bluuebunny/crossref_metadata_2025 huggingface dataset:
State of the neoadjuvant therapy for glioblastoma multiforme—Where do we stand?
Authors: Nabian Naeim , Ghalehtaki Reza , Zeinalizadeh Mehdi , Balaña Carmen , Jablonska Paola Anna
Published: March 2024

Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. Despite several investigations in this field, maximal safe resection followed by chemoradiotherapy and adjuvant temozolomide with or without tumor-treating fields remains the standard of care with poor survival outcomes. Many endeavors have failed to make a dramatic change in the outcomes of GBM patients. This study aimed to review the available strategies for newly diagnosed GBM in the neoadjuvant setting, which have been mainly neglected in contrast to other solid tumors.
Decreased human leukocyte antigen-D–related expression on CD14+ monocytes in patients with out-of-hospital cardiac arrest provided target temperature management therapy: a prospective observational study
Authors: Shao Huan , Yuan Wei , Tang Ziren , Qi Zhijiang , An Le , Zhang Qiang , Li Chunsheng
Published: March 2024

Background

Post–cardiac arrest syndrome involves systemic inflammation, which causes subsequent neurological impairments. We investigated the influence of targeted temperature management (TTM) therapy in patients with out-of-hospital cardiac arrest (OHCA) after return of spontaneous circulation (ROSC) by observing the changes in circulating CD14+ monocytes and the expression of human leukocyte antigen D–related (HLA-DR) and programmed cell death ligand 1 (PD-L1) in CD14+ monocytes.

Methods

Adult patients admitted to the emergency department of Beijing Chao-Yang Hospital after OHCA between January 2017 and March 2018 were included in this study. Thirty control subjects, 10 patients with OHCA, and 37 patients with OHCA who received 72 hours of TTM therapy were enrolled. Peripheral blood samples of patients in the OHCA and TTM groups were collected on Days 1 and 3 (D1 and D3) after ROSC and evaluated for HLA-DR and PD-L1 expression on CD14+ monocytes using flow cytometry.

Results

Compared with control subjects, the percentage of circulating CD14+ monocytes, HLA-DR+/CD14+ monocyte ratios, and mean fluorescence intensity were significantly decreased in patients with OHCA. After ROSC, HLA-DR expression in CD14 + monocytes in the TTM group was lower than that in patients with OHCA. However, there were no significant differences in the percentage of PD-L1+/CD14+ monocytes or the mean fluorescence intensity between patients with OHCA and healthy volunteers.

Conclusion

After ROSC, circulating CD14+ monocytes and HLA-DR+/CD14+ monocyte ratios decreased significantly in patients with OHCA. Human leukocyte antigen D–related expression in CD14+ monocytes was lower in patients treated with TTM.
Success Rates of Finger Revascularization and Replantation
Authors: Kobayashi Koichi , Shinoura Susumu , Nishimura Ken , Masuyama Naoko
Published: March 2024

Background:

Revascularization surgery has been reported to have a higher success rate than replantation due to sufficient venous return. However, in complex cases, success depends on a wide range of indications. This study aimed to investigate success rates in cohorts that included severe cases.

Methods:

This single-center, noninterventional, retrospective cohort study included 292 patients (349 digits) who underwent revascularization or replantation at our institution between January 2000 and December 2022. Sex, age, smoking history, comorbidities, affected digit, amputation level, complete or incomplete amputation, type of fracture and mechanism, artery diameter, needle, vein anastomosis in the revascularization subgroup, vein grafting, warm ischemic time, and outcomes were investigated and compared between the revascularization and replantation subgroups of the distal and proximal amputation groups.

Results:

In the distal amputation group, the arterial diameter in the revascularization subgroup was larger than that in the replantation subgroup (P < 0.05). In the proximal amputation group, the revascularization subgroup had a lower frequency of multiple amputations than the replantation subgroup (P < 0.05). Vein grafts were more frequently used in both revascularization subgroups than in the replantation subgroups (P < 0.05). However, the other injury severity indices were similar, and the success rates were not significantly different between the subgroups.

Conclusions:

The revascularization success rate was similar to that of replantation. Vein anastomosis or vein grafting to the veins should be advocated for revascularization in severe cases where skin bridges may not have sufficient venous return.
Standardization of acupuncture and moxibustion technique in traditional Chinese medicine: taking Gua Sha therapy as an example
Authors: Liu Zhao , Jing Yeteng , Wu Yuan , Yang Li , Wang Yingying
Published: March 2024

Gua Sha (also known as scraping) therapy, one of the important external treatment techniques in traditional Chinese medicine (TCM), has developed into a mature system of technical standards through long-term clinical practice. In this paper, the development process of Gua Sha technical standardization is reviewed and the characteristics of the current standards system are accordingly analyzed. It turns out that standardization plays a vital role in promoting the inheritance and innovation of the Gua Sha technique. As a typical case of TCM standardization, the construction of the standardization system of Gua Sha provides valuable inspiration for further improving the TCM standardization system. For future TCM standardization, it is suggested that the problem-oriented principle should be adhered to and the formulation of standards should be based on China’s national conditions and demands; the top-level design should be strengthened and the standardized system should be perfected; the implementation of standards should be enhanced and international exchange and cooperation should be promoted. The standardization of TCM has a long way to go and needs the joint efforts of all stakeholders.
Effect of internal heat-type acupuncture on bone remodeling in a glucocorticoid-induced osteoporosis model rabbit by regulating the triplet of OPG-RANKL-RANK
Authors: Tian Fubao , Ma Haibo , Lian Jiawei , Chen Mengying , Chen Kun , Ma Liangchen , Wen Bojun , Lai Zheying , Tao Ying , Xu Yujuan , Tian Xinbao , Huang Yuan , Zhu Ning , Xu Jianfeng , Lin Ruizhu
Published: March 2024

Introduction:

Internal heat-type acupuncture therapy is a new therapeutic method that integrates acupuncture and heat therapy and effectively reduces local muscle inflammation. It has a good effect on the clinical application of osteoporosis. The purpose of this study was to assess the improvement of glucocorticoid-induced osteoporosis (GIOP) after internal heat-type acupuncture treatment as well as its role in promoting the balance of bone remodeling in the GIOP rabbit model by regulating the triplet of osteoprotegerin(OPG)-receptor activator of nuclear factor-KB ligand (RANKL)-receptor activator of nuclear factor-KB (RANK).

Methods:

The rabbits were divided into the control, model (GIOP), GIOP+Alendronate, and GIOP+Internal heat-type acupuncture groups, with 8 rabbits in each group. At the end of the treatment, all rabbits were sacrificed. The pathologic changes of lumbar vertebrae were observed by x-ray, the morphology of lumbar trabecular bone was observed by HE staining, and the apoptosis of lumbar vertebrae was detected by Tunel. The protein expressions of OPG, RANKL, and RANK in lumbar vertebrae were detected by immunohistochemistry staining, immunofluorescence staining, and Western blotting.

Results:

Internal heat-type acupuncture partly prevented osteopenia among GIOP-induced rabbits, improved the morphology of lumbar vertebrae, and inhibited the apoptosis of lumbar vertebrae osteocytes. Moreover, by increasing the protein expression level of OPG and reducing the protein expression of RANKL and RANK, internal heat-type acupuncture effectively promoted the balance of bone remodeling and eventually achieved the treatment of GIOP.

Conclusion:

Internal heat-type acupuncture therapy may promote the balance of bone remodeling by regulating the triplet of osteoprotegerin-receptor activator of nuclear factor-KB ligand-receptor activator of nuclear factor-KB, thereby treating osteoporosis which was induced by glucocorticoid.
Hepatocellular carcinoma cells downregulate NADH:Ubiquinone Oxidoreductase Subunit B3 to maintain reactive oxygen species homeostasis
Authors: Zhang Zhendong , Zhao Qianwei , Wang Zexuan , Xu Fang , Liu Yixian , Guo Yaoyu , Li Chenglong , Liu Ting , Zhao Ying , Tang Xiaolei , Zhang Jintao
Published: March 2024

Background:

HCC is a leading cause of cancer-related death. The role of reactive oxygen species (ROS) in HCC remains elusive. Since a primary ROS source is the mitochondrial electron transport chain complex Ι and the NADH:ubiquinone Oxidoreductase Subunit B3 (NDUFB3), a complex I subunit, is critical for complex I assembly and regulates the associated ROS production, we hypothesize that some HCCs progress by hijacking NDUFB3 to maintain ROS homeostasis.

Methods:

NDUFB3 in human HCC lines was either knocked down or overexpressed. The cells were then analyzed in vitro for proliferation, migration, invasiveness, colony formation, complex I activity, ROS production, oxygen consumption, apoptosis, and cell cycle. In addition, the in vivo growth of the cells was evaluated in nude mice. Moreover, the role of ROS in the NDUFB3-mediated changes in the HCC lines was determined using cellular and mitochondrion-targeted ROS scavengers.

Results:

HCC tissues showed reduced NDUFB3 protein expression compared to adjacent healthy tissues. In addition, NDUFB3 knockdown promoted, while its overexpression suppressed, HCC cells’ growth, migration, and invasiveness. Moreover, NDUFB3 knockdown significantly decreased, whereas its overexpression increased complex I activity. Further studies revealed that NDUFB3 overexpression elevated mitochondrial ROS production, causing cell apoptosis, as manifested by the enhanced expressions of proapoptotic molecules and the suppressed expression of the antiapoptotic molecule B cell lymphoma 2. Finally, our data demonstrated that the apoptosis was due to the activation of the c-Jun N-terminal kinase (JNK) signaling pathway and cell cycle arrest at G0/G1 phase.

Conclusions:

Because ROS plays essential roles in many biological processes, such as aging and cancers, our findings suggest that NDFUB3 can be targeted for treating HCC and other human diseases.
Long-Term Follow-Up of Pediatric Excimer Laser-Assisted Penetrating Keratoplasty for Congenital Stromal Corneal Dystrophy
Authors: Berger Tim , Hasenfus Andrea , Bredrup Cecilie , Gatzioufas Zisis , Flockerzi Fidelis , Käsmann-Kellner Barbara , Daas Loay , Flockerzi Elias , Knappskog Per M. , Stang Espen , Seitz Berthold
Published: March 2024

Purpose:

The purpose of this study was to highlight characteristic clinical and microscopic findings and report the long-term follow-up of pediatric excimer laser-assisted penetrating keratoplasty (excimer-PKP) for congenital stromal corneal dystrophy (CSCD).

Methods:

A 2-year-old Greek child presented with CSCD at our department. Clinical examination showed bilateral flake-like whitish corneal opacities affecting the entire corneal stroma up to the limbus. Genetic testing identified a mutation of the decorin gene (c.962delA). The variant was not present in the parents and represented a de novo mutation. The uncorrected visual acuity was 20/100 in both eyes. Excimer-PKP (8.0/8.1 mm) was performed on the right eye at the age of 2.5 years and on the left eye at the age of 3 years. Postoperatively, alternating occlusion treatment was performed.

Results:

The light microscopic examination demonstrated a disorganized extracellular matrix of the corneal stroma characterized by a prominent irregular arrangement of stromal collagen lamellae with large interlamellar clefts containing ground substance, highlighted by periodic acid–Schiff- and Alcian blue–positive reaction detecting acid mucopolysaccharides. Electron microscopy showed disorganization and caliber variation of collagen lamellae and thin filaments within an electron-lucent ground substance. The postoperative course was unremarkable. Both grafts remained completely clear 14 years postoperatively. Corneal tomography showed moderate regular astigmatism with normal corneal thickness. The corrected distance visual acuity was 20/25 in both eyes.

Conclusions:

Excimer-PKP for CSCD might be associated with excellent long-term results and a good prognosis, particularly when the primary surgery is performed at a very young age. However, this requires close postoperative follow-up examinations by an experienced pediatric ophthalmologist to avoid severe amblyopia.
Characteristics and Significance of Tertiary Lymphoid Structures Based on Molecular Subtypes in Endometrial Cancer
Authors: Jia Hui-Qing , Zhang Shu-Ping , Chen Yang , Qiao Ye-Hua , Yao Yi-Fan , Zhang Xiang-Yan , Wu Si-Yu , Song Yao-Lin , Xing Xiao-Ming
Published: March 2024

The purpose of this study is to investigate the characteristics and significance of tertiary lymphoid structures (TLSs) in endometrial cancer (EC) based on molecular subtypes. A total of 220 patients with EC were retrospectively enrolled, including 20 with polymerase epsilon ultramutated (POLE-mut), 63 with mismatch repair deficient, 32 with p53 abnormal, and 105 with no specific molecular profile. The presence and maturity of TLSs were determined by immunohistochemical markers (CD3, CD20, CD21, and Bcl6). Disease-free survival served as the endpoint event. TLSs were found in 91 out of 220 patients (41.1%), with 68 located in peritumoral tissues and 37 exhibiting well-formed germinal center structures. The presence and different maturity of TLSs were closely associated with tumor-infiltrating lymphocytes and the programmed cell death ligand-1 expression. Moreover, TLSs displayed heterogeneity across different molecular subtypes. Notably, the TLSs, tumor-infiltrating lymphocytes, and expression of the programmed cell death ligand-1 were significantly enriched in POLE-mut EC. Multivariate logistic regression analysis showed the presence of TLSs (odds ratio: 3.483, 95% CI: 1.044–11.623, P = 0.042) as a potential predictor of POLE-mut EC. Kaplan-Meier survival curves revealed that molecular subtypes significantly stratified prognosis in patients with EC (P = 0.002), whereas TLSs did not. Multivariate Cox regression analysis indicated that The International Federation of Gynecology and Obstetrics stage and Ki-67 expression were independent prognostic factors affecting disease-free survival in patients with EC, and TLSs were not included. In conclusion, TLSs in EC exhibit heterogeneity based on molecular subtypes, necessitating further exploration to determine their clinical application value.
Financial Hardship and Sleep Quality Among Black American Women With and Without Systemic Lupus Erythematosus
Authors: Abdallah Khadijah , Udaipuria Shivika , Murden Raphiel , McKinnon Izraelle I. , Erving Christy L. , Fields Nicole , Moore Reneé , Booker Bianca , Burey Taylor , Dunlop-Thomas Charmayne , Drenkard Cristina , Johnson Dayna A. , Vaccarino Viola , Lim S. Sam , Lewis Tené T.
Published: March 2024

Objective

To compare dimensions of financial hardship and self-reported sleep quality among Black women with versus without systemic lupus erythematosus (SLE).

Methods

Participants were 402 Black women (50% with validated diagnosis of SLE) living in Georgia between 2017 and 2020. Black women with SLE were recruited from a population-based cohort established in Atlanta, and Black women without SLE were recruited to be of comparable age and from the same geographic areas as SLE women. Financial hardship was measured using three different scales: financial adjustments, financial setbacks, and financial strain. Sleep was assessed continuously using the Pittsburgh Sleep Quality Index (PSQI) scale. Each dimension of financial hardship was analyzed separately in SLE-stratified multivariable linear regression models and adjusted by sociodemographic and health status factors.

Results

Dimensions of financial hardship were similarly distributed across the two groups. Sleep quality was worse in Black women with, versus without, SLE (p < .001). Among Black women with SLE, financial adjustment was positively associated with a 0.40-unit increase in poor sleep quality (95% CI = 0.12–0.67, p = .005). When accounting for cognitive depressive symptoms, financial setbacks and strain were somewhat attenuated for Black women with SLE. Overall, no associations between financial hardships and sleep quality were observed for the women without SLE.

Conclusions

Black women with SLE who experience financial hardships may be more at risk for poor sleep quality than Black women without SLE. Economic interventions targeting this population may help improve their overall health and quality of life.
Addressing the Contrast Media Recognition Challenge
Authors: Baldini Giulia , Hosch René , Schmidt Cynthia S. , Borys Katarzyna , Kroll Lennard , Koitka Sven , Haubold Patrizia , Pelka Obioma , Nensa Felix , Haubold Johannes
Published: March 2024

Objectives

Accurately acquiring and assigning different contrast-enhanced phases in computed tomography (CT) is relevant for clinicians and for artificial intelligence orchestration to select the most appropriate series for analysis. However, this information is commonly extracted from the CT metadata, which is often wrong. This study aimed at developing an automatic pipeline for classifying intravenous (IV) contrast phases and additionally for identifying contrast media in the gastrointestinal tract (GIT).

Materials and Methods

This retrospective study used 1200 CT scans collected at the investigating institution between January 4, 2016 and September 12, 2022, and 240 CT scans from multiple centers from The Cancer Imaging Archive for external validation. The open-source segmentation algorithm TotalSegmentator was used to identify regions of interest (pulmonary artery, aorta, stomach, portal/splenic vein, liver, portal vein/hepatic veins, inferior vena cava, duodenum, small bowel, colon, left/right kidney, urinary bladder), and machine learning classifiers were trained with 5-fold cross-validation to classify IV contrast phases (noncontrast, pulmonary arterial, arterial, venous, and urographic) and GIT contrast enhancement. The performance of the ensembles was evaluated using the receiver operating characteristic area under the curve (AUC) and 95% confidence intervals (CIs).

Results

For the IV phase classification task, the following AUC scores were obtained for the internal test set: 99.59% [95% CI, 99.58–99.63] for the noncontrast phase, 99.50% [95% CI, 99.49–99.52] for the pulmonary-arterial phase, 99.13% [95% CI, 99.10–99.15] for the arterial phase, 99.8% [95% CI, 99.79–99.81] for the venous phase, and 99.7% [95% CI, 99.68–99.7] for the urographic phase. For the external dataset, a mean AUC of 97.33% [95% CI, 97.27–97.35] and 97.38% [95% CI, 97.34–97.41] was achieved for all contrast phases for the first and second annotators, respectively. Contrast media in the GIT could be identified with an AUC of 99.90% [95% CI, 99.89–99.9] in the internal dataset, whereas in the external dataset, an AUC of 99.73% [95% CI, 99.71–99.73] and 99.31% [95% CI, 99.27–99.33] was achieved with the first and second annotator, respectively.

Conclusions

The integration of open-source segmentation networks and classifiers effectively classified contrast phases and identified GIT contrast enhancement using anatomical landmarks.
Factors Impacting Academic Productivity and Satisfaction of Surgeon-scientists
Authors: Marincola Smith Paula , Martinez Amy , Irlmeier Rebecca , Solórzano Carmen C. , Magge Deepa , Ye Fei , Goldenring James R.
Published: March 2024

Objective:

To identify factors related to research success for academic surgeons.

Background:

Many recognize mounting barriers to scientific success for academic surgeons, but little is known about factors that predict success for individual surgeons.

Methods:

A phase 1 survey was emailed to department chairpersons at highly funded U.S. departments of surgery. Participating chairpersons distributed a phase 2 survey to their faculty surgeons. Training and faculty-stage exposures and demographic data were collected and compared with participant-reported measures of research productivity. Five primary measures of productivity were assessed, including the number of grants applied for, grants funded, papers published, first/senior author papers published, and satisfaction with research.

Results:

Twenty chairpersons and 464 faculty surgeons completed the survey, and 444 faculty responses were included in the final analysis. Having a research-focused degree was significantly associated with more grants applied for [Doctor of Philosophy, incidence rate ratio (IRR) = 6.93; Masters, IRR = 4.34] and funded (Doctor of Philosophy, IRR = 4.74; Masters, IRR = 4.01) compared with surgeons with only clinical degrees (all P < 0.01). Having a formal research mentor was significantly associated with more grants applied for (IRR = 1.57, P = 0.03) and higher satisfaction in research (IRR = 2.22, P < 0.01). Contractually protected research time was significantly associated with more grants applied for (IRR = 3.73), grants funded (IRR = 2.14), papers published (IRR = 2.12), first/senior authors published (IRR = 1.72), and research satisfaction (odds ratio = 2.15; all P < 0.01). The primary surgeon-identified barrier to research productivity was lack of protection from clinical burden.

Conclusions:

Surgeons pursuing research-focused careers should consider the benefits of attaining a research-focused degree, negotiating for contractually protected research time, and obtaining formal research mentorship.
Contributions of transcriptional noise to leukaemia evolution: KAT2A as a case-study
Authors: Pina Cristina
Published: March 2024

Transcriptional noise is proposed to participate in cell fate changes, but contributions to mammalian cell differentiation systems, including cancer, remain associative. Cancer evolution is driven by genetic variability, with modulatory or contributory participation of epigenetic variants. Accumulation of epigenetic variants enhances transcriptional noise, which can facilitate cancer cell fate transitions. Acute myeloid leukaemia (AML) is an aggressive cancer with strong epigenetic dependencies, characterized by blocked differentiation. It constitutes an attractive model to probe links between transcriptional noise and malignant cell fate regulation. Gcn5/KAT2A is a classical epigenetic transcriptional noise regulator. Its loss increases transcriptional noise and modifies cell fates in stem and AML cells. By reviewing the analysis of KAT2A-depleted pre-leukaemia and leukaemia models, I discuss that the net result of transcriptional noise is diversification of cell fates secondary to alternative transcriptional programmes. Cellular diversification can enable or hinder AML progression, respectively, by differentiation of cell types responsive to mutations, or by maladaptation of leukaemia stem cells. KAT2A-dependent noise-responsive genes participate in ribosome biogenesis and KAT2A loss destabilizes translational activity. I discuss putative contributions of perturbed translation to AML biology, and propose KAT2A loss as a model for mechanistic integration of transcriptional and translational control of noise and fate decisions.

This article is part of a discussion meeting issue ‘Causes and consequences of stochastic processes in development and disease’.
Stochasticity in genetics and gene regulation
Authors: van Heyningen Veronica
Published: March 2024

Development from fertilized egg to functioning multi-cellular organism requires precision. There is no precision, and often no survival, without plasticity. Plasticity is conferred partly by stochastic variation, present inherently in all biological systems. Gene expression levels fluctuate ubiquitously through transcription, alternative splicing, translation and turnover. Small differences in gene expression are exploited to trigger early differentiation, conferring distinct function on selected individual cells and setting in motion regulatory interactions. Non-selected cells then acquire new functions along the spatio-temporal developmental trajectory. The differentiation process has many stochastic components. Meiotic segregation, mitochondrial partitioning, X-inactivation and the dynamic DNA binding of transcription factor assemblies—all exhibit randomness. Non-random X-inactivation generally signals deleterious X-linked mutations. Correct neural wiring, such as retina to brain, arises through repeated confirmatory activity of connections made randomly. In immune system development, both B-cell antibody generation and the emergence of balanced T-cell categories begin through stochastic trial and error followed by functional selection. Aberrant selection processes lead to immune dysfunction. DNA sequence variants also arise through stochastic events: some involving environmental fluctuation (radiation or presence of pollutants), or genetic repair system malfunction. The phenotypic outcome of mutations is also fluid. Mutations may be advantageous in some circumstances, deleterious in others.

This article is part of a discussion meeting issue ‘Causes and consequences of stochastic processes in development and disease’.
Prevalence of hepatitis A virus among migrant workers in Qatar: A national study
Authors: Younes Nadin , Chemaitelly Hiam , Nizamuddin Parveen Banu , Al-Hamad Tasneem , Abdallah Marah , Yassine Hadi M , Abu-Raddad Laith J , Nasrallah Gheyath K.
Published: March 2024

Background

Hepatitis A virus (HAV) is the predominant cause of acute viral hepatitis worldwide; however, data on HAV antibody prevalence (seroprevalence) among migrant populations are limited. This study aimed to investigate HAV seroprevalence among Qatar’s migrant craft and manual workers (CMWs), constituting approximately 60% of the country’s population.

Methods

HAV antibody testing was conducted on stored serum specimens obtained from CMWs during a nationwide severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) population- based cross-sectional survey between July 26 and September 9, 2020. Associations with HAV infection were investigated through regression analyses.

Results

Of the 2,607 specimens with HAV antibody test results, 2,393 were positive, and 214 were negative. The estimated HAV seroprevalence among CMWs was 92.0% (95% CI: 90.9- 93.1%). HAV seroprevalence was generally high but exhibited some variation, ranging from 70.9% (95% CI: 62.4-78.2%) among Sri Lankans to 99.8% (95% CI: 98.2-99.9%) among Pakistanis. The multivariable regression analysis identified age, nationality, and educational attainment as statistically significant factors associated with HAV infection. Relative to CMWs aged ≤29 years, the adjusted relative risk (ARR) was 1.06 (95% CI: 1.03-1.10) in CMWs aged 30- 39 years and reached 1.15 (95% CI: 1.10-1.19) in those aged ≥50 years. In comparison to Indians, the ARR was lower among Sri Lankans, assessed at 0.81 (95% CI: 0.72-0.91), but higher among Nepalese at 1.07 (95% CI: 1.04-1.11), Bangladeshis at 1.10 (95% CI: 1.07-1.13), Pakistanis at 1.12 (95% CI: 1.09-1.15), and Egyptians at 1.15 (95% CI: 1.08-1.23). No evidence for differences was found by geographic location or occupation.

Conclusions

HAV seroprevalence among Qatar’s CMW population is very high, with over nine out of every ten individuals having been exposed to this infection, likely during childhood.
IMPACT OF GEOSPATIAL FOOD ACCESS ON ACUTE PANCREATITIS OUTCOMES
Authors: Chhoda Ankit , Noriega Marco , Kahan Tamara , Cartelle Anabel Liyen , Anderson Kelsey , Zuberi Shaharyar A. , Olivares Miriam , Kelly Jill , Freedman Steven D. , Rabinowitz Loren G. , Sheth Sunil G.
Published: March 2024

BACKGROUND AND AIM

Food access is an important social determinant of health and refers to geographical and infrastructural aspects of food availability. Using publicly available data on food access from the United States Department of Agriculture (USDA), geospatial analyses can identify regions with variable food access, which may impact acute pancreatitis (AP), an acute inflammatory condition characterized by unpredictable outcomes and substantial mortality. This study aimed to investigate the association of clinical outcomes in patients with AP with geospatial food access.

METHODS

We examined AP-related hospitalizations at a tertiary center from January 2008 to December 2018. The physical addresses were geocoded through ArcGIS Pro2.7.0 (ESRI, Redlands, CA). USDA Food Access Research Atlas defined low food access as urban areas with 33% or more of the population residing over one mile from the nearest food source. Regression analyses enabled assessment of the association between AP outcomes and food access.

RESULTS

The study included 772 unique patients with AP residing in Massachusetts with 931 AP-related hospitalizations. One hundred and ninety-eight (25.6%) patients resided in census tracts withnormalurban food access and 574 (74.4%) patients resided in tracts withlowfood access. AP severity per revised Atlanta classification [OR: 1.88 (95%CI: 1.21-2.92);p=0.005], and 30-day AP-related readmission [OR: 1.78(95%CI: 1.11-2.86);p=0.02] had significant association with food access, despite adjustment for demographics, healthcare behaviors, and comorbidities (Charlson Comorbidity Index). However, food access lacked significant association with AP-related mortality (p=0.40) and length of stay (LOS:p=0.99).

CONCLUSION

Low food access had a significant association with 30-day AP-related readmissions and AP severity. However, mortality and LOS lacked significant association with food access. The association between nutrition, lifestyle, and AP outcomes warrants further prospective investigation.
Thymidine Phosphorylase Promotes the Formation of Abdominal Aortic Aneurysm in Mice Fed a Western Diet
Authors: Hong Liang , Yue Hong , Cai Dunpeng , DeHart Autumn , Toloza-Alvarez Gretel , Du Lili , Zhou Xianwu , Fan Xiaoping , Huang Huanlei , Chen Shiyou , Rahaman Shaik O. , Zhuang Jian , Li Wei
Published: March 2024

Aims

The precise molecular drivers of abdominal aortic aneurysm (AAA) remain unclear. Thymidine phosphorylase (TYMP) contributes to increased platelet activation, thrombosis, and inflammation, all of which are key factors in AAA development. Additionally, TYMP suppresses the proliferation of vascular smooth muscle cells (VSMCs), which are central to the development and progression of AAA. We hypothesize that TYMP plays a key role in AAA development.

Methods and Results

We conducted a histological study using human AAA samples and normal abdominal aortas, revealing heightened levels of TYMP in human AAA vessel walls. To validate this observation, we utilized an Ang II perfusion-induced AAA model in wild-type C57BL/6J (WT) andTymp−/−mice, feeding them a Western diet (TD.88137) starting from 4 weeks of age. We found thatTymp−/−mice were protected from Ang II perfusion-induced AAA formation. Furthermore, by using TYMP-expressing VSMCs as well as primarily cultured VSMCs from WT andTymp−/−mice, we elucidated the essential role of TYMP in regulating MMP2 expression and activation. TYMP deficiency or inhibition by tipiracil, a selective TYMP inhibitor, led to reduced MMP2 production, release, and activation in VSMCs. Additionally, TYMP was found to promote pro-inflammatory cytokine expression systemically, and its absence attenuates TNF-α-stimulated activation of MMP2 and AKT. By co-culturing VSMCs and platelets, we observed that TYMP-deficient platelets had a reduced inhibitory effect on VSMC proliferation compared to WT platelets. Moreover, TYMP appeared to enhance the expression of activated TGFβ1 in cultured VSMCs in vitro and in human AAA vessel walls in vivo. TYMP also boosted the activation of thrombospondin-1 type 1 repeat domain-enhanced TGFβ1 signaling, resulting in increased connective tissue growth factor production.

Conclusion

Our findings collectively demonstrated that TYMP serves as a novel regulatory force in vascular biology, exerting influence over VSMC functionality and inflammatory responses that promote the development of AAA.

Translational Perspective

Thymidine phosphorylase (TYMP) is increased in the vessel walls of patients with abdominal aortic aneurysm (AAA), and TYMP deficiency in mice reduces the incidence of AAA, suggesting that TYMP plays a crucial role in AAA development. This could be attributed to TYMP’s role in enhancing systemic inflammation and thrombosis, inhibiting vascular smooth muscle cell function, increasing the activation of matrix metalloproteinase and AKT, as well as enhancing the expression of TGFβ1 and connective tissue growth factor. Tipiracil is an FDA-approved drug known to inhibit TYMP-enhanced thrombosis. Targeting TYMP with tipiracil could represent a promising new therapeutic strategy for AAA development.
The trade-off between grain weight and grain number in wheat is explained by the overlapping of the key phases determining these major yield components
Authors: Vicentin Lucas , Canales Javier , Calderini Daniel F.
Published: March 2024

Enhancing grain yield is a primary goal in the cultivation of major staple crops, including wheat. Recent research has focused on identifying the physiological and molecular factors that influence grain weight, a critical determinant of crop yield. However, a bottleneck has arisen due to the trade-off between grain weight and grain number, whose underlying causes remain elusive. In a novel approach, a wheat expansin gene, TaExpA6, known for its expression in root tissues, was engineered to express in the grains of the spring wheat cultivar Fielder. This modification led to increases in both grain weight and yield without adversely affecting grain number. Conversely, a triple mutant line targeting the gene TaGW2, a known negative regulator of grain weight, resulted in increased grain weight but decreased grain number, potentially offsetting yield gains. This study aimed to evaluate four wheat genotypes: (i) a transgenic line expressing TaExpA6, (ii) its wild-type counterpart (Fielder), (iii) a TaGW2 triple mutant line, and (iv) its wild-type. Conducted in southern Chile, the study employed a Complete Randomized Block Design with four replications, under well-managed field conditions including fertilization, irrigation, and pest control. The primary metrics assessed were grain yield, grain number, and average grain weight per spike, along with detailed measurements of grain weight and dimensions across the spike, and ovary weight at pollination (Waddington’s scale 10). The expression levels of TaExpA6 and TaGW2 were also monitored post-anthesis. Results indicated that both the TaExpA6 line and the triple mutant line achieved significantly higher average grain weights compared to their respective wild types. Notably, the TaExpA6 line did not exhibit a reduction in grain number, thereby enhancing grain yield per spike. In contrast, the triple mutant line showed a reduced grain number per spike, with no significant change in overall yield. Analysis of ovary size, grain weight dynamics, and gene expression patterns suggests that the trade-off between grain weight and number could be attributed to the overlapping of the critical periods for the determination of these traits.
MMCCI: multimodal integrative analysis of single-cell and spatial cell-type communications to uncover overarching and condition-specific ligand-receptor interaction pathways
Authors: Hockey Levi , Mulay Onkar , Xiong Zherui , Tan Samuel X. , Khosrotehrani Kiarash , Nefzger Christian M. , Nguyen Quan
Published: March 2024

Cell-cell interaction (CCI) analyses are an indispensable tool for harnessing the detail and depth of spatial and single-cell transcriptomics datasets by inferring inter-cellular communications, but no methods to integrate CCI results across samples exist currently. To address this, we have developed a computational pipeline, Multimodal CCI (MMCCI), to statistically integrate and analyze CCI results from existing popular CCI tools. We benchmarked MMCCI’s integration on single-cell spatial datasets and found it to be highly accurate compared to simpler methods. We utilized MMCCI’s integration and downstream biological analyses to uncover global and differential interaction patterns in multimodal aging brain and melanoma spatial datasets.
HY5 and COP1 function antagonistically in the light-dependent regulation of nicotine biosynthesis in tobacco
Authors: Singh Deeksha , Dwivedi Shambhavi , Singh Nivedita , Trivedi Prabodh Kumar
Published: March 2024

Nicotine constitutes approximately 90% of the total alkaloid content within theNicotianaspecies, rendering it the most prevalent alkaloid. While the majority of genes responsible for nicotine biosynthesis express in root tissue, the influence of light on this process through shoot-to-root mobile ELONGATED HYPOCOTYL 5 (HY5) has been recognized. CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1), a key regulator of light-associated responses, known for its role in modulating HY5 accumulation, remains largely unexplored in its relationship to light-dependent nicotine accumulation. Here, we identified NtCOP1, a COP1 homolog inNicotiana tabacum, and demonstrated its ability to complement thecop1mutant inArabidopsis thalianaat molecular, morphological, and biochemical levels. Through the development of NtCOP1 overexpression (NtCOP1OX) plants, we observed a significant reduction in nicotine and flavonol content, inversely correlated with the down-regulation of nicotine and phenylpropanoid pathway. Conversely, CRISPR/Cas9-based knockout mutant plants (NtCOP1CR) exhibited an increase in nicotine levels. Further investigations, including yeast-two hybrid assays, grafting experiments, and western blot analyses, revealed that NtCOP1 modulates nicotine biosynthesis by targeting NtHY5, thereby impeding its transport from shoot-to-root. We conclude that the interplay between HY5 and COP1 functions antagonistically in the light-dependent regulation of nicotine biosynthesis in tobacco.

Highlight

Characterization of CONSTITUTIVE PHOTOMORPHOGENIC1 (COP1) overexpressing and CRISPR/Cas9-based mutant plants suggests the intricate role of COP1 in modulating nicotine biosynthesis in tobacco.
Functional Specialization and Distributed Processing across Marmoset Lateral Prefrontal Subregions
Authors: Wong Raymond Ka , Selvanayagam Janahan , Johnston Kevin D , Everling Stefan
Published: March 2024

A prominent aspect of the organization of primate lateral prefrontal cortex (lPFC) is its division into a number of cytoarchitecturally distinct subregions. Investigations in macaque lPFC using neurophysiological approaches have provided much insight into the functions associated with these subregions; however, our understanding is based largely on a patchwork of findings from many studies and across many animals, rarely covering the entire lPFC in individual subjects. Here, we leveraged the small size and lissencephalic cortex of the common marmoset (Callithrix jacchus) to characterize the responses of large numbers of single lPFC neurons to a diverse collection of test stimuli recorded across sets of lPFC subregions using high-density microelectrode arrays. Untethered extracellular electrophysiological recordings were obtained from two adult marmosets with 4 x 4 mm 96-channel Utah arrays implanted in lPFC, covering areas 8aD, 8aV, 9, 10, 46D, 46V and 47. We employed a test battery comprised of a variety of visual stimuli including faces and body parts, auditory stimuli including marmoset calls, and a spatial working memory task. Task-modulated units and units responsive to different stimulus modalities were distributed throughout the lPFC. Visual, auditory and call-selective units were distributed across all lPFC subregions. Neurons with contralateral visual receptive fields were found in 8aV and 8aD. Neurons responsive to faces and saccade-related units were found in 8aV, 8aD, 10, 46V and 47. These findings demonstrate that responses to some stimuli are relatively restricted within specific lPFC subregions, while others are more distributed throughout the marmoset lPFC.
Comparing cellular response to two radiation treatments based on key features visualization
Authors: Arsenteva Polina , Guipaud Olivier , Paget Vincent , Santos Morgane Dos , Tarlet Georges , Milliat Fabien , Cardot Hervé , Benadjaoud Mohamed Amine
Published: March 2024

Motivation

In modern treatment by radiotherapy, different irradiation modalities can be used, potentially producing different amounts of adverse effects. The differences between these modalities are often studied via two-sample time course in vitro experiments. The resulting data may be of high complexity, in which case simple methods are unadapted for extracting all the relevant information.

Methods

In this article we introduce network-based tools for the visualization of the key statistical features, extracted from the data. For the key features extraction we utilize a statistical framework performing estimation, clustering with alignment of temporal omic fold changes originating from two-sample time course data.

Results

The approach was applied to real transcriptomic data obtained with two different types of irradiation. The results were analyzed using biological literature and enrichment analysis, thus validating the robustness of the proposed tools as well as achieving better understanding of the differences in the impact of the treatments in question.

Availability and implementation

Python package freely available here:https://github.com/parsenteva/scanofc.

Contact

polina.arsenteva@u-bourgogne.fr
Assessing the Effects of Various Physiological Signal Modalities on Predicting Different Human Cognitive States
Authors: Aygun Ayca , Nguyen Thuan , Scheutz Matthias
Published: March 2024

Robust estimation of systemic human cognitive states is critical for a variety of applications, from simply detecting inefficiencies in task assignments, to the adaptation of artificial agents’ behaviors to improve team performance in mixed-initiative human-machine teams. This study showed that human eye gaze, in particular, the percentage change in pupil size (PCPS), is the most reliable biomarker for assessing three human cognitive states including workload, sense of urgency, and mind wandering compared to electroencephalogram (EEG), functional near-infrared spectroscopy (fNIRS), respiration, and skin conductance. We used comprehensive multi-modal driving dataset to examine the accuracy of signals to assess these cognitive states. We performed comprehensive statistical tests to validate the performance of several physiological signals to determine human cognitive states and demonstrated that PCPS shows noticeably superior performance. We also characterized the link between workload and sense of urgency with eye gaze and observed that consecutive occurrences of higher sense of urgency were prone to increase overall workload. Finally, we trained five machine learning (ML) models and showed that four of them had similar accuracy in cognitive state classification (with one, random forest, showing inferior performance). The results provided evidence that the PCPS is a reliable physiological marker for cognitive state estimation.
Noise leads to the perceived increase in evolutionary rates over short time scales
Authors: O’Meara Brian C. , Beaulieu Jeremy M.
Published: March 2024

Across a variety of biological datasets, from genomes to conservation to the fossil record, evolutionary rates appear to increase toward the present or over short time scales. This has long been seen as an indication of processes operating differently at different time scales, even potentially as an indicator of a need for new theory connecting macroevolution and microevolution. Here we introduce a set of models that assess the relationship between rate and time and demonstrate that these patterns are statistical artifacts of time-independent errors present across ecological and evolutionary datasets, which produce hyperbolic patterns of rates through time. We show that plotting a noisy numerator divided by time versus time leads to the observed hyperbolic pattern; in fact, randomizing the amount of change over time generates patterns functionally identical to observed patterns. Ignoring errors can not only obscure true patterns but create novel patterns that have long misled scientists.
Alpha-synuclein regulates the repair of genomic DNA double-strand breaks in a DNA-PKcs-dependent manner
Authors: Rose Elizabeth P. , Osterberg Valerie R. , Banga Jovin S. , Gorbunova Vera , Unni Vivek K.
Published: March 2024

α-synuclein (αSyn) is a presynaptic and nuclear protein that aggregates in important neurodegenerative diseases such as Parkinson’s Disease (PD), Parkinson’s Disease Dementia (PDD) and Lewy Body Dementia (LBD). Our past work suggests that nuclear αSyn may regulate forms of DNA double-strand break (DSB) repair in HAP1 cells after DNA damage induction with the chemotherapeutic agent bleomycin1. Here, we report that genetic deletion of αSyn specifically impairs the non-homologous end-joining (NHEJ) pathway of DSB repair using an extrachromosomal plasmid-based repair assay in HAP1 cells. Importantly, induction of a single DSB at a precise genomic location using a CRISPR/Cas9 lentiviral approach also showed the importance of αSyn in regulating NHEJ in HAP1 cells and primary mouse cortical neuron cultures. This modulation of DSB repair is dependent on the activity of the DNA damage response signaling kinase DNA-PKcs, since the effect of αSyn loss-of-function is reversed by DNA-PKcsinhibition. Usingin vivomultiphoton imaging in mouse cortex after induction of αSyn pathology, we find an increase in longitudinal cell survival of inclusion-bearing neurons after Polo-like kinase (PLK) inhibition, which is associated with an increase in the amount of aggregated αSyn within inclusions. Together, these findings suggest that αSyn plays an important physiologic role in regulating DSB repair in both a transformed cell line and in primary cortical neurons. Loss of this nuclear function may contribute to the neuronal genomic instability detected in PD, PDD and DLB and points to DNA-PKcsand PLK as potential therapeutic targets.
Prioritizing replay when future goals are unknown
Authors: Sagiv Yotam , Akam Thomas , Witten Ilana B. , Daw Nathaniel D.
Published: March 2024

Although hippocampal place cells replay nonlocal trajectories, the computational function of these events remains controversial. One hypothesis, formalized in a prominent reinforcement learning account, holds that replay plans routes to current goals. However, recent puzzling data appear to contradict this perspective by showing that replayed destinations lag current goals. These results may support an alternative hypothesis that replay updates route information to build a “cognitive map.” Yet no similar theory exists to formalize this view, and it is unclear how such a map is represented or what role replay plays in computing it. We address these gaps by introducing a theory of replay that learns a map of routes to candidate goals, before reward is available or when its location may change. Our work extends the planning account to capture a general map-building function for replay, reconciling it with data, and revealing an unexpected relationship between the seemingly distinct hypotheses.