bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer-specific functional profiling in microsatellite-unstable (MSI) colon and endometrial cancers using combined differentially expressed genes and biclustering analysis
Authors: Na Woong , Lee Il Ju , Koh Insong , Kwon Mihye , Song Young Soo , Lee Sung Hak
Published: May 2023

Microsatellite-unstable (MSI) cancers have distinct genetic and clinical features from microsatellite-stable cancers, but the molecular functional differences between MSI cancers originating from different tissues or organs have not been well studied because the application of usual differentially expressed gene (DEG) analysis is error-prone, producing too many noncancer-specific normally functioning genes. To maximize therapeutic efficacy, biomarkers reflecting cancer-specific differences between MSI cancers of different tissue origins should be identified. To identify functional differences between MSI colon and endometrial cancers, we combined DEG analysis and biclustering instead of DEG analysis alone and refined functionally relevant biclusters reflecting genuine functional differences between the 2 tumors. Specifically, using The Cancer Genome Atlas and genome-tissue expression as data sources, gene ontology (GO) enrichment tests were performed after routinely identifying DEGs between the 2 tumors with the exclusion of DEGs identified in their normal counterparts. Cancer-specific biclusters and associated enriched GO terms were obtained by biclustering with enrichment tests for the preferences for cancer type (either colon or endometrium) and GO enrichment tests for each cancer-specific bicluster, respectively. A novel childness score was developed to select functionally relevant biclusters among cancer-specific biclusters based on the extent to which the enriched GO terms of the biclusters tended to be child terms of the enriched GO terms in DEGs. The selected biclusters were tested using survival analysis to validate their clinical significance. We performed multiple sequential analyses to produce functionally relevant biclusters from the RNA sequencing data of MSI colon and endometrial cancer samples and their normal counterparts. We identified 3066 cancer-specific DEGs. Biclustering analysis revealed 153 biclusters and 41 cancer-specific biclusters were selected using Fisher exact test. A mean childness score over 0.6 was applied as the threshold and yielded 8 functionally relevant biclusters from cancer-specific biclusters. Functional differences appear to include gland cavitation and the TGF-β receptor, G protein, and cytokine pathways. In the survival analysis, 6 of the 8 functionally relevant biclusters were statistically significant. By attenuating noise and applying a synergistic contribution of DEG results, we refined candidate biomarkers to complement tissue-specific features of MSI tumors.
The hemoglobin, albumin, lymphocyte, and platelet (HALP) is a potent indicator for the prognosis in hemodialysis patients
Authors: Zhang Fengping , Li Luohua , Shi Taotao , Liu Yu , Xie Jun , Yu Le
Published: May 2023

The hemoglobin, albumin, lymphocyte, and platelet (HALP) values were marked as a original index of general nutritional and inflammatory conditions. The purpose of this investigation was to evaluate the potential relationship between HALP and prognosis in hemodialysis (HD) patients. Patients with maintenance HD from multiple dialysis centers in China were retrospectively analyzed. The primary poor outcome were cardiovascular disease (CVD) and all-cause death. The computational equation of HALP values as the follows: hemoglobin (g/L) × albumin (g/L) × lymphocytes (/L)/ platelets (/L). All participants were divided into Tertile 1, Tertile 2, and Tertile 3 according to the tertiles of baseline HALP values. The Kaplan–Meier curve and the Cox regression was done to figure out the relationship about HALP and adverse outcomes. The restricted cubic splines further identified the possible associations. The time-dependent receiver operating characteristic curve and C-index were implemented for evaluate the predictive values of the HALP composite model. There were 4796 patients incorporate into ultimate study. Compared with patients in Tertile 1, patients in Tertile 3 had an lower risk of all-cause mortality [hazard ratios = 0.66, 95% confidence intervals: 0.49–0.86, P = .007] and CVD mortality [sub-distribution hazard ratio = 0.51, 95% confidence intervals: 0.34–0.80, P = .005]. The composite model with the supplement of HALP outperformed the traditional factor model in the time-dependent receiver operating characteristic curve. High HALP values at baseline are related to a diminished risk of CVD death and all-cause death in HD patients. HALP is a novel and potent index for the prognosis of HD patients.
Influencing factors of early dramatic recovery of neurological function after intravenous thrombolysis in patients with branch atheromatous disease
Authors: Meng Yuanyuan , Zhao Yanjun , Wang Ruixia , Wen Jiangshan , Tang Tianping
Published: May 2023

Background:

Intravenous thrombolysis can significantly improve the neurological function of patients with acute ischemic stroke. However, the expected early dramatic recovery (EDR) of neurological function after thrombolysis is not achieved in some patients with branch atheromatous disease (BAD). Here we evaluated the factors associated with EDR after thrombolysis in BAD patients.

Methods:

We conducted a retrospective study on 580 consecutive BAD patients. All patients met the diagnostic criteria of BAD and received intravenous recombinant tissue-type plasminogen activator (rt-PA). EDR was defined when the improvement of National Institutes of Health Stroke Scale (NIHSS) score was >8 points within 2 or 24 hours after rt-PA, or the total NIHSS score was 0 or 1. The factors associated with EDR were analyzed with multivariate logistic regression analysis.

Results:

Among 580 patients, the incidence of EDR was 35.2% (204 cases). Compared with patients without EDR, patients with EDR had lower incidence of diabetes (15.7% vs 29.3%, P < .001), lower NIHSS scores at 2 and 24 hours after rt-PA (P < .001), less cerebral hemorrhage (0% vs 5.3%, P = .001), and shorter onset to treatment time (OTT) (P < .001). Multivariate logistic regression analysis in propensity score-matched cohort showed that EDR was associated with OTT (adjusted OR = 0.994; 95% CI, 0.989–0.999) and NIHSS score after rt-PA (adjusted OR = 0.768; 95% CI, 0.663–0.890). Notably, diabetes (adjusted OR = 0.477, 95% CI, 0.234–0.972) was an independent factor related to EDR of neurological function in BAD patients. In the subgroup analysis, a lower incidence of diabetes (adjusted OR = 0.205, 95% CI: 0.059–0.714, P = .013) and a lower NIHSS score after thrombolysis in patients with paramedian pontine infarction (adjusted OR = 0.809, 95% CI: 0.656–0.997, P = .047) were significantly associated with EDR.

Conclusion:

Diabetes is not conducive to EDR of neurological function in patients with BAD, especially in patients with paramedian pontine infraction. Low NIHSS score and short OTT after thrombolysis may be closely related to EDR after intravenous thrombolysis.
Axillary accessory breast cancer reconstructed by a thoracodorsal artery perforator flap: A case report
Authors: Yumoto Akiko , Otsuki Yuki , Nuri Takashi , Higashino Erika , Kimura Kosei , Iwamoto Mitsuhiko , Ueda Koichi
Published: May 2023

Introduction:

Primary accessory breast cancer is rare and most commonly occurs in the axilla. Due to its low incidence, few studies have discussed axillary reconstruction after accessory breast cancer resection. In the present report, we describe a patient who underwent axillary reconstruction with a thoracodorsal artery perforator (TAP) flap after resection, and reconstruction methods after resection of axillary accessory breast cancer are discussed based on current and previous reports.

Patient concerns:

A 60-year-old woman presented with a 7-year history of a gradually growing lump in the left axilla.

Diagnosis:

The patient was diagnosed with latent breast cancer, axillary lymph node metastasis, or carcinoma of the accessory axillary breast with axillary lymph node metastasis.

Interventions:

After preoperative chemotherapy, tumor resection and axillary lymph node dissection were performed, followed by immediate axillary reconstruction using a TAP flap. The patient received postoperative adjuvant endocrine and radiation therapy (50 Gy).

Outcomes:

No recurrence or metastasis was observed for 5 years postoperatively. The reconstructed axilla was not bulky, and scar contracture was not observed, with a full range of motion of the shoulder joint.

Conclusion:

We described a patient who underwent immediate TAP flap reconstruction after resection of accessory breast cancer and axillary lymph node dissection, followed by postoperative radiation, which could cause scar contracture. The patient was followed up for more than 5 years after the operation and radiation therapy, and the appearance of the axilla and range of motion of the shoulder were good despite postoperative radiation.
Antimicrobial stewardship in the era of the COVID-19 pandemic: A systematic review protocol on the opportunities and challenges for Sub-Saharan Africa
Authors: Njuma Libwea John , Ngwa Che Henry , Ngomba Armelle Viviane , Wirsiy Frankline Sevidzem , Mpofu Limkile , Ndongo Chanceline Bilounga , Koulla-Shiro Sinata , Graham Stephen , Djieuya Lionelle Patricia Tchokokam , Mandeng Nadia , Mballa Georges Alain Etoundi , Sobh Eman , Nwaru Bright I. , Ndombo Paul Koki , Epee Emilienne
Published: May 2023

Background:

Antimicrobial resistance (AMR) remains one of the leading threats to global public health and this may increase following COVID-19 pandemic. This is particularly the case in Africa where regulations on antimicrobial usage are weak. This protocol outlines the steps to undertake a systematic review to synthesize evidence on drivers of AMR and evaluate existing approaches to strengthening antimicrobial stewardship (AMS) programs in Sub-Saharan Africa (SSA). On the basis of the evidence generated from the evidence synthesis, the overarching goal of this work is to provide recommendations to support best practices in AMS implementation in SSA.

Methods:

A systematic search will be conducted using the following databases: Global Health Library, PubMed, Cumulative Index to Nursing and Allied Health Literature, Scopus, Google Scholar, Global Health, Embase, African Journals Online Library, Web of Science, antimicrobial databases (WHO COVID-19, TrACSS, NDARO, and JPIAMR), and the Cochrane databases for systematic reviews. Studies will be included if they assess AMR and AMS in SSA from January 2000 to January 31, 2023.

Results:

The primary outcomes will include the drivers of AMR and approaches to AMS implementation in SSA. The Preferred Reporting Items for Systematic Reviews and Meta-analyses will guide the reporting of this systematic review.

Conclusions:

The findings are expected to provide evidence on best practices and resource sharing for policy consideration to healthcare providers and other stakeholders both at the local and international levels. Additionally, the study seeks to establish drivers specific to AMR during the COVID-19 era in the SSA, for example, with the observed increasing trend of antimicrobial misuse during the first or second year of the pandemic may provide valuable insights for policy recommendation in preparedness and response measures to future pandemics.

PROSPERO registration number:

CRD42022368853.
Application of critical pathway of integrative medical service for lumbar herniated nucleus pulposus: A protocol for single-centered prospective observational study
Authors: Seo Joon-Won , Shin Woochul , Kim Bo-Hyung , Choi Man Kyu , Kim Sung Bum , Kim Hyungsuk , Cho Jae-Heung , Chung Won-Seok
Published: May 2023

Background:

Lumbar herniated nucleus pulposus (L-HNP) is a condition in which fibroblasts escape due to degenerative changes or external forces in the intervertebral disc, causing neurological symptoms by compressing the dura mater or nerve root.

Objectives:

The purpose of this study is to analyze and compare the effectiveness, economic feasibility, and safety of using an integrated medical service critical pathway (CP) in L-HNP patients.

Methods:

This single-center prospective observational study will be performed at Kyung Hee University Medicine Hospital and Kyung Hee University Korean Medicine Hospital. The inclusion criteria are a diagnosis of L-HNP on magnetic resonance imaging or computed tomography scans, age under 80 years, a visual analog scale score of 7 or higher for either lower back pain or lower extremity pain. The included 102 participants will be classified into 6 groups (n = 17 in each group): CP application with conservative treatment; CP application with open discectomy; CP application with intrabody fusion; conservative treatment without CP application; open discectomy without CP application; and interbody fusion without CP application. We will collect data on the visual analog scale, ODI, SF-36, and EQ-5D-3L scores; number of admission days; medical staff satisfaction; patients health service satisfaction; waiting time for consultations; use of pain relievers; and CP application and completion rates.

Conclusion:

In future, this study is expected to serve as a basis for follow-up studies on the development and application of CPs in integrated medical services for various diseases, including lumbar herniated nucleus pulposus.
Proton pump inhibitor use and the risk for Parkinson’s disease: A nationwide population-based study in Taiwan
Authors: Chen Huan-Lin , Lei Wei-Yi , Wang Jen-Hung , Bair Ming-Jong , Chen Chien-Lin
Published: May 2023

Previous studies have shown that proton pump inhibitors (PPIs) are associated with an increased risk of dementia. However, little is known about the relationship between PPIs use and Parkinson’s disease (PD). This study aimed to examine whether PPI use was associated with an increased risk of developing clinically verified PD. This used data from the Taiwan National Health Insurance Research Database for the period between 1999 and 2011, and patients with PPI use were compared with 1 to 1 propensity score-matched controls by age, sex, cohort entry year, and comorbidity. A multivariate analysis was performed using Cox proportional hazards models to estimate the association between PPI use and PD risk. Subgroup analyses according to sex, age, and comorbidities were also conducted. In total, 56,785 PPI users and 56,785 matched controls were enrolled in this study. In the PPI cohort, 366 patients developed PD during a median follow-up of 5.0 years. The incidence rate of PD was 1.48-fold higher in PPI users than in non-PPI users (90.0 vs 133.2 per 100,000 person-years), with an adjusted hazard ratio of 1.76 (95% confidence interval, 1.48–2.08). In the subgroup analysis, the adjusted risk of PD in the PPI and non-PPI cohorts increased in the subgroups regardless of age, sex, and comorbidities. The results of this retrospective, nationwide, population-based cohort study in Taiwan indicate that PPI use is associated with the risk of PD development. Further mechanistic studies on the effect of PPI on PD are needed.
Comparison of the application of 18F-FDG and 68Ga-DOTATATE PET/CT in neuroendocrine tumors: A retrospective study
Authors: Hu Xianwen , Li Dandan , Wang Rui , Wang Pan , Cai Jiong
Published: May 2023

The present study aimed to compare the efficacy of 68Ga-DOTATATE PET/CT and 18F-FDG PET/CT imaging in the diagnosis, staging, and prognosis evaluation of neuroendocrine tumors (NET). A total of 55 patients (43 were initially evaluated, 12 were evaluated after treatment) who underwent fluorine-18 labeled fluorodeoxyglucose (18F-FDG) and 68Ga DOTATE PET/CT examinations were reviewed retrospectively, and the pathological data were collected. In the initial evaluation, 27/43 were pathologically confirmed as NET patients, as detected by gallium-68 labeld 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraaceticacid-D-Phel-Tyr3-Thr8-OC; among them, 23 were correctly detected by 18F-FDG. In lesion-based comparison, 119/168 focal lesions were depicted on 18F-FDG PET/CT and 68Ga-DOTATATE PET/CT, respectively (P = .0363). Strikingly, gallium-68 labeld 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraaceticacid-D-Phel-Tyr3-Thr8-OC had higher maximum standard uptake value than 18F-FDG but was negatively related to the NET grade for the former, while the latter was positively related to the NET. The value of 68Ga-DOTATATE PET/CT in the diagnosis and staging of NET is higher than that of 18F-FDG PET/CT in NETs, while the value of 18F-FDG PET/CT cannot be ignored in the NET. The combined application of the 2 tracers has major clinical significance in the management of patients with NET.
Endoscopic pancreatic duct stenting combined with 3D laparoscopic pancreatic tumor resection: Three case reports
Authors: Wu Bo , Bai Yang , Yu Shi’an , Li Xuemin , Wu Xiaokang
Published: May 2023

Rationale:

This study explored the safety and feasibility of 3D laparoscopy and intraoperative ultrasound techniques, which made minimally invasive pancreatic surgery more precise and detailed.

Patient concern:

Case 1 was a 51-year-old man with a primary complaint of pancreatic tumor. Case 2 was a 60-year-old woman with complaints of tinnitus for 1 week. Case 3 was a 21-year-old woman with complaints of epigastric pain and abdominal distension for 1 day.

Diagnosis:

Case 1 and Case 2 were diagnosed with pancreatic neuroendocrine tumors, and Case 3 was diagnosed with an infected solid pseudopapillary tumor of the pancreas.

Interventions:

All 3 patients underwent laparoscopic pancreatic surgery in our hospital.

Outcomes:

All cases received the same perioperative management and no localized stenosis or dilatation of the pancreatic duct was found during follow-up.

Lessons:

With the development of minimally invasive surgery and the application of 3D laparoscopy and intraoperative ultrasound technology, pancreatic tumors that are tightly adhered to the main pancreatic duct can successfully be removed using 3D laparoscopic operation.
A senescence-related signature for predicting the prognosis of breast cancer: A bioinformatics analysis
Authors: Xing Tengfei , Hu Yiyi , Wang Hongying , Zou Qiang
Published: May 2023

Breast cancer is a heterogeneous disease with diverse prognosis and treatment outcomes. Current gene signatures for prognostic prediction are limited to specific subtypes of breast cancer. Cellular senescence is a state of irreversible cell cycle arrest that affects various physiological and pathological processes. This study aimed to develop and validate a senescence-related signature for predicting the prognosis of breast cancer patients. We retrieved 744 senescence-associated genes from the SeneQuest database and analyzed their expression profiles in 2 large datasets of breast cancer patients: The Cancer Genome Atlas (TCGA) and the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). We used univariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression, and multivariate Cox regression analysis to derive a 29-gene senescence-related risk signature. The risk signature was significantly associated with disease-specific survival (DSS), clinical characteristics, molecular subtypes, and immune checkpoint genes expressions in both datasets. The risk signature also stratified high-risk and low-risk patients within the same clinical stage and molecular subtype. The risk signature was an independent prognostic factor for breast cancer patients. The senescence-related signature may be a useful biomarker for predicting prognosis and immunotherapy response of breast cancer patients. The risk signature may also guide adjuvant chemotherapy decisions, especially in hormone receptor positive (HR+) and human epidermal growth factor receptor type 2 (HER2)− subtypes.
Typical clinical presentation of acute myocardial infarction and confusing coronary angiography: A case report and literature review of coronary embolism
Authors: Yin Mo-Qing , Fan Li-Hua , Chen Yun-Hu
Published: May 2023

Rationale:

The purpose of this article is to discuss the characteristics, diagnosis, treatment, and outcomes of cases of multiple coronary embolism (CE) highly suspected to be caused by a dislodged aneurysm of the ventricular membranous septum (AVMS) thrombus.

Patient concerns:

A 35-year-old man was rushed to the Chest Pain Center of Taicang TCM Hospital Affiliated to Nanjing University of Chinese Medicine for sudden onset of chest pain. The patient had severe and persistent chest pain without relief, accompanied by sweating throughout the body.

Diagnosis:

An electrocardiogram showed ST-segment elevation in the inferior wall leads, and blood tests suggested elevated troponin I levels. The initial diagnosis was acute ST-segment elevation myocardial infarction. Emergency coronary angiography revealed complete occlusion of the first diagonal branch, thrombolysis in myocardial infarction grade 0 flow, and smooth remaining vessels. Complete occlusion of the left anterior descending artery unexpectedly occurred during interventional treatment. Postoperative cardiac ultrasonography revealed the presence of a thrombus within the AVMS and in the apical portion of the heart. The final diagnosis was a CE.

Interventions:

Intraoperatively, the diagonal branch occluded segment was dilated with a balloon and intracoronary administration of tirofiban and nitroglycerin. Postoperatively, antithrombotic therapy (aspirin, clopidogrel, and rivaroxaban) was administered.

Outcomes:

Ten days after admission, a repeat coronary angiography showed complete restoration of left anterior descending artery flow on its own, balloon dilation was again performed on the diagonal branch, and flow was restored to thrombolysis in myocardial infarction grade 1. Six months later, the intracardiac thrombus disappeared on repeat cardiac ultrasound.

Lessons:

AVMS is a potential source of embolism in patients with CE. CE has features that distinguish it from atherosclerosis, and a timely and correct diagnosis can help improve patient clinical outcomes.
Hyperthermic Intraperitoneal Chemotherapy May Damage Renal Function and Cause Serum Electrolyte Disturbance: A Retrospective Observational Study
Authors: Yu Zhiyuan , Zhao Xudong , Qiu Shuzhong , Zhou Sixin , Li Peiyu , Liu Na
Published: May 2023

Objective:

The objective of this study was to evaluate the efficacy of postoperative hyperthermic intraperitoneal chemotherapy (HIPEC) on bone marrow hematopoiesis, liver and kidney function, and serum electrolytes for patients who underwent open radical gastrectomy, and investigate the variation tendency of above indicators.

Materials and Methods:

The clinical data of 153 patients who underwent open radical gastrectomy were retrospectively analyzed and were divided into HIPEC group (n=83) and control group (n=70). Repeated analysis of variance was used to analyze the variation tendency of bone marrow hematopoiesis, liver and kidney function, and serum electrolytes in the HIPEC and control group, respectively, and then made a comparison between the 2 groups.

Results:

There were statistical differences in alanine aminotransferase (P=0.034), phosphorus (P
+) (P<0.05), potassium (K+) (P=0.023), sodium (Na+) (P<0.001), and chloride (Cl−) (P=0.008) between HIPEC and control group. All outcome indicators changed significantly over time (P<0.05). No significant difference was found in hemoglobin, white blood cell, platelet, aspartate aminotransferase, total bilirubin, or uric acid between the 2 treatment groups at each time point. On the next day after HIPEC treatment, the levels of blood urea nitrogen, creatinine, and P
+ were higher in the HIPEC group, whereas the calcium (Ca+), magnesium (Mg+), and K+ levels of HIPEC group tended to be lower. However, the effects of HIPEC on alanine aminotransferase, Na+, and Cl− levels needed to be further explored.

Conclusions:

HIPEC treatment after open radical gastrectomy has no significant effect on hematopoietic bone marrow and liver function but may damage renal function; reduce Ca+, Mg+, K+ levels; and increase P
+ level.
What Value of Sixth Month Excess Weight Loss (Postsleeve Gastrectomy) Is Necessary for Better Sleep Quality?
Authors: Başak Fatih , Şişik Abdullah , Demirpolat Muhammed Taha , Çalişkan Yahya Kemal , Ülgür Hanife Şeyda
Published: May 2023

Background:

Obesity, caused by caloric intake over output, is a global health problem. The relationship between sleep and obesity is discussed in the literature. Little is known about the compliance of sleep quality and patients’ weight loss. This study aimed to review how sleep quality is affected by bariatric surgery, assess whether compliance with sleep quality can be predicted after bariatric surgery, and establish its correlation with excess weight loss.

Methods:

A cross-sectional study was conducted for patients undergoing bariatric surgery (laparoscopic sleeve gastrectomy). Sleep quality was assessed with the Pittsburgh sleep quality index (PSQI) scale preoperatively and in the sixth postoperative month. A PSQI global score above 5 indicated poor sleep quality. Participants were divided into 2 groups: good and poor sleep quality. Receiver operating characteristics and logistic regression analysis were also performed to predict sleep quality.

Results:

The questionnaire was completed by 100 subjects. All PSQI components, except the sixth (sleep medication) component, improved in patients at the sixth postoperative month versus baseline values. In the receiver operating characteristic analysis to test the availability of excess weight loss (EWL%) cutoff values relative to predict successful sleepers, 65.1 of the sixth month EWL% was found for the diagnosis of successful sleeper patients with 72.6% sensitivity and 63% specificity (area under the curve: 0.706, P=0.002, 95% CI, 0.586 to 0.825).

Conclusions:

For patients undergoing weight loss surgery, while assessing the sixth postoperative month, the EWL% value over 65.1 was recommended for better sleep quality.
Learning Curve of Single-site Robotic Cholecystectomy: A Cumulative Sum Analysis
Authors: Kudsi Omar Y. , Kaoukabani Georges , Friedman Alexander , Sekigami Yurie , Bou-Ayash Naseem , Bahadir Jenna , Crawford Allison S. , Gokcal Fahri
Published: May 2023

Background:

Minimally invasive surgery has significantly improved cosmesis and clinical outcomes after either laparoscopic or robotic cholecystectomy. In an effort to minimize the number of incisions in multiport procedures, single-site approaches have been developed. However, single-site robotic cholecystectomy (SSRC) can be technically challenging for novice surgeons. The goal of this study is to establish the learning curve (LC) of SSRC through an assessment of operative times and clinical outcomes.

Materials and Methods:

A retrospective analysis of patients undergoing SSRC over a period of 5 years was performed. Consecutive cholecystectomy cases were assessed based on the procedure setting (elective vs. emergent). Cumulative sum analysis were used to establish the LC through an evaluation of the skin-to-skin (STS) time and postoperative complications rate. Afterward, a direct comparison was performed between the established phases.

Results:

This study included a total of 259 SSRCs with an overall mean STS time of 41.1 minutes. Elective cases took on average of 38.8 minutes, whereas emergent cases spanned over 60.5 minutes (P=0.005). The cumulative sum-LC was obtained by summing the differences between each procedure’s STS time, revealing a quadratic best-fit line maximum and an inflection point between the early and late phases at case 91. A significant difference between STS time was seen between the early and late phases (53.8 vs. 30.0 min, P<0.0001). There were no significant differences in terms of postoperative complications between the 2 phases. Incisional hernia rates were comparable between the 2 phases (early: 4.4% vs. late: 2.5%, P<0.461).

Conclusions:

This is the largest study to assess the LC of SSRC through operative time and clinical outcomes. A steady decrease in STS time was observed during the completion of the first 91 consecutive cases.
Photorhabdus aballayi sp. nov. and Photorhabdus luminescens subsp. venezuelensis subsp. nov., isolated from Heterorhabditis amazonensis entomopathogenic nematodes
Authors: Machado Ricardo A. R. , Bhat Aashaq Hussain , Castaneda-Alvarez Carlos , Půža Vladimir , San-Blas Ernesto
Published: May 2023

Six Gram-negative, rod-shaped bacterial strains isolated fromHeterorhabditis amazonensisentomopathogenic nematodes were characterized to determine their taxonomic position. 16S rRNA andgyrBgene sequences indicate that they belong to the classGammaproteobacteria, familyMorganellaceaeand genusPhotorhabdus, and that some of them are conspecifics. Two of them, APURETand JART, were selected for further molecular characterization using whole genome- and whole-proteome-based phylogenetic reconstructions and sequence comparisons. Phylogenetic reconstructions using whole genome and whole proteome sequences show that strains APURETand JARTare closely related toPhotorhabdus luminescenssubsp.luminescensATCC 29999Tand toP. luminescenssubsp.mexicanaMEX47-22T. Moreover, digital DNA–DNA hybridization (dDDH) values between APURETandP. luminescenssubsp.luminescensATCC 29999T, APURETandP. luminescenssubsp.mexicanaMEX47-22T, and APURETand JARTare 61.6, 61.2 and 64.1 %, respectively. These values are below the 70 % divergence threshold that delimits prokaryotic species. dDDH scores between JARTandP. luminescenssubsp.luminescensATCC 29999Tand between JARTandP. luminescenssubsp.mexicanaMEX47-22Tare 71.9 and 74.8 %, respectively. These values are within the 70 and 79 % divergence thresholds that delimit prokaryotic subspecies. Based on these genomic divergence values, APURETand JARTrepresent two different taxa, for which we propose the names:Photorhabdus aballayisp. nov. with APURET(=CCM 9236T=CCOS 2019T) as type strain andPhotorhabdus luminescenssubsp.venezuelensissubsp. nov. with JART(=CCM 9235T=CCOS 2021T) as type strain. Our study contributes to a better understanding of the biodiversity of an important bacterial group with enormous biotechnological and agricultural potential.
Role of lipid nanodomains for inhibitory FcγRIIb function
Authors: Spiegel Franziska , Trollmann Marius F.W. , Kara Sibel , Pöhnl Matthias , Brandner Astrid F. , Nimmerjahn Falk , Lux Anja , Böckmann Rainer A.
Published: May 2023

The inhibitory Fcγ receptor FcγRIIb is involved in immune regulation and is known to localize to specific regions of the plasma membrane called lipid rafts. Previous studies suggested a link between the altered lateral receptor localization within the plasma membrane and the functional impairment of the FcγRIIb-I232T variant that is associated with systemic lupus erythematosus.

Here, we conducted microsecond all-atom molecular dynamics simulations and IgG binding assays to investigate the lipid nano-environment of FcγRIIb monomers and of the FcγRIIb-I232T mutant within a plasma membrane model, the orientation of the FcγRIIb ectodomain, and its accessibility to IgG ligands. In contrast to previously proposed models, our simulations indicated that FcγRIIb does not favor a cholesterol-or a sphingolipid-enriched lipid environment. Interestingly, cholesterol was depleted for all studied FcγRIIb variants within a 2-3 nm environment of the receptor, counteracting the usage of raft terminology for models on receptor functionality. Instead, the receptor interacts with lipids that have poly-unsaturated fatty acyl chains and with (poly-) anionic lipids within the cytosolic membrane leaflet.

We also found that FcγRIIb monomers adopt a conformation that is not suitable for binding to its IgG ligand, consistent with a lack of detectable binding of monomeric IgG in experiments on primary immune cells. However, our results propose that multivalent IgG complexes might stabilize FcγRIIb in a binding-competent conformation. We suggest differences in receptor complex formation within the membrane as a plausible cause of the altered membrane localization or clustering and the altered suppressive function of the FcγRIIb-I232T variant.

Significance Statement

Our study sheds new light on the molecular mechanisms underlying the regulation of immune signaling mediated by the inhibitory Fcγ receptor (FcγRIIb). By utilizing atomistic simulations and experimental assays, we demonstrate that FcγRIIb interacts with specific lipids in the plasma membrane. Notably, our findings challenge the current view of membrane heterogeneity in immune cells, as FcγRIIb is not localized in specialized membrane domains known as rafts. Rather, we propose that receptor complex formation modulates receptor localization and conformation, thereby enabling ligand binding.

Our findings have important implications for understanding how immune receptors function and communicate with each other, and may provide new opportunities for developing therapeutic strategies targeting FcγRIIb in diseases such as autoimmunity and cancer.
Automated model discovery for muscle using constitutive recurrent neural networks
Authors: Wang Lucy M. , Linka Kevin , Kuhl Ellen
Published: May 2023

The stiffness of soft biological tissues not only depends on the applied deformation, but also on the deformation rate. To model this type of behavior, traditional approaches select a specific time-dependent constitutive model and fit its parameters to experimental data. Instead, a new trend now suggests a machine-learning based approach that simultaneously discovers both the best model and best parameters to explain given data. Recent studies have shown that feed-forward constitutive neural networks can robustly discover constitutive models and parameters for hyperelastic materials. However, feed-forward architectures fail to capture the history dependence of viscoelastic soft tissues. Here we combine a feed-forward constitutive neural network for the hyperelastic response and a recurrent neural network for the viscous response inspired by the theory of quasi-linear viscoelasticity. Our novel rheologically-informed network architecture discovers the time-independent initial stress using the feed-forward network and the time-dependent relaxation using the recurrent network. We train and test our combined network using unconfined compression relaxation experiments of passive skeletal muscle and compare our discovered model to a neo Hookean standard linear solid and to a vanilla recurrent neural network with no mechanics knowledge. We demonstrate that, for limited experimental data, our new constitutive recurrent neural network discovers models and parameters that satisfy basic physical principles and generalize well to unseen data. We discover a Mooney-Rivlin type two-term initial stored energy function that is linear in the first invariantI1and quadratic in the second invariantI2with stiffness parameters of 0.60kPa and 0.55kPa. We also discover a Prony-series type relaxation function with time constants of 0.362s, 2.54s, and 52.0s with coefficients of 0.89, 0.05, and 0.03. Our newly discovered model outperforms both the neo Hookean standard linear solid and the vanilla recurrent neural network in terms of prediction accuracy on unseen data. Our results suggest that constitutive recurrent neural networks can autonomously discover both model and parameters that best explain experimental data of soft viscoelastic tissues. Our source code, data, and examples are available athttps://github.com/LivingMatterLab.
Red Fluorescent Carbon Nanoparticles Derived fromSpinacia oleracea L.: A Versatile Tool for Bioimaging & Biomedical Applications
Authors: Barve Ketki , Singh Udisha , Kansara Krupa , Vaswani Payal , Yadav Pankaj , Kumar Ashutosh , Bhatia Dhiraj
Published: May 2023

Carbon-based fluorescent quantum dots are an emerging class of nanoparticles for targeted bioimaging and biomedical applications. We present a facile microwave-assisted approach for synthesizing carbon nanoparticles with bright red fluorescence using ethanolic extracts ofSpinacia oleracealeaves, with a quantum yield of 94.67%. These nanoparticles, called CNPs, ranging from 15-50 nm, demonstrated fluorescence emission in the near-infrared (NIR) region between 650 and 700 nm, independent of excitation wavelength. Upon excitation at a wavelength of 410 nm, they exhibit an emission maxima peak at 672 nm. The significant uptake of CNPs in mammalian cells and zebrafish larvae highlights their potential as bioimaging agents in diverse biomedical applicationsin vivo. Further, these quantum dots enhance cellular proliferation and migration as observed by wound healing assay in mammalian cells, indicating their possible application in tissue engineering and regenerative medicine. These findings suggest that biosynthesized carbon nanoparticles possess significant potential for biomedical activities, which can serve as a robust benchmark for researchers towards promoting sustainability.
Seasonally variable thermal performance curves prevent adverse effects of heatwaves
Authors: Sasaki Matthew C. , Finiguerra Michael , Dam Hans G.
Published: May 2023

The increasing frequency and intensity of heatwaves may represent a significant challenge for predicting vulnerability of populations in a warming ocean. The direct impacts of heatwaves on populations depend on the relative position of environmental temperatures to the thermal performance curve optima. If thermal performance curves are static, the effects of heatwaves may therefore change seasonally over the annual temperature cycle. However, these seasonal changes in the effects of heatwaves may be dampened by corresponding variation in thermal performance curves which, in organisms with relatively short generation times, may be driven by phenotypic plasticity as well as genetic differentiation. Here we investigate the effects of seasonal timing and duration on the impacts of heatwaves in the ecologically important copepod congenersAcartia tonsaandAcartia hudsonica, and test the hypotheses that 1) seasonal variation in thermal performance curves will reduce overall population vulnerability to heatwaves, and 2) that seasonal variation in TPCs will prevent negative transgenerational effects of heatwave. We characterized seasonal variation in thermal performance curves for several fitness-related traits. These experiments uncovered strong seasonal variation in the thermal performance curves ofAcartia tonsa, and indicate that this variation buffers against negative effects of simulated heatwaves. We also quantified both direct and trans-generational effects of different duration heatwaves on copepods collected at various times throughout the season using simulated heatwave experiments. There was no consistent pattern in the transgenerational effects of parental exposure to heatwaves, which may indicate that seasonal variation in thermal performance curves reduces the effects of parental stress on offspring performance. Our results show that seasonal variation in thermal performance curves will likely play an important role in limiting the adverse effects of heatwaves on populations.
Nuclear cytoglobin associates with HMGB2 and regulates DNA damage and genome-wide transcriptional output in the vasculature
Authors: Mathai Clinton , Jourd’heuil Frances , Pham Le Gia Cat , Gilliard Kurrim , Howard Dennis , Balnis Joseph , Jaitovich Ariel , Chittur Sridar V. , Rilley Mark , Peredo-Wende Ruben , Ammoura Ibrahim , Shin Sandra J. , Barroso Margarida , Barra Jonathan , Shishkova Evgenia , Coon Joshua J. , Lopez-Soler Reynold I. , Jourd’heuil David
Published: May 2023

Identifying novel regulators of vascular smooth muscle cell function is necessary to further understand cardiovascular diseases. We previously identified cytoglobin, a hemoglobin homolog, with myogenic and cytoprotective roles in the vasculature. The specific mechanism of action of cytoglobin is unclear but does not seem to be related to oxygen transport or storage like hemoglobin. Herein, transcriptomic profiling of injured carotid arteries in cytoglobin global knockout mice revealed that cytoglobin deletion accelerated the loss of contractile genes and increased DNA damage. Overall, we show that cytoglobin is actively translocated into the nucleus of vascular smooth muscle cells through a redox signal driven by NOX4. We demonstrate that nuclear cytoglobin heterodimerizes with the non-histone chromatin structural protein HMGB2. Our results are consistent with a previously unknown function by which a non-erythrocytic hemoglobin inhibits DNA damage and regulates gene programs in the vasculature by modulating the genome-wide binding of HMGB2.
SEMORE: SEgmentation and MORphological fingErprinting by machine learning automates super-resolution data analysis
Authors: Bender Steen W. B. , Dreisler Marcus W. , Zhang Min , Kæstel-Hansen Jacob , Hatzakis Nikos S.
Published: May 2023

The morphology of protein assemblies impacts their behavior and contributes to beneficial and aberrant cellular responses. While single-molecule localization microscopy provides the required spatial resolution to investigate these assemblies, the lack of universal robust analytical tools to extract and quantify underlying structures limits this powerful technique. Here we present SEMORE, a semi-automatic machine learning framework for universal, system and input-dependent, analysis of super-resolution data. SEMORE implements a multi-layered density-based clustering module to dissect biological assemblies and amorphology fingerprintingmodule for quantification by multiple geometric and kinetics-based descriptors. We demonstrate SEMORE on simulations and diverse raw super-resolution data; time-resolved insulin aggregates and imaging of nuclear pore complexes. SEMORE extracts and quantifies all protein assemblies enabling classification of heterogeneous insulin aggregation pathways and NPC geometry in minutes. SEMORE is a general analysis platform for super-resolution data, and being the first time-awar e framework can also support the rise of 4D super-resolution data.
High-throughput bactericidal assays for monoclonal antibody screening against antimicrobial resistantNeisseria gonorrhoeae
Authors: Stazzoni Samuele , Troisi Marco , Abbiento Valentina , Sala Claudia , Andreano Emanuele , Rappuoli Rino
Published: May 2023

Neisseria gonorrhoeae(gonococcus) is an obligate human pathogen and the etiological agent of the sexually transmitted disease gonorrhea. The rapid rise in gonococcal resistance to all currently available antimicrobials has become a significant public health burden and the need to develop novel therapeutic and prophylactic tools is now a global priority. While high-throughput screening methods allowed rapid discovery of extremely potent monoclonal antibodies (mAbs) against viral pathogens, the field of bacteriology suffers from the lack of assays that allow efficient screening of large panels of samples. To address this point, we developed luminescence-based (L-ABA) and resazurin-based (R-ABA) antibody bactericidal assays that measureN. gonorrhoeaemetabolic activity as a proxy of bacterial viability. Both L-ABA and R-ABA are applicable on the large scale for the rapid identification of bactericidal antibodies and were validated by conventional methods. Implementation of these approaches will be instrumental to the development of new medications and vaccines againstN. gonorrhoeaeand other bacterial pathogens to support the fight against antimicrobial resistance.
Molecular Mechanism of Regulation of RhoA GTPase by Phosphorylation of RhoGDI
Authors: Sinha Krishnendu , Kumawat Amit , Jang Hyunbum , Nussinov Ruth , Chakrabarty Suman
Published: May 2023

Rho-specific guanine dissociation inhibitors (RhoGDIs) play a crucial role in the regulation of Rho family GTPases. They act as negative regulators that prevent the activation of Rho GTPases by forming complexes with the inactive GDP-bound state of GTPase. Release of Rho GTPase from the RhoGDI-bound complex is necessary for Rho GTPase activation. Biochemical studies provide evidence of a “phosphorylation code”, where phosphorylation of some specific residues of RhoGDI selectively releases its GTPase partner (RhoA, Rac1, Cdc42 etc.). This work attempts to understand the molecular mechanism behind this phosphorylation code. Using several microseconds long atomistic molecular dynamics (MD) simulations of the wild-type and phosphorylated states of the RhoA–RhoGDI complex, we propose a molecular-interaction-based mechanistic model for the dissociation of the complex. Phosphorylation induces major structural changes, particularly in the positively charged polybasic region (PBR) of RhoA and the negatively charged N-terminal region of RhoGDI that contribute most to the binding affinity. MM-PBSA binding free energy calculations show a significant weakening of interaction on phosphorylation at the RhoA-specific site of RhoGDI. In contrast, phosphorylation at a Rac1-specific site leads to the strengthening of the interaction confirming the presence of a phosphorylation code. RhoA-specific phosphorylation leads to a reduction in the number of contacts between the PBR of RhoA and the N-terminal region of RhoGDI, which manifests reduction of the binding affinity. Using hydrogen bond occupancy analysis and energetic perturbation network, we propose a mechanistic model for the allosteric response, i.e., long range signal propagation from the site of phosphorylation to the PBR and buried geranylgeranyl group in the form of rearrangement and rewiring of hydrogen bonds and salt bridges. Our results highlight the crucial role of specific electrostatic interactions in manifestation of the phosphorylation code.
Mcam stabilizes luminal progenitor breast cancer phenotypes via Ck2 control and Src/Akt/Stat3 attenuation
Authors: Balcioglu Ozlen , Gates Brooke L. , Freeman David W. , Hagos Berhane M. , Mehrabad Elnaz Mirzaei , Ayala-Talavera David , Spike Benjamin T.
Published: May 2023

Breast cancers are categorized into subtypes with distinctive therapeutic vulnerabilities and prognoses based on their expression of clinically targetable receptors and gene expression patterns mimicking different cell types of the normal gland. Here, we tested the role of Mcam in breast cancer cell state control and tumorigenicity in a luminal progenitor-like murine tumor cell line (Py230) that exhibits lineage and tumor subtype plasticity. Mcam knockdown Py230 cells show augmented Stat3 and Pi3K/Akt activation associated with a lineage state switch away from a hormone-sensing/luminal progenitor state toward alveolar and basal cell related phenotypes that were refractory to growth inhibition by the anti-estrogen therapeutic, tamoxifen. Inhibition of Stat3, or the upstream activator Ck2, reversed these cell state changes. Mcam binds Ck2 and acts as a regulator of Ck2 substrate utilization across multiple mammary tumor cell lines. In Py230 cells this activity manifests as increased mesenchymal morphology, migration, and Src/Fak/Mapk/Paxillin adhesion complex signalingin vitro, in contrast to Mcam’s reported roles in promoting mesenchymal phenotypes.In vivo, Mcam knockdown reduced tumor growth and take rate and inhibited cell state transition to Sox10+/neural crest like cells previously been associated with tumor aggressiveness. This contrasts with human luminal breast cancers where MCAM copy number loss is highly coupled to Cyclin D amplification, increased proliferation, and the more aggressive Luminal B subtype. Together these data indicate a critical role for Mcam and its regulation of Ck2 in control of breast cancer cell state plasticity with implications for progression, evasion of targeted therapies and combination therapy design.

HIGHLIGHTS

Mcam is expressed by diverse breast cancer subtypes.

Mcam regulates breast cancer cell state plasticity.

Mcam maintains the mammary luminal progenitor state.

Mcam attenuates Stat activity.

Mcam dictates Ck2 substrate utilization.