunt and critical enzymes involved in its synthesis. Next, strategies to enhance microbial GABA production are discussed, including optimization of fermentation factors, different fermentation methods such as co-culture strategy and two-step fermentation, and modification of the GABA metabolic pathway. The review also explores methods for determining glutamate (Glu) and GABA levels, emphasizing the importance of accurate quantification. Furthermore, a comprehensive market analysis and prospects are provided, highlighting current trends, potential applications, and challenges in the GABA industry. Overall, this review serves as a valuable resource for researchers and industrialists working on GABA advancements, focusing on its efficient synthesis processes and various applications, and providing novel ideas and approaches to improve GABA yield and quality.

Graphical Abstract
Effects of latroeggtoxin-VI on dopamine and α-synuclein in PC12 cells and the implications for Parkinson’s disease
Authors: Yu Dianmei , Wang Haiyan , Zhai Yiwen , Lei Zhixiang , Sun Minglu , Chen Si , Yin Panfeng , Wang Xianchun
Published: March 2024

Background

Parkinson’s disease (PD) is characterized by death of dopaminergic neurons leading to dopamine deficiency, excessive α-synuclein facilitating Lewy body formation, etc. Latroeggtoxin-VI (LETX-VI), a proteinaceous neurotoxin discovered from the eggs of spider L. tredecimguttatus, was previously found to promote the synthesis and release of PC12 cells, showing a great potential as a drug candidate for PD. However, the relevant mechanisms have not been understood completely. The present study explored the mechanism underlying the effects of LETX-VI on dopamine and α-synuclein of PC12 cells and the implications for PD.

Results

After PC12 cells were treated with LETX-VI, the level of dopamine was significantly increased in a dose-dependent way within a certain range of concentrations. Further mechanism analysis showed that LETX-VI upregulated the expression of tyrosine hydroxylase (TH) and L-dopa decarboxylase to enhance the biosynthesis of dopamine, and downregulated that of monoamine oxidase B to reduce the degradation of dopamine. At the same time, LETX-VI promoted the transport and release of dopamine through modulating the abundance and/or posttranslational modification of vesicular monoamine transporter 2 (VMAT2) and dopamine transporter (DAT). While the level of dopamine was increased by LETX-VI treatment, α-synuclein content was reduced by the spider toxin. α-Synuclein overexpression significantly decreased the dopamine level and LETX-VI efficiently alleviated the inhibitory action of excessive α-synuclein on dopamine. In the MPTP-induced mouse model of PD, application of LETX-VI ameliorated parkinsonian behaviors of the mice, and reduced the magnitude of MPTP-induced α-synuclein upregulation and TH downregulation. In addition, LETX-VI displayed neuroprotective effects by inhibiting MPTP-induced decrease in the numbers of TH-positive and Nissl-stained neurons in mouse brain tissues.

Conclusions

All the results demonstrate that LETX-VI promotes the synthesis and release of dopamine in PC12 cells via multiple mechanisms including preventing abnormal α-synuclein accumulation, showing implications in the prevention and treatment of PD.