bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a chemically disclosed serum-free medium for mouse pluripotent stem cells
Authors: Katayama Tomoka , Takechi Marina , Murata Yamato , Chigi Yuta , Yamaguchi Shinpei , Okamura Daiji
Published: May 2024

Mouse embryonic stem cells (mESCs) have been widely used as a model system to study the basic biology of pluripotency and to develop cell-based therapies. Traditionally, mESCs have been cultured in a medium supplemented with fetal bovine serum (FBS). However, serum with its inconsistent chemical composition has been problematic for reproducibility and for studying the role of specific components. While some serum-free media have been reported, these media contain commercial additives whose detailed components have not been disclosed. Recently, we developed a serum-free medium, DA-X medium, which can maintain a wide variety of adherent cancer lines. In this study, we modified the DA-X medium and established a novel serum-free condition for both naïve mESCs in which all components are chemically defined and disclosed (DA-X-modified medium for robust growth of pluripotent stem cells: DARP medium). The DARP medium fully supports the normal transcriptome and differentiation potential in teratoma and the establishment of mESCs from blastocysts that retain the developmental potential in all three germ layers, including germ cells in chimeric embryos. Utility of chemically defined DA-X medium for primed mouse epiblast stem cells (mEpiSCs) revealed that an optimal amount of cholesterol is required for the robust growth of naïve-state mESCs, but is dispensable for the maintenance of primed-state mEpiSCs. Thus, this study provides reliable and reproducible culture methods to investigate the role of specific components regulating self-renewal and pluripotency in a wide range of pluripotent states.
Interacting and joint effects of triglyceride-glucose index and hypertension on stroke risk in middle-aged and older Chinese adults: a population-based prospective cohort study
Authors: Luo Yun-Dan , Gan Ying-Yuan , Liao Qian , Li Xu , Huo Rong-Rui
Published: May 2024

Background

Triglyceride-glucose (TyG) index and hypertension were well-established risk factors for stroke. And TyG index was associated with hypertension. However, no prior study has investigated the interactive effects of the TyG index and hypertension on stroke. This study examined whether hypertension mediates associations of TyG index with incident stroke and the extent of interaction or joint relations of TyG index and hypertension with stroke in middle-aged and older Chinese adults.

Methods

The China Health and Retirement Longitudinal Study (CHARLS) is an ongoing nationally representative prospective cohort study initiated in 2011. This cohort study included 9,145 middle-aged and older Chinese adults without stroke at baseline. The eposures were TyG index and the logarithmized product of hypertension, as determined during the baseline health examination. The main outcome was self-reported physician-diagnosed stroke which followed up from June 1, 2011, to June 30, 2018.

Results

Of the 9,145 participants, 4,251 were men (46.5%); the mean (SD) age was 59.20 (9.33) years. During a median follow-up of 7.1 years, 637 (7.0%) participants developed stroke. In multivariable-adjusted models, the TyG index was significantly associated with the risk of hypertension [odds ratio (OR) per 1-SD increase, 1.29; 95% CI, 1.19–1.41] and stroke [hazard ratio (HR) per 1-SD increase, 1.16; 95% CI, 1.02–1.33]. Both multiplicative and additive interactions were observed between TyG index and hypertension on stroke (HR for multiplicative: 2.34, 95% CI, 1.57–3.48; Synergy index: 4.13, 95% CI, 2.73–6.25). Mediation analysis showed that 20.0% of the association between TyG index and stroke was mediated through hypertension.

Conclusions

This study suggests a synergistic effect of TyG index and hypertension on stroke, and a small proportion of the association between TyG index and stroke was mediated by hypertension, indicating the benefit of coordinated control strategies for both exposures.
I have three more than you, you have three less than me? Levels of flexibility in dealing with additive situations
Authors: Ufer Stefan , Kaiser Anna , Niklas Frank , Gabler Laura
Published: May 2024

Assessment and intervention in the early years should ideally be based on evidence-based models describing the structure and development of students’ skills. Mathematical word problems have been identified as a challenge for mathematics learners for a long time and in many countries. We investigate flexibility in dealing with additive situations as a construct that develops during grades 1 through 3 and contributes to the development of students’ word problem solving skills. We introduce the construct based on prior research on the difficulty of different situation structures entailed in word problems. We use data from three prior empirical studies with N = 383 German grade 2 and 3 students to develop a model of discrete levels of students’ flexibility in dealing with additive situations. We use this model to investigate how the learners in our sample distribute across the different levels. Moreover, we apply it to describe students’ development over several weeks in one study comprising three measurements. We derive conclusions about the construct in terms of determinants of task complexity, and about students’ development and then provide an outlook on potential uses of the model in research and practice.
Cellular collusion: cracking the code of immunosuppression and chemo resistance in PDAC
Authors: Musiu Chiara , Lupo Francesca , Agostini Antonio , Lionetto Gabriella , Bevere Michele , Paiella Salvatore , Carbone Carmine , Corbo Vincenzo , Ugel Stefano , De Sanctis Francesco
Published: May 2024

Despite the efforts, pancreatic ductal adenocarcinoma (PDAC) is still highly lethal. Therapeutic challenges reside in late diagnosis and establishment of peculiar tumor microenvironment (TME) supporting tumor outgrowth. This stromal landscape is highly heterogeneous between patients and even in the same patient. The organization of functional sub-TME with different cellular compositions provides evolutive advantages and sustains therapeutic resistance. Tumor progressively establishes a TME that can suit its own needs, including proliferation, stemness and invasion. Cancer-associated fibroblasts and immune cells, the main non-neoplastic cellular TME components, follow soluble factors-mediated neoplastic instructions and synergize to promote chemoresistance and immune surveillance destruction. Unveiling heterotypic stromal-neoplastic interactions is thus pivotal to breaking this synergism and promoting the reprogramming of the TME toward an anti-tumor milieu, improving thus the efficacy of conventional and immune-based therapies. We underscore recent advances in the characterization of immune and fibroblast stromal components supporting or dampening pancreatic cancer progression, as well as novel multi-omic technologies improving the current knowledge of PDAC biology. Finally, we put into context how the clinic will translate the acquired knowledge to design new-generation clinical trials with the final aim of improving the outcome of PDAC patients.
Pre-existing cell populations with cytotoxic activity against SARS-CoV-2 in people with HIV and normal CD4/CD8 ratio previously unexposed to the virus
Authors: Casado-Fernández Guiomar , Cantón Juan , Nasarre Laura , Ramos-Martín Fernando , Manzanares Mario , Sánchez-Menéndez Clara , Fuertes Daniel , Mateos Elena , Murciano-Antón María Aranzazu , Pérez-Olmeda Mayte , Cervero Miguel , Torres Montserrat , Rodríguez-Rosado Rafael , Coiras Mayte
Published: May 2024

Introduction

HIV-1 infection may produce a detrimental effect on the immune response. Early start of antiretroviral therapy (ART) is recommended to preserve the integrity of the immune system. In fact, people with HIV (PWH) and normal CD4/CD8 ratio appear not to be more susceptible to severe forms of COVID-19 than the general population and they usually present a good seroconversion rate in response to vaccination against SARS-CoV-2. However, few studies have fully characterized the development of cytotoxic immune populations in response to COVID-19 vaccination in these individuals.

Methods

In this study, we recruited PWH with median time of HIV-1 infection of 6 years, median CD4/CD8 ratio of 1.0, good adherence to ART, persistently undetectable viral load, and negative serology against SARS-CoV-2, who then received the complete vaccination schedule against COVID-19. Blood samples were taken before vaccination against COVID-19 and one month after receiving the complete vaccination schedule.

Results

PWH produced high levels of IgG against SARS-CoV-2 in response to vaccination that were comparable to healthy donors, with a significantly higher neutralization capacity. Interestingly, the cytotoxic activity of PBMCs from PWH against SARS-CoV-2-infected cells was higher than healthy donors before receiving the vaccination schedule, pointing out the pre-existence of activated cell populations with likely unspecific antiviral activity. The characterization of these cytotoxic cell populations revealed high levels of Tgd cells with degranulation capacity against SARS-CoV-2-infected cells. In response to vaccination, the degranulation capacity of CD8+ T cells also increased in PWH but not in healthy donors.

Discussion

The full vaccination schedule against COVID-19 did not modify the ability to respond against HIV-1-infected cells in PWH and these individuals did not show more susceptibility to breakthrough infection with SARS-CoV-2 than healthy donors after 12 months of follow-up. These results revealed the development of protective cell populations with broad-spectrum antiviral activity in PWH with normal CD4/CD8 ratio and confirmed the importance of early ART and treatment adherence to avoid immune dysfunctions.
A potential defensive role of TIM-3 on T lymphocytes in the inflammatory involvement of diabetic kidney disease
Authors: Chen Xiao-Jun , Tang Runyan , Zha Jie , Zeng Li , Zhou Linshan , Liu Zhiwen , Yang Danyi , Zeng Mengru , Zhu Xuejing , Chen Anqun , Liu Hong , Chen Huihui , Chen Guochun
Published: May 2024

Objective

The aberrant mobilization and activation of various T lymphocyte subpopulations play a pivotal role in the pathogenesis of diabetic kidney disease (DKD), yet the regulatory mechanisms underlying these processes remain poorly understood. Our study is premised on the hypothesis that the dysregulation of immune checkpoint molecules on T lymphocytes disrupts kidney homeostasis, instigates pathological inflammation, and promotes DKD progression.

Methods

A total of 360 adult patients with DKD were recruited for this study. The expression of immune checkpoint molecules on T lymphocytes was assessed by flow cytometry for peripheral blood and immunofluorescence staining for kidney tissue. Single-cell sequencing (scRNA-seq) data from the kidneys of DKD mouse model were analyzed.

Results

Patients with DKD exhibited a reduction in the proportion of CD3+TIM-3+ T cells in circulation concurrent with the emergence of significant albuminuria and hematuria (p=0.008 and 0.02, respectively). Conversely, the incidence of infection during DKD progression correlated with an elevation of peripheral CD3+TIM-3+ T cells (p=0.01). Both univariate and multivariate logistic regression analysis revealed a significant inverse relationship between the proportion of peripheral CD3+TIM-3+ T cells and severe interstitial mononuclear infiltration (OR: 0.193, 95%CI: 0.040,0.926, p=0.04). Immunofluorescence assays demonstrated an increase of CD3+, TIM-3+ and CD3+TIM-3+ interstitial mononuclear cells in the kidneys of DKD patients as compared to patients diagnosed with minimal change disease (p=0.03, 0.02 and 0.002, respectively). ScRNA-seq analysis revealed decreased gene expression of TIM3 on T lymphocytes in DKD compared to control. And one of TIM-3's main ligands, Galectin-9 on immune cells showed a decreasing trend in gene expression as kidney damage worsened.

Conclusion

Our study underscores the potential protective role of TIM-3 on T lymphocytes in attenuating the progression of DKD and suggests that monitoring circulating CD3+TIM3+ T cells may serve as a viable strategy for identifying DKD patients at heightened risk of disease progression.
IL-2Rα KO mice exhibit maternal microchimerism and reveal nuclear localization of IL-2Rα in lymphoid and non-lymphoid cells
Authors: Wong Victoria A. , Dinh Kristie N. , Chen Guangchun , Wrenshall Lucile E.
Published: May 2024

Introduction

IL-2Rα knock out (KO) mice have been instrumental to discovering the immunoregulatory properties of IL-2Rα. While initially thought of only as a stimulatory cytokine, IL-2 and IL-2Rα KO mice revealed that this cytokine-receptor system controls immune responses through restimulation-induced cell death and by promoting the survival of T regulatory cells. Although described mostly in the context of lymphocytes, recent studies by our laboratory showed that IL-2R is expressed in smooth muscle cells. Given this finding, we sought to use IL-2Rα KO to determine the function of this receptor in vascular smooth muscle cells. Surprisingly, we found that IL-2Rα KO vascular smooth muscle cells had detectable IL-2Rα.

Methods

We used multiple gene and protein-based methods to determine why IL-2Rα KO vascular smooth muscle cells exhibited IL-2Rα protein. These methods included: genomic sequencing, assessing cells and tissues for evidence of maternal microchimerism, and determining the half-life of IL-2Rα protein.

Results

Our studies demonstrated the following: (1) in addition to the cell surface, IL-2Rα is localized to the nucleus; (2) the genetic deletion of IL-2Rα is intact in IL-2Rα KO mice; (3) both IL-2Rα KO and WT tissues show evidence of maternal microchimerism, the likely source of IL-2Rα (4) IL-2Rα is transmitted between cells; (5) IL-2Rα has a long half-life; and (6) nuclear IL-2Rα contributes to the regulation of cell proliferation and size.

Conclusion

Our findings suggest that the phenotype of complete IL-2Rα loss is more severe than demonstrated by IL-2Rα KO mice, and that IL-2Rα plays a here-to-fore unrecognized role in regulating cell proliferation in non-lymphoid cells.
Ex vivo characterization of acute myeloid leukemia patients undergoing hypomethylating agents and venetoclax regimen reveals a venetoclax-specific effect on non-suppressive regulatory T cells and bona fide PD-1+TIM3+ exhausted CD8+ T cells
Authors: Corradi Giulia , Forte Dorian , Cristiano Gianluca , Polimeno Andrea , Ciciarello Marilena , Salvestrini Valentina , Bandini Lorenza , Robustelli Valentina , Ottaviani Emanuela , Cavo Michele , Ocadlikova Darina , Curti Antonio
Published: May 2024

Acute myeloid leukemia (AML) is an aggressive heterogeneous disease characterized by several alterations of the immune system prompting disease progression and treatment response. The therapies available for AML can affect lymphocyte function, limiting the efficacy of immunotherapy while hindering leukemia-specific immune reactions. Recently, the treatment based on Venetoclax (VEN), a specific B-cell lymphoma 2 (BCL-2) inhibitor, in combination with hypomethylating agents (HMAs) or low-dose cytarabine, has emerged as a promising clinical strategy in AML. To better understand the immunological effect of VEN treatment, we characterized the phenotype and immune checkpoint (IC) receptors’ expression on CD4+ and CD8+ T cells from AML patients after the first and second cycle of HMA in combination with VEN. HMA and VEN treatment significantly increased the percentage of naïve CD8+ T cells and TIM-3+ CD4+ and CD8+ T cells and reduced cytokine-secreting non-suppressive T regulatory cells (Tregs). Of note, a comparison between AML patients treated with HMA only and HMA in combination with VEN revealed the specific contribution of VEN in modulating the immune cell repertoire. Indeed, the reduction of cytokine-secreting non-suppressive Tregs, the increased TIM-3 expression on CD8+ T cells, and the reduced co-expression of PD-1 and TIM-3 on both CD4+ and CD8+ T cells are all VEN-specific. Collectively, our study shed light on immune modulation induced by VEN treatment, providing the rationale for a novel therapeutic combination of VEN and IC inhibitors in AML patients.
The efficacy and safety of neoadjuvant chemoradiotherapy combined with immunotherapy for locally advanced rectal cancer patients: a systematic review
Authors: Yang Lei , Cui Xiujing , Wu Fengpeng , Chi Zifeng , Xiao Linlin , Wang Xuan , Liang Zezheng , Li Xiaoning , Yu Qiyao , Lin Xueqin , Gao Chao
Published: May 2024

Background

Several studies have explored the effectiveness of PD-1/PD-L1 inhibitors combined with neoadjuvant chemoradiotherapy (nCRT) in the treatment of locally advanced rectal cancer(LARC), particularly in microsatellite stable(MSS) or mismatch repair proficient(pMMR) LARC patients. We undertook a single-arm systematic review to comprehensively evaluate the advantages and potential risks associated with the use of PD-1/PD-L1 inhibitors in conjunction with nCRT for patients diagnosed with locally advanced rectal cancer.

Methods

The PubMed, Embase, Cochrane Library, ClinicalTrials.gov, ASCO and ESMO were searched for related studies. The main outcomes were pathologic complete response (pCR), major pathological response (MPR), anal preservation, and adverse effects (AEs).

Results

Fourteen articles including 533 locally advanced rectal cancer (LARC) patients were analyzed. The pooled pCR, MPR, and anal preservation rates were 36%, 66% and 86%. Grade ≥3 adverse events occurred in 20%. Subgroup analysis showed that; dMMR/MSI-H had a pooled pCR (100%) and MPR (100%), pMMR/MSS had a pooled pCR (38%) and MPR (60%); the short-course radiotherapy and long-course radiotherapy had pooled pCR rates of 51% and 30%, respectively. The rates of pCR for the concurrent and sequential immuno-chemoradiotherapy subgroups at 30% and 40%, mirroring pCR rates for the PD-L1 and PD-1 inhibitor subgroups were 32% and 40%, respectively.

Conclusion

In cases of locally advanced rectal cancer, PD-1/PD-L1 inhibitors combined with neoadjuvant chemoradiotherapy have shown promising response rates and acceptable toxicity profiles. PD-1/PD-L1 inhibitors combined with neoadjuvant chemoradiotherapy hence has a positive outcome even in MSS LARC patients.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/#myprospero, identifier CRD42023465380.
Artificial intelligence based data curation: enabling a patient-centric European health data space
Authors: de Zegher Isabelle , Norak Kerli , Steiger Dominik , Müller Heimo , Kalra Dipak , Scheenstra Bart , Cina Isabella , Schulz Stefan , Uma Kanimozhi , Kalendralis Petros , Lotman Eno-Martin , Benedikt Martin , Dumontier Michel , Celebi Remzi
Published: May 2024

The emerging European Health Data Space (EHDS) Regulation opens new prospects for large-scale sharing and re-use of health data. Yet, the proposed regulation suffers from two important limitations: it is designed to benefit the whole population with limited consideration for individuals, and the generation of secondary datasets from heterogeneous, unlinked patient data will remain burdensome. AIDAVA, a Horizon Europe project that started in September 2022, proposes to address both shortcomings by providing patients with an AI-based virtual assistant that maximises automation in the integration and transformation of their health data into an interoperable, longitudinal health record. This personal record can then be used to inform patient-related decisions at the point of care, whether this is the usual point of care or a possible cross-border point of care. The personal record can also be used to generate population datasets for research and policymaking. The proposed solution will enable a much-needed paradigm shift in health data management, implementing a ‘curate once at patient level, use many times’ approach, primarily for the benefit of patients and their care providers, but also for more efficient generation of high-quality secondary datasets. After 15 months, the project shows promising preliminary results in achieving automation in the integration and transformation of heterogeneous data of each individual patient, once the content of the data sources managed by the data holders has been formally described. Additionally, the conceptualization phase of the project identified a set of recommendations for the development of a patient-centric EHDS, significantly facilitating the generation of data for secondary use.
Paraspinal muscle parameters’ predictive value for new vertebral compression fractures post-vertebral augmentation: Nomogram development and validation
Authors: Tang Ming , Zhang Guangdong , Zeng Fanyi , Chang Xindong , Fang Qingqing , He Mingfei , Yin Shiwu
Published: May 2024

Objective

Prior research underscores the significance of paraspinal muscles in maintaining spinal stability. This study aims to investigate the predictive value of paraspinal muscle parameters for the occurrence of new vertebral compression fractures (NVCF) following percutaneous vertebroplasty (PVP) or percutaneous kyphoplasty (PKP) in patients with osteoporotic vertebral compression fractures (OVCF).

Methods

Retrospectively collected data from October 2019 to February 2021 (internal validation, n = 235) and March 2021 to November 2021 (external validation, n = 105) for patients with OVCF treated with PVP/PKP at our institution. They were randomly divided into training (188 cases) and validation groups (47 cases) at an 8:2 ratio. Lasso regression and multivariable logistic regression identified independent risk factors in the training set, and a Nomogram model was developed. Accuracy was assessed using receiver operating characteristic curves (ROC), calibration was evaluated with calibration curves and the Hosmer-Lemeshow test, and clinical utility was analyzed using decision curve analysis (DCA) and clinical impact curve (CIC).

Results

Surgical approach, spinal computed tomography (CT) values, and multifidus skeletal muscle index (SMI) are independent predictors of postoperative NVCF in OVCF patients. A Nomogram model, based on the identified predictors, was developed and uploaded online. Internal validation results showed area under the curve (AUC) values of 0.801, 0.664, and 0.832 for the training set, validation set, and external validation, respectively. Hosmer-Lemeshow goodness-of-fit tests (χ2 = 7.311–14.474, p = 0.070–0.504) and calibration curves indicated good consistency between observed and predicted values. DCA and CIC demonstrated clinical net benefit within risk thresholds of 0.06–0.84, 0.12–0.23, and 0.01–0.27. At specificity 1.00–0.80, the partial AUC (0.106) exceeded that at sensitivity 1.00–0.80 (0.062).

Conclusion

Compared to the spinal CT value, the multifidus SMI has certain potential in predicting the occurrence of NVCF. Additionally, the Nomogram model of this study has a greater negative predictive value.
Rapid progression of condyloma acuminatum caused by IL-17A antibody treatment: a case report
Authors: Sun Fang , Yu Zhenze
Published: May 2024

Anti interleukin (IL)-17A therapy is a common and effective treatment for psoriasis, but there are also risks of infection. In this case, we presented a patient who experienced a swift progression of condyloma acuminatum on the genitals during psoriasis treatment with secukinumab, a human IL-17A antagonist. Through this case, we strongly suspect that anti IL-17A treatment may promote the onset and rapid progression of low-risk HPV-associated condyloma acuminatum.
A prognostic nomogram for the cancer-specific survival rate of choroidal melanoma using the Surveillance, Epidemiology, and End Results database
Authors: Cao Xianfen , Zeng Jing , Ou Yulun , Chen Jian , Lyu Jun , Zhou Qing
Published: May 2024

Objective

This study was conducted to develop a comprehensive nomogram for individuals with choroidal melanoma (CM) to determine their cancer-specific survival (CSS).

Methods

Data of individuals with CM, diagnosed between 2004 and 2015, were accessed at the Surveillance, Epidemiology, and End Results (SEER) database. The selected individuals were randomly categorized into a training and validation cohort. Multivariate Cox regression analysis was applied to screen the relevant variables. Followed by the development of a nomogram based on independent variables. Ultimately, the net reclassification index (NRI), concordance index (C-index), calibration charts, integrated discrimination improvement (IDI), receiver operating characteristic curves (ROC), area under the curve (AUC), and decision-curve analysis (DCA), were utilized to evaluate the discrimination, accuracy, and effectiveness of the model.

Results

This study enrolled 3,782 patients. Seven independent factors linked to prognosis were screened via multivariate Cox regression analysis, encompassing age at diagnosis; race; AJCC (American Joint Committee on Cancer) stage; histologic type; and therapy method of radiotherapy, surgery, and chemotherapy. The respective C-indexes of the training and validation cohorts were 0.709 and 0.726, indicative of the excellent accuracy of the nomogram. Furthermore, the AUCs of the training and validation cohorts across 3, 5, and 8 years were 0.767, 0.744, and 0.722 as well as 0.772, 0.770, and 0.753, respectively. Evident of the superiority of the established nomogram over the AJCC staging, both the NRI and IDI values exhibited improvement. The favorable clinical impact and good performance of the nomogram were evident via decision curve analyses (DCAs) and calibration plots, respectively.

Conclusion

This research dealt with establishing and validating a nomogram as a prognostic tool for assessing the prognosis of adult patients with CM utilizing the SEER database. A comprehensive assessment of the nomogram via diverse variables demonstrated its accuracy in predicting the CSS probabilities of CM patients across 3, 5, and 8 years in clinical settings. Notably, its performance surpassed that of the AJCC staging system.
Acute complicated jejunum diverticulitis: a case report with a short literature review
Authors: Chiorescu Stefan , Mocan Mihaela , Santa Maria Elena , Mihăileanu Florin , Chiorescu Roxana Mihaela
Published: May 2024

Introduction

Jejunal diverticulosis is a rare condition. Most of the time, it is asymptomatic; but it can cause severe complications such as intestinal perforation, mechanical occlusion, and hemorrhage.

Case presentation

A patient aged 78 years, with a history of biological aortic valve prosthesis, atrial fibrillation, type 2 diabetes mellitus, and chronic obstructive pulmonary disease, presented in the emergency department for acute abdominal pain in the lower abdominal floor, nausea, and inappetence. Abdominal computed tomography revealed an inflammatory block in the hypogastrium, agglutinated small intestinal loops, fecal stasis, and air inclusions. Pulled mesentery and associated internal hernia are suspected. Exploratory laparotomy was performed, revealing an inflammatory block in the hypogastrium, whose dissection revealed inner purulent collection and the appearance of jejunal diverticulitis, a diagnosis confirmed by histopathological examination. Segmental resection of the jejunum with double-layer terminal–terminal enteroenteric anastomosis, lavage, and drainage was performed. The evolution was favorable.

Conclusion

Based on our brief review, the diagnosis of complicated jejunal diverticulosis is difficult and sometimes not accurately established, even by high-resolution imaging techniques, with diagnostic laparotomy being necessary for these situations. Surgical treatment should be considered before severe complications develop.
Integrated sequence and -omic features reveal novel small proteome of Mycobacterium tuberculosis
Authors: Sinha Priyansha Raj , Balasubramanian Rami , Hegde Shubhada R.
Published: May 2024

Bioinformatic studies on small proteins are under-represented due to difficulties in annotation posed by their small size. However, recent discoveries emphasize the functional significance of small proteins in cellular processes including cell signaling, metabolism, and adaptation to stress. In this study, we utilized a Random Forest classifier trained on sequence features, RNA-Seq, and Ribo-Seq data to uncover small proteins (smORFs) in M. tuberculosis. Independent predictions for the exponential and starvation conditions resulted in 695 potential smORFs. We examined the functional implications of these smORFs using homology searches, LC-MS/MS, and ChIP-seq data, testing their expression in diverse growth conditions, and identifying protein domains. We provide evidence that some of these smORFs could be part of operons, or exist as upstream ORFs. This expanded data resource for the proteins of M. tuberculosis would aid in fine-tuning the existing protein and gene regulatory networks, thereby improving system-wide studies. The primary goal of this study was to uncover and characterize smORFs in M. tuberculosis through bioinformatic analysis, shedding light on their functional roles and genomic organization. Further investigation of these potential smORFs would provide valuable insights into the genome organization and functional diversity of the M. tuberculosis proteome.
Insights into copper sensing and tolerance in Pneumocystis species
Authors: Porollo Aleksey , Sayson Steven G. , Ashbaugh Alan , Rebholz Sandra , Landero Figueroa Julio A. , Cushion Melanie T.
Published: May 2024

Introduction

Pneumocystis species are pathogenic fungi known to cause pneumonia in immunocompromised mammals. They are obligate to their host, replicate extracellularly in lung alveoli and thrive in the copper-enriched environment of mammalian lungs. In this study, we investigated the proteome of Pneumocystis murina, a model organism that infects mice, in the context of its copper sensing and tolerance.

Methods and results

The query for copper-associated annotations in FungiDB followed by a manual curation identified only 21 genes in P. murina, significantly fewer compared to other clinically relevant fungal pathogens or phylogenetically similar free-living fungi. We then employed instrumental analyses, including Size-Exclusion Chromatography Inductively Coupled Plasma Mass Spectrometry (SEC-ICP-MS), Immobilized Metal Affinity Chromatography (IMAC), and Liquid Chromatography–Tandem Mass Spectrometry (LC–MS/MS), to isolate and identify copper-binding proteins from freshly extracted organisms, revealing 29 distinct cuproproteins. The RNA sequencing (RNA-seq) analysis of P. murina exposed to various CuSO4 concentrations at three temporal intervals (0.5, 2, and 5 h) indicated that significant gene expression changes occurred only under the highest CuSO4 concentration probed (100 μM) and the longest exposure duration (5 h). This stimulus led to the upregulation of 43 genes and downregulation of 27 genes compared to untreated controls. Quantitative PCR (qPCR) confirmed the expression of four out of eight selected upregulated genes, including three assumed transcription factors (PNEG_01236, PNEG_01675, and PNEG_01730) and a putative copper transporter (PNEG_02609). Notably, the three applied methodologies — homology-based annotation, SEC-ICP-MS/IMAC/LC–MS/MS, and RNA-seq — yielded largely distinct findings, with only four genes (PNEG_02587, PNEG_03319, PNEG_02584, and PNEG_02989) identified by both instrumental methods.

Discussion

The insights contribute to the broader knowledge of Pneumocystis copper homeostasis and provide novel facets of host-pathogen interactions for extracellular pathogens. We suggest that future studies of Pneumocystis pathogenicity and copper stress survival should consider the entire spectrum of identified genes.
Delivering CRISPR to the HIV-1 reservoirs
Authors: Gurrola Theodore E. , Effah Samuel N. , Sariyer Ilker K. , Dampier Will , Nonnemacher Michael R. , Wigdahl Brian
Published: May 2024

Human immunodeficiency virus type 1 (HIV-1) infection is well known as one of the most complex and difficult viral infections to cure. The difficulty in developing curative strategies arises in large part from the development of latent viral reservoirs (LVRs) within anatomical and cellular compartments of a host. The clustered regularly interspaced short palindromic repeats/ CRISPR-associated protein 9 (CRISPR/Cas9) system shows remarkable potential for the inactivation and/or elimination of integrated proviral DNA within host cells, however, delivery of the CRISPR/Cas9 system to infected cells is still a challenge. In this review, the main factors impacting delivery, the challenges for delivery to each of the LVRs, and the current successes for delivery to each reservoir will be discussed.
Nicotine-mediated therapy for Parkinson’s disease in transgenic Caenorhabditis elegans model
Authors: Ullah Inam , Zhao Longhe , Uddin Shahab , Zhou Yangtao , Wang Xin , Li Hongyu
Published: May 2024

Parkinson’s disease resultant in the degeneration of Dopaminergic neurons and accumulation of α-synuclein in the substantia nigra pars compacta. The synthetic therapeutics for Parkinson’s disease have moderate symptomatic benefits but cannot prevent or delay disease progression. In this study, nicotine was employed by using transgenic Caenorhabditis elegans Parkinson’s disease models to minimize the Parkinson’s disease symptoms. The results showed that the nicotine at 100, 150, and 200 μM doses reduced degeneration of Dopaminergic neurons caused by 6-hydroxydopamine (14, 33, and 40%), lowered the aggregative toxicity of α-synuclein by 53, 56, and 78%, respectively. The reduction in food-sensing behavioral disabilities of BZ555 was observed to be 18, 49, and 86%, respectively, with nicotine concentrations of 100 μM, 150 μM, and 200 μM. Additionally, nicotine was found to enhance Daf-16 nuclear translocation by 14, 31, and 49%, and dose-dependently increased SOD-3 expression by 10, 19, and 23%. In summary, the nicotine might a promising therapy option for Parkinson’s disease.
MicroRNAs in microglia: deciphering their role in neurodegenerative diseases
Authors: Jadhav Shweta Pradip
Published: May 2024

This review presents a comprehensive analysis of the role of microRNAs in microglia and their implications in the pathogenesis of neurodegenerative diseases. Microglia, as the resident immune cells of the central nervous system (CNS), are pivotal in maintaining neural homeostasis and responding to pathological changes. Recent studies have highlighted the significance of miRNAs, small non-coding RNA molecules, in regulating microglial functions. In neurodegenerative diseases, such as Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), dysregulated miRNA expression in microglia contributes to disease progression through various mechanisms such regulation of gene expression, as modulation of cytokine response and phagocytosis. This review synthesizes current knowledge on how miRNAs influence microglial activation, cytokine production, and phagocytic activity. Specific miRNAs, such as miR-155, are explored for their roles in modulating microglial responses in the context of neuroinflammation and neurodegeneration. The study also discusses the impact of miRNA dysregulation on the transition of microglia from a neuroprotective to a neurotoxic phenotype, a critical aspect in the progression of neurodegenerative diseases.
Idarucizumab in dabigatran-treated patients with acute stroke: a review and clinical update
Authors: Frol Senta , Pretnar Oblak Janja , Šabovič Mišo , Ntaios George , Kermer Pawel
Published: May 2024

Idarucizumab is an antibody fragment specific for the immediate reversal of dabigatran anticoagulation effects. The use of idarucizumab is approved for dabigatran-treated patients suffering from life-threatening or uncontrolled bleeding and those in need of urgent surgery or invasive procedures. Data from randomized controlled clinical trials and real-world experience provide reassuring evidence about the efficacy and safety of idarucizmab use in patients with acute stroke. In this narrative review, we summarize the available real-world evidence and discuss the relevance and importance of idarucizumab treatment in acute stroke patients in everyday clinical practice. In addition, we also discuss special issues like prothrombin complex concentrate application as an alternative to idarucizumab, its application before endovascular therapy, sensitivity of thrombi to lysis, and necessary laboratory examinations.
Acupuncture modulates the AMPK/PGC-1 signaling pathway to facilitate mitochondrial biogenesis and neural recovery in ischemic stroke rats
Authors: Guo Kaixin , Lu Yan
Published: May 2024

Aims

The main objective of this study was to investigate the role and mechanism of acupuncture on anti-nerve injury in the acute phase by regulating mitochondrial energy metabolism via monophosphate-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) axis in rat ischemic stroke.

Main methods

Middle cerebral artery occlusion (MCAO) was established by middle cerebral artery occlusion/reperfusion. One-week of acupuncture was performed during the acute phase of ischemic stroke. The neurological function and brain tissue integrity were evaluated. Mitochondrial function (intracellular ATP level and the activity of mitochondrial respiratory chain complex I) and the level of NADH oxidase (NOX) were detected by enzymatic chemistry. Next, the potential molecular mechanisms were explored by western blotting, fluorescence quantitative PCR and immunohistochemistry method.

Key findings

(1) Acupuncture treatment for MCAO/R rats showed a significant improvement in the infarcted tissue accompanied by functional recovery in Zea-Longa score and balance beam score outcomes, motor function performances. (2) Acupuncture increased the levels of ATP and mitochondrial respiratory chain complex I, decreased the NOX levels in cerebral ischemia established by suture-occluded method. (3) Acupuncture reduced the necrosis dissolution of neuronal cells and meningeal edema, while promoting angiogenesis. (4) Quantitative immunohistochemical staining results showed acupuncture can increase the expression of AMPK, p-AMPK and the mitochondrial transcription factor PGC-1α, NRF2, TFAM and uncoupling protein 2 (UCP2). Meanwhile, acupuncture treatment up-regulated the expression of the corresponding protein. (5) Subsequently, acupuncture enhanced AMPK phosphorylation as well as the expression of PGC-1α, NRF2, TFAM and UCP2, implicated in mitochondrial synthesis and cellular apoptosis. (6) Finally, injections of AMPK antagonists and activators confirmed AMPK as a therapeutic target for the anti-nerve damage effects of acupuncture.

Significance

Acupuncture intervention relieved ischemic stroke progression in MCAO rats by promoting energy metabolism and mitochondrial biogenesis in the brain and alleviating neuronal apoptosis, which was mediated by eliciting AMPK/PGC-1α axis, among them AMPK is a therapeutic target.
Synergistic modification of hot-melt extrusion and nobiletin on the multi-scale structures, interactions, thermal properties, and in vitro digestibility of rice starch
Authors: Zhang Zhihong , Feng Ying , Wang Honglan , He Hai
Published: May 2024

Background

Rice starch has high digestibility due to its large carbohydrate content. Synergistic modification of hot-melt extrusion (HME) and additives such as flavonoids, hydrocolloids, proteins, lipids, and other additives has the tendency to retard the rate of starch hydrolysis. Hence, the current investigation aimed to study the combined effect of the HME-assisted addition of nobiletin (NOB, 0, 2, 4, and 6%) on the multi-scale structures, interactions, thermal, and digestibility characteristics of rice starch.

Methods

The study employed density functional theory calculations and an infrared second derivative of an Fourier-transform infrared (FTIR) spectrometer to analyze the interactions between NOB and starch. The physicochemical properties of the starch extrudates were characterized by FTIR, 13C nuclear magnetic resonance, X-ray diffraction, and differential scanning calorimetry, while the digestibility was evaluated using an in vitro digestion model.

Results

HME was found to disrupt the crystalline structure, helix structure, short-ordered structure, and thermal properties of starch. The interaction between NOB and starch involved hydrophobic interactions and hydrogen bonds, effectively preventing the molecular chains of starch from interacting with each other and disrupting their double helix structure. The addition of NOB led to the formation of a highly single-helical V-type crystalline structure, along with the formation of ordered structural domains. Consequently, the combined treatment significantly enhanced the ordered structure and thermal stability of starch, thus effectively leading to an increase in resistant starch and slowly digestion starch.

Discussion

The study underscores that synergistic modification of HME and NOB holds promise for enhancing both the nutritional value and functional properties of rice starch. These findings offer valuable insights for developing high-quality rice starch products with broader applications.
MiRNA polymorphisms affect the prognosis of gastric cancer: insights from Xianyou, Fujian
Authors: Wu Ping , Zhang Yuling , Lyu Yanping , Chen Jingwen , Jiang Yu , Xiang Jianjun , Liu Baoying , Wu Chuancheng
Published: May 2024

Introduction

Gastric cancer, characterized by high incidence and substantial disease burden, has drawn continuous attention regarding its occurrence and prognosis. Genetics plays a crucial role in influencing the prognosis of gastric cancer, and single nucleotide polymorphisms are closely associated with the occurrence, development, and prognosis of this malignant tumor. Our study aims to conduct survival analysis on patients carrying different single nucleotide polymorphisms, exploring the relationship between miRNA single nucleotide polymorphisms and the prognosis of gastric cancer.

Methods

Genetic data from 344 patients in Xianyou, Fujian, formed the basis of our study. We delineated the survival rate and median survival time, utilizing the log-rank test and COX regression analysis as statistical tools.

Results

Upon stratifying the data by sex or operation, it was discerned that the GG genotype at MSH2 rs17502941 independently posed a heightened risk for gastric cancer. Other stratification analyses suggested that the subsequent single nucleotide polymorphisms were correlated with patient prognosis: rs17502941, rs884225, rs1468063, rs7143252, and rs2271738.

Discussion

The outcomes of this study strongly suggest that miRNA polymorphisms significantly influence the survival time of gastric cancer patients and can serve as effective predictors for the prognosis of gastric cancer.
Ultrasound image-based nomogram combining clinical, radiomics, and deep transfer learning features for automatic classification of ovarian masses according to O-RADS
Authors: Liu Lu , Cai Wenjun , Tian Hongyan , Wu Beibei , Zhang Jing , Wang Ting , Hao Yi , Yue Guanghui
Published: May 2024

Background

Accurate and rapid discrimination between benign and malignant ovarian masses is crucial for optimal patient management. This study aimed to establish an ultrasound image-based nomogram combining clinical, radiomics, and deep transfer learning features to automatically classify the ovarian masses into low risk and intermediate-high risk of malignancy lesions according to the Ovarian- Adnexal Reporting and Data System (O-RADS).

Methods

The ultrasound images of 1,080 patients with 1,080 ovarian masses were included. The training cohort consisting of 683 patients was collected at the South China Hospital of Shenzhen University, and the test cohort consisting of 397 patients was collected at the Shenzhen University General Hospital. The workflow included image segmentation, feature extraction, feature selection, and model construction.

Results

The pre-trained Resnet-101 model achieved the best performance. Among the different mono-modal features and fusion feature models, nomogram achieved the highest level of diagnostic performance (AUC: 0.930, accuracy: 84.9%, sensitivity: 93.5%, specificity: 81.7%, PPV: 65.4%, NPV: 97.1%, precision: 65.4%). The diagnostic indices of the nomogram were higher than those of junior radiologists, and the diagnostic indices of junior radiologists significantly improved with the assistance of the model. The calibration curves showed good agreement between the prediction of nomogram and actual classification of ovarian masses. The decision curve analysis showed that the nomogram was clinically useful.

Conclusion

This model exhibited a satisfactory diagnostic performance compared to junior radiologists. It has the potential to improve the level of expertise of junior radiologists and provide a fast and effective method for ovarian cancer screening.
Mutation characteristics of cancer susceptibility genes in Chinese ovarian cancer patients
Authors: Wang Jie , Fu Kaiyu , Zhang Mengpei , Liang Lunggang , Ni Meng , Sun Hai-Xi , Yin Rutie , Tang Meifang
Published: May 2024

Introduction

The association between mutations in susceptibility genes and the occurrence of ovarian cancer has been extensively studied. Previous research has primarily concentrated on genes involved in the homologous recombination repair pathway, particularly BRCA1 and BRCA2. However, a wider range of genes related to the DNA damage response pathways has not been fully explored.

Methods

To investigate the mutation characteristics of cancer susceptibility genes in the Chinese ovarian cancer population and the associations between gene mutations and clinical data, this study initially gathered a total of 1171 Chinese ovarian cancer samples and compiled a dataset of germline mutations in 171 genes.

Results

In this study, it was determined that MC1R and PRKDC were high-frequency ovarian cancer susceptibility genes in the Chinese population, exhibiting notable distinctions from those in European and American populations; moreover high-frequency mutation genes, such as MC1R: c.359T>C and PRKDC: c.10681T>A, typically had high-frequency mutation sites. Furthermore, we identified c.8187G>T as a characteristic mutation of BRCA2 in the Chinese population, and the CHEK2 mutation was significantly associated with the early onset of ovarian cancer, while the CDH1 and FAM175A mutations were more prevalent in Northeast China. Additionally, Fanconi anemia pathway-related genes were significantly associated with ovarian carcinogenesis.

Conclusion

In summary, this research provided fundamental data support for the optimization of ovarian cancer gene screening policies and the determination of treatment, and contributed to the precise intervention and management of patients.