bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of distinct cytokine/chemokine profiles in dermatomyositis with anti-transcriptional intermediary factor 1-γ antibody
Authors: Zhao Qian , Chen Yongheng , Diao Licheng , Zhang Shimin , Wu Dan , Xue Feng , Xia Qunli , Li Hao , Zheng Jie , Cao Hua
Published: September 2021

Objectives

DM and clinically amyopathic DM (CADM) patients with positive expression of anti-transcription intermediary factor 1-γ (anti-TIF1-γ) antibody (Ab) are characterized by distinct clinicopathological features. We aimed to determine the role of cytokine/chemokine profiles in the classification of anti-TIF1-γ positive DM/CADM patients.

Methods

Serum levels of 24 cytokines/chemokines were measured in 27 anti-TIF1-γ positive DM/CADM patients by a Luminex 200 system. Principal components analysis and unsupervised hierarchical clustering were used to reduce variables and establish patient subgroups. Spearman’s correlation coefficient was calculated between cytokine/chemokine levels and disease activity markers.

Results

Among anti-TIF1-γ positive DM/CADM patients, two distinct patient clusters were identified. The diagnosis of CADM was more common in cluster 1 than in cluster 2 (58.3% vs 6.7%, P = 0.008). Skin disease activity was higher in cluster 2 than in cluster 1 as measured by Cutaneous DM Disease Area and Severity Index–Activity [38.6  (10.4) vs 25.3  (10.0), P = 0.003]. Patients within cluster 2 exhibited significant muscle weakness (Medical Research Council scale ≤ 3, 33.3% vs 0.0%, P = 0.047), higher levels of anti-TIF1-γ Ab [92.4  (20.6) vs 66.9  (13.9), P = 0.001] and an increased malignancy rate (73.3% vs 25.0%, P = 0.021). Cluster 2 exhibited higher serum levels of CXCL10 [564.2  (258.8) vs 122.0  (97.8), P < 0.001], CCL2 [1136.6  (545.4) vs 441.6  (163.3), P < 0.001], galectin-9 [38879.6  (20009.3) vs 12612.4  (6640.0), P < 0.001], IL-18 [436.1  (188.9) vs 243.0  (114.5), P = 0.003], TNF-α [9.3  (3.8) vs 5.6  (2.4), P = 0.007] and TNFRI [1385.1  (338.2) vs 2605.6  (928.5), P < 0.001] than cluster 1.

Conclusion

In anti-TIF1-γ positive DM/CADM, we identified a ‘skin-predominant’ cluster and a ‘hyperinflammation’ cluster based on the cytokine/chemokine profiles.Cytokine/chemokine profiles in anti-TIF1-γ positive DM/CADM can identify discrete clusters of patients with different disease patterns, organ involvements and clinical outcomes.
Transformative Learning in an International Immersion Experience for Nursing and Other Undergraduates
Authors: Kennison Monica , Lamb Connie
Published: September 2021

This qualitative study described the experience of undergraduates in an international immersion experience designed to foster health promotion among rural Ghanaians. Data in the form of students’ reflective writings were analyzed in a rigorous process of literal, interpretive, and reflective readings. Two themes (character building and feeling inspired by others) emerged from the data. The findings suggest that this immersion trip facilitated the transformation of the participants and the development of their cultural competence.
Humanities-Based Educational Preparation and Empathy in Novice Nurses: Critical Thinking and Analytic Practice
Authors: Adams Sara B. , Scott Linda D.
Published: September 2021

Empathy has been associated with improved patient outcomes in practicing nurses, but empathy levels have been shown to decline in nursing students with increased clinical exposure. Integrating content from the humanities in the nursing classroom, not common in nursing education, supports professional empathy development and maintenance. Whether competencies gained from humanities-based liberal education courses support empathy in nursing students as they emerge into practice is not known. The purpose of this quantitative, nonexperimental, descriptive, pilot research was to explore the relationship between humanities-based liberal education and empathy in recently graduated, baccalaureate-prepared practicing nurses (n = 40).
Perioperative Pulmonary Atelectasis: Part I. Biology and Mechanisms
Authors: Zeng Congli , Lagier David , Lee Jae-Woo , Vidal Melo Marcos F.
Published: September 2021

Pulmonary atelectasis is common in the perioperative period. Physiologically, it is produced when collapsing forces derived from positive pleural pressure and surface tension overcome expanding forces from alveolar pressure and parenchymal tethering. Atelectasis impairs blood oxygenation and reduces lung compliance. It is increasingly recognized that it can also induce local tissue biologic responses, such as inflammation, local immune dysfunction, and damage of the alveolar–capillary barrier, with potential loss of lung fluid clearance, increased lung protein permeability, and susceptibility to infection, factors that can initiate or exaggerate lung injury. Mechanical ventilation of a heterogeneously aerated lung (e.g., in the presence of atelectatic lung tissue) involves biomechanical processes that may precipitate further lung damage: concentration of mechanical forces, propagation of gas–liquid interfaces, and remote overdistension. Knowledge of such pathophysiologic mechanisms of atelectasis and their consequences in the healthy and diseased lung should guide optimal clinical management.
Scientific Accuracy Matters
Authors: Larson C. Philip
Published: September 2021

The Solubility of Halothane in Blood and Tissue Homogenates. By Larson CP, Eger EI, Severinghaus JW. Anesthesiology 1962; 23:349–55.

Measured samples of human and bovine blood, human hemoglobin, and tissue homogenates from human fat and both human and bovine liver, kidney, muscle, whole brain, and separated gray and white cortex were added to stoppered 2,000-ml Erlenmeyer flasks. To each flask, 0.1 ml of liquid halothane was added under negative pressure using a calibrated micropipette. After the flask was agitated for 2 to 4 h to achieve equilibrium between the gas and blood or tissue contents, a calibrated infrared halothane analyzer was used to measure the concentration of halothane vapor. Calculated partition coefficients ranged from 0.7 for water to 2.3 for blood and from 3.5 for human or bovine kidney to 6 for human whole brain or liver and 8 for human muscle. Human peritoneal fat had a value of 138. The human blood–gas partition coefficient of 2.3 as determined by this equilibration method was well below the previously published value of 3.6.
Surgical Resection or Ablation for Recurrent Pancreatic Ductal Adenocarcinoma
Authors: Lee Boram , Han Ho-Seong , Lee Jun Suh , Yoon Yoo-Seok
Published: September 2021

Objective:

To evaluate the survival benefits of curative-intent treatment (CIT, including surgery or ablation) for recurrent pancreatic ductal adenocarcinoma (PDAC) depending on the recurrence type and compared the survival outcomes with other treatment modalities.

Background:

The treatment for recurrent PDAC is mostly chemotherapy or best supportive care (BSC). Still, the role of CIT for recurrent PDAC is not well established.

Methods:

PDAC patients who underwent pancreatectomy between 2004 and 2019 were included. Recurrences were categorized as locoregional (LR), distant, or disseminated. Recurrent PDAC management was classified as CIT, chemotherapy ± radiation therapy (CTX ± RTX), or BSC. The survival after recurrence (SAR) rate was measured from the first day of recurrence to the date of death or last follow-up.

Results:

Two hundred eighteen patients had recurrent PDAC and were analyzed (27 CIT, 128 CTX ± RTX, 63 BSC). The 1-, 3-, and 5-year SAR rates were 65.4%, 11.5%, and 11.5% for CIT, 42.1%, 4.0%, and 0% for CTX ± RTX, and 15.9%, 1.6%, and 0% for BSC, respectively. Subgroup analysis indicated the SAR rate was significantly better in the CIT group than in the CTX ± RTX and BSC groups in LR type (P = 0.027) and distant type (P < 0.001). In multivariate analysis, the albumin level at recurrence (hazard ratio, 2.14; 95% confidence interval, 1.15–18.3, P = 0.038) and operation time of the second operation (hazard ratio, 0.98; 95% confidence interval, 0.97–0.99, P = 0.021) were associated with a favorable prognosis of SAR in the CIT group.

Conclusions:

CIT should be considered in recurrent PDAC for LR and distant metastases in selected patients.
BCMA CAR-T Therapy Is Safe and Effective for Refractory/Relapsed Multiple Myeloma With Central Nervous System Involvement
Authors: Wang Yiyun , Zu Cheng , Teng Xinyi , Yang Li , Zhang Mingming , Hong Ruimin , Zhao Houli , Cui Jiazhen , Xu Huijun , Hongsheng Alex Chang , Hu Yongxian , Huang He
Published: September 2021

Central nervous system (CNS) involvement is a rare complication of multiple myeloma (MM) that portends an extremely poor prognosis. Although chimeric antigen receptor (CAR)-T cell therapy is considered a promising strategy for patients with MM, the role of CAR-T cell therapy in MM involving the CNS has not been fully elucidated. In this study, we retrospectively analyzed 4 cases of B-cell maturation antigen CAR-T cell therapy for patients with relapsed/refractory MM involving the CNS. Patients received a range of 2–7 lines of prior therapy, including 1 autologous hematopoietic stem cell transplant. The most common adverse event was cytokine release syndrome, which was observed in all 4 patients, including 2 with grade 1 and 2 with grade 2. No patient was complicated with immune effector cell–associated neurotoxicity syndrome. Within the follow-up (median: 257 d, range: 116–392 d), 3 of 4 patients reached complete remission (CR), and 1 patient reached partial response. At the data cutoff, 1 patient continued to remain in CR at day 220, and the patient with partial response died at day 116. The other 2 patients relapsed at 317 and 111 days with CR durations of 287 and 81 days, respectively. Our results show promising effectiveness and acceptable safety of CAR-T cell therapy for heavily pretreated patients with CNS MM.
Increasing accesibility to surgical knowledge-sharing across Southern Africa: the “horizontal” conference model (conference report)
Authors: Verhage Savannah S. , Breedt Danyca S.
Published: September 2021

Recognizing that advancements in global surgery are urgently needed in South Africa, where health inequity is rampant and surgical knowledge gaps remain, the Southern African Student Surgical Society partnered with the University of Cape Town Division of Global Surgery to organize a symposium entitled “Reimagining Perioperative Care in Africa.” The aim of the symposium was to address these needs through informative Global Surgery presentations, a virtual research competition, and an online Theory of Change Workshop, thereby advocating for improved surgical care in Africa through knowledge-sharing and education. By breaking down hierarchical structures through the formation of a collaborative, multidisciplinary Organizing Committee comprised of students and clinicians, a virtual “horizontal” conference model was created. This successfully allowed for the development of a cost-effective, far-reaching, collaboratively organized conference, that catered to both students’ and clinicians’ needs. Endorsed by the Director General of the World Health Organisation, Dr Tedros Ghebreyesus, this virtual “horizontal” model enabled the Organizing Committees to assemble experts from multiple surgical disciplines across Southern Africa, to achieve their mutual goal of finding African solutions to strengthen surgical systems.
Effectiveness and Safety of Tofacitinib for Ulcerative Colitis
Authors: Taneja Vikas , El-Dallal Mohammed , Haq Zadid , Tripathi Kartikeya , Systrom Hannah K. , Wang Linda F. , Said Hyder , Bain Paul A. , Zhou Youlian , Feuerstein Joseph D.
Published: September 2021

Background:

The objective of our systematic review and meta-analysis was to evaluate the effectiveness and safety of tofacitinib in the treatment of moderate-severe ulcerative colitis (UC).

Methods:

We searched Medline, Embase, Web of Science, and Cochrane Central to identify articles and abstracts reporting efficacy or safety data on tofacitinib use in UC. Primary outcome assessed was remission. Secondary outcomes included clinical response, steroid free remission, and adverse events (AEs).

Results:

A total of 26 studies were included. The rates of remission were 29.81% [95% confidence interval (CI): 22.37%-37.25%, I
2: 90%] at week 8, 32.27% (95% CI: 27.67%-36.88%, I
2: 42%) at 6 months and 38.03% (95% CI: 33.59%-42.48%, I
2: 0%) at 1-year. Clinical response rates were 59.41% (95% CI: 55.03%-63.94%, I
2: 61%) at week 8, 48.99% (95% CI: 36.92%-61.06%, I
2: 91%) at 6 months and 50.87% (95% CI: 42.16%-59.58%, I
2: 67%) at 1-year. Odds ratio of clinical response at week 8 in biologic naive versus biologic experienced patients was 1.59 (95% CI: 0.54-4.63). Pooled incidence rate for serious infections, major adverse cardiovascular events, and nonmelanotic squamous cell malignancies across all doses was 4.41 per 100-patient years (PYs) (95% CI: 2.32-8.38 per 100-PY, I
2: 78%), 0.91 per 100-PY (95% CI: 0.43-1.93 per 100-PY, I
2: 37%) and 0.91 per 100-PY (95% CI: 0.61-1.34 per 100-PY, I
2: 0%), respectively. Higher dose was associated with an increased frequency of AEs.

Conclusions:

While the overall efficacy and safety of tofacitinib in moderate-severe UC is consistent with clinical trial data, the dose dependent increase in AEs highlights the significance of early dose de-escalation. Rate of clinical response after tofacitinb induction was similar in biologic naive and biologic experienced patients.
Oral Fluconazole Therapy in Patients With Active Ulcerative Colitis Who Have Detectable Candida in the Stool
Authors: Jena Anuraag , Dutta Usha , Shah Jimil , Sharma Vishal , Prasad Kaushal K. , Shivaprakash Rudramurthy M. , Mandavdhare Harshal S. , Samanta Jayanta , Sharma Pankaj , Popli Priyanka , Sharma Arun K. , Sinha Saroj K. , Chakrabarti Arunaloke , Kochhar Rakesh
Published: September 2021

Background:

There is an emerging role of fungal dysbiosis in the pathogenesis of inflammatory bowel disease. Prevalence ofCandidain patients with active ulcerative colitis (UC) and the effect of fluconazole therapy in reducing disease activity of UC are not known.

Patients and Methods:

All consecutive consenting patients with active UC defined as Mayo score ≥3 were evaluated for presence ofCandidaby stool culture and predictors for presence ofCandidawere identified. Those who had evidence ofCandidain the stool were randomized to receive oral fluconazole 200 mg daily or placebo for 3 weeks along with standard medical therapy. Patients were assessed by clinical, sigmoidoscopy, and laboratory parameters at baseline and at 4 weeks. The primary outcome was clinical and endoscopic response at 4 weeks defined by a 3-point reduction in Mayo score. Secondary outcomes were reduction in fecal calprotectin, histologic response, and adverse events.

Results:

Of the 242 patients with active UC, 68 (28%) patients hadCandidain stool culture. Independent predictors for presence ofCandidain patients with active UC were partial Mayo score of ≥3 and steroid exposure. Among those withCandidaon stool culture (n=68), 61 patients fulfilled eligibility criteria and were randomized to receive fluconazole (n=31) or placebo (n=30). Three-point reduction in Mayo score though was numerically higher in the fluconazole group than the placebo group but was not statistically significant [5 (16.1%) vs. 1 (3.33%);P=0.19]. Postintervention median Mayo score was lower in fluconazole than placebo group [4 (3, 5) vs. 5 (4, 6);P=0.034]. Patients in fluconazole group had more often reduction in fecal calprotectin [26 (83.9%) vs. 11 (36.7%);P=0.001] and histologic scores [23 (74.1%) vs. 10 (33.3%);P=0.001] compared with placebo. All patients were compliant and did not report any serious adverse event.

Conclusion:

Candidacolonization is found in 28% of patients with UC. Steroid exposure and active disease were independent predictors for the presence ofCandida. There was no statistically significant difference in the number of patients who achieved 3-point reduction in Mayo score between 2 groups. However, clinical, histologic, and calprotectin levels showed significant improvement in fluconazole group.
The Use of Community Health Workers in Community Health Centers
Authors: Park Jeongyoung , Regenstein Marsha , Chong Nicholas , Onyilofor Chinelo L.
Published: September 2021

Background:

Until 2016, community health centers (CHCs) reported community health workers (CHWs) as part of their overall enabling services workforce, making analyses of CHW use over time infeasible in the annual Uniform Data System (UDS).

Objective:

The objective of this study was to examine changes in the CHW workforce among CHCs from 2016 to 2018 and factors associated with the use of CHWs.

Research Design, Subjects, Measures:

The two-part model estimated separate effects for the probability of using any CHW and extent of CHW full-time equivalents (FTEs) reported in those CHCs, using a total of 4102 CHC-year observations from 2016 to 2018. To estimate the extent to which increases in CHW workforce are attributable to real growth or rather are a consequence of a change in reporting category, we also conducted a difference-in-differences analysis to compare non-CHW enabling services FTEs between CHCs with and without CHWs before (2013–2015) and after (2016–2018) the reporting change in 2016.

Results:

The rate of CHCs that employed CHWs rose from 20.04% in 2016 to 28.34% in 2018, while average FTEs stayed relatively flat (3.32 FTEs). Patient visit volume (larger CHCs) and grant funding (less reliant on federal but more reliant on private funding) were significant factors associated with CHW use. However, we found that a substantial portion of this growth was attributable to a change in UDS reporting categories.

Conclusion:

While we do not address the reasons why CHCs have been slow to use CHWs, our results point to substantial financial barriers associated with CHCs’ expanding the use of CHWs.
Alternative Approaches to Ensuring Adequate Nurse Staffing
Authors: Han Xinxin , Pittman Patricia , Barnow Burt
Published: September 2021

Objective:

The objective of this study was to addresses the basic question of whether alternative legislative approaches are effective in encouraging hospitals to increase nurse staffing.

Methods:

Using 16 years of nationally representative hospital-level data from the American Hospital Association (AHA) annual survey, we employed a difference-in-difference design to compare changes in productive hours per patient day for registered nurses (RNs), licensed practical/vocational nurses (LPNs), and nursing assistive personnel (NAP) in the state that mandated staffing ratios, states that legislated staffing committees, and states that legislated public reporting, to changes in states that did not implement any nurse staffing legislation before and after the legislation was implemented. We constructed multivariate linear regression models to assess the effects with hospital and year fixed effects, controlling for hospital-level characteristics and state-level factors.

Results:

Compared with states with no legislation, the state that legislated minimum staffing ratios had an 0.996 (P<0.01) increase in RN hours per patient day and 0.224 (P<0.01) increase in NAP hours after the legislation was implemented, but no statistically significant changes in RN or NAP hours were found in states that legislated a staffing committee or public reporting. The staffing committee approach had a negative effect on LPN hours (difference-in-difference=−0.076, P<0.01), while the public reporting approach had a positive effect on LPN hours (difference-in-difference=0.115, P<0.01). There was no statistically significant effect of staffing mandate on LPN hours.

Conclusions:

When we included California in the comparison, our model suggests that neither the staffing committee nor the public reporting approach alone are effective in increasing hospital RN staffing, although the public reporting approach appeared to have a positive effect on LPN staffing. When we excluded California form the model, public reporting also had a positive effect on RN staffing. Future research should examine patient outcomes associated with these policies, as well as potential cost savings for hospitals from reduced nurse turnover rates.
The Association of Race, Ethnicity, and Wages Among Registered Nurses in Long-term Care
Authors: Wagner Laura M. , Bates Timothy , Spetz Joanne
Published: September 2021

Objective:

This study seeks to measure wage differences between registered nurses (RNs) working in long-term care (LTC) (eg, nursing homes, home health) and non-LTC settings (eg, hospitals, ambulatory care) and whether differences are associated with the characteristics of the RN workforce between and within settings.

Study Design:

This was a cross-sectional design. This study used the 2018 National Sample Survey of Registered Nurses (NSSRN) public-use file to examine RN employment and earnings.

Methods:

Our study population included a sample of 15,373 RNs who were employed at least 1000 hours in nursing in the past year and active in patient care. Characteristics such as race/ethnicity, type of RN degree completed, census region, and union status were included. Multiple regression analyses examined the effect of these characteristics on wages. Logistic regression was used to predict RN employment in LTC settings.

Results:

RNs in LTC experienced lower wages compared with those in non-LTC settings, yet this difference was not associated with racial/ethnic or international educational differences. Among RNs working in LTC, lower wages were associated with part-time work, less experience, lack of union representation, and regional wage differences.

Conclusion:

Because RNs in LTC earn lower wages than RNs in other settings, policies to minimize pay inequities are needed to support the RN workforce caring for frail older adults.
Gender and racial disparities in the transplant surgery workforce
Authors: Valbuena Valeria S.M. , Obayemi Joy E. , Purnell Tanjala S. , Scantlebury Velma P. , Olthoff Kim M. , Martins Paulo N. , Higgins Robert S. , Blackstock Daryle M. , Dick André A.S. , Watkins Anthony C. , Englesbe Michael J. , Simpson Dinee C.
Published: September 2021

Purpose of review

This review explores trends in the United States (US) transplant surgery workforce with a focus on historical demographics, post-fellowship job market, and quality of life reported by transplant surgeons. Ongoing efforts to improve women and racial/ethnic minority representation in transplant surgery are highlighted. Future directions to create a transplant workforce that reflects the diversity of the US population are discussed.

Recent findings

Representation of women and racial and ethnic minorities among transplant surgeons is minimal. Although recent data shows an improvement in the number of Black transplant surgeons from 2% to 5.5% and an increase in women to 12%, the White to Non-White transplant workforce ratio has increased 35% from 2000 to 2013. Transplant surgeons report an average of 4.3 call nights per week and less than five leisure days a month. Transplant ranks 1st among surgical sub-specialties in the prevalence of three well-studied facets of burnout. Concerns about lifestyle may contribute to the decreasing demand for advanced training in abdominal transplantation by US graduates.

Minimal improvements have been made in transplant surgery workforce diversity. Sustained and intentional recruitment and promotion efforts are needed to improve the representation of women and minority physicians and advanced practice providers in the field.
Shame in Response to Affective Expression and Its Relation to Social Anhedonia and Schizotypy Traits
Authors: Gerhart James , Russ Eric U. , Alonzi Sarah , Hoerger Michael
Published: September 2021

Schizotypy is marked by negative symptoms including blunted affect, social isolation, and social anhedonia. Contemporary personality theory suggests that maladaptive shame regulation may disrupt interpersonal function across personality disorders. We hypothesized that “affect shame”—a conditioned response of shame evoked by openly expressing emotions would co-occur with interpersonal deficits in schizotypy. As hypothesized, affect shame was associated with interpersonal deficits (r = 0.17, p < 0.001), physical anhedonia (r = 0.13, p = 0.001), and social anhedonia (r = 0.17, p = 0.001). The observed findings were upheld in analyses controlling for demographic characteristics, depression symptom severity, and neuroticism and were maintained consistently across sensitivity analyses. Findings suggest that shame related to emotional expression is related to interpersonal deficits in schizotypy and have implications for our understanding of the etiology and treatment of this disorder.
A Qualitative Investigation Into Faith and LGBTQ Identities in a Nonclinical Sample of Readers of the Dear Abby Column
Authors: Ghazzawi Alhasan , Casoy Flávio , Libby Naomi , McIntosh Chris , Barber Mary , Adelson Stewart , Ahola Joanne , Ashley Kenneth , Chavez Alexis M. , Erickson-Schroth Laura , Fadus Matthew , Goldenberg David , Hung Kenneth , Lothwell Lorraine , Mattson Marlin , McAfee Scot G. , Nowaskie Dustin Z. , Schwartz Alan , Tompkins David Andrew , Yarbrough Eric R. , Drescher Jack
Published: September 2021

To better understand the relationship between faith and LGBTQ+ identity, we conducted a qualitative analysis of 86 respondents to a general question posed through the Dear Abby column. Responses were anonymized and analyzed using a grounded theory approach. Analysis revealed six themes, reflecting a diversity of lived experience from community rejection to acceptance, and self-rejection to feelings of acceptance by God. Despite frequent media portrayals of conflict between faith and LGBTQ+ identity, the reality is more complex, and faith and LGBTQ+ identity development can be complementary.
Common coupling map advances GPCR-G protein selectivity
Authors: Hauser Alexander S. , Avet Charlotte , Normand Claire , Mancini Arturo , Inoue Asuka , Bouvier Michel , Gloriam David E.
Published: September 2021

Two-thirds of human hormones and one-third of clinical drugs act on membrane receptors that couple to G proteins to achieve appropriate functional responses. While G protein transducers from literature are annotated in the Guide to Pharmacology database, two recent large-scale datasets now expand the receptor-G protein ‘couplome’. However, these three datasets differ in scope and reported G protein couplings giving different coverage and conclusions on GPCR-G protein signaling. Here, we report a common coupling map uncovering novel couplings supported by both large-scale studies, the selectivity/promiscuity of GPCRs and G proteins, and how the co-coupling and co-expression of G proteins compare to the families from phylogenetic relationships. The coupling map and insights on GPCR-G protein selectivity will catalyze advances in receptor research and cellular signaling towards the exploitation of G protein signaling bias in design of safer drugs.
Interpretable deep learning for chromatin-informed inference of transcriptional programs driven by somatic alterations across cancers
Authors: Tao Yifeng , Ma Xiaojun , Palmer Drake , Schwartz Russell , Lu Xinghua , Osmanbeyoglu Hatice Ulku
Published: September 2021

Cancer is a disease of gene dysregulation, where cells acquire somatic and epigenetic alterations that drive aberrant cellular signaling. These alterations adversely impact transcriptional programs and cause profound changes in gene expression. Interpreting somatic alterations within context-specific transcriptional programs will facilitate personalized therapeutic decisions but is a monumental task. Toward this goal, we develop a partially interpretable neural network model called Chromatin-informed Inference of Transcriptional Regulators Using Self-attention mechanism (CITRUS). CITRUS models the impact of somatic alterations on transcription factors and downstream transcriptional programs. Our approach employs a self-attention mechanism to model the contextual impact of somatic alterations. Furthermore, CITRUS uses a layer of hidden nodes to explicitly represent the state of transcription factors (TFs) to learn the relationships between TFs and their target genes based on TF binding motifs in the open chromatin regions of tumor samples. We apply CITRUS to genomic, transcriptomic, and epigenomic data from 17 cancer types profiled by The Cancer Genome Atlas. CITRUS predicts patient-specific TF activities and reveals transcriptional program variations between and within tumor types. We show that CITRUS yields biological insights into delineating TFs associated with somatic alterations in individual tumors. Thus, CITRUS is a promising tool for precision oncology.
Dysfunction of an energy sensor NFE2L1 triggers uncontrollable AMPK signal and glucose metabolism reprogramming
Authors: Yang Qiufang , Zhao Wenshan , Xing Yadi , Li Peng , Zhou Xiaowen , Ning Haoming , Shi Ranran , Gou Shanshan , Chen Yalan , Zhai Wenjie , Wu Yahong , Li Guodong , Chen Zhenzhen , Ren Yonggang , Gao Yanfeng , Zhang Yiguo , Qi Yuanming , Qiu Lu
Published: September 2021

NFE2L1 (also called Nrf1) acts a core regulator of redox signaling and metabolism homeostasis, and thus its dysfunction results in multiple systemic metabolic diseases. However, the molecular mechanism(s) by which NFE2L1 regulates glycose and lipid metabolism is still elusive. Here, we found that the loss of NFE2L1 in human HepG2 cells led to a lethal phenotype upon glucose deprivation. The uptake of glucose was also affected by NFE2L1 deficiency. Further experiments unveiled that although the glycosylation of NFE2L1 was monitored through the glycolysis pathway, it enabled to sense the energy state and directly interacted with AMPK. These indicate that NFE2L1 can serve as a dual sensor and regulator of glucose homeostasis. In-depth sights into transcriptome, metabolome and seahorse data further unraveled that glucose metabolism was reprogrammed by disruption of NFE2L1, so as to aggravate the Warburg effect in NFE2L1-silenced hepatoma cells, along with the mitochondrial damage observed under the electron microscope. Collectively, these demonstrate that disfunction of NFE2L1 triggers the uncontrollable signaling by AMPK towards glucose metabolism reprogramming in the liver cancer development.
Population modelling insights of extinct environments: the case of the Kem Kem palaeocommunity
Authors: dos Anjos Lucas
Published: September 2021

The Kem Kem beds are well-known palaeontological deposits. Among the species that lived there, there are some large theropods, such as Deltadromeus agilis, Carcharodontosaurus saharicus, and Spinosaurus aegyptiacus. It is possible that these large predators were facultative scavengers, and they could compete for carrion. In the present paper, I simulate a small community module of this environment, consisting of Carrion, Fishes, Spinosaurus, and a functional group composed of large terrestrial Theropods. I assume that these top predators feed on carrion, but they also have exclusive food sources. I show that these exclusive food sources could have assured the possibility of coexistence, and in their absence, one top predator could be locally extinct.
Response of the Oligo-Miocene Bivalve Fauna of the Kutch Basin (Western India) to Regional Tectonic Events
Authors: Dutta Saurav , Chattopadhyay Devapriya
Published: September 2021

Tectonic changes has influenced the evolution of the marine community by changing the land and seaway configuration through time. Two such tectonic events during Oligo-Miocene times — the closure of the Tethyan seaway due to development of theGomphotherium-Landbridge leading to separation of the Arabian Sea from proto-Mediterranean Sea (∼19 Ma) and significant uplift of the Tibetan plateu marking the initiation of the monsoon (∼16 Ma) — represent a classic case of tectonic shift influencing the regional environment of the Indian subcontinent. We investigated the taxonomic and body size related response of the shallow marine fauna to this regional change using bivalves from 11 time-constrained shellbeds of the Kutch Basin (western India) from three formations — Maniyara Fort (Chattian), Khari Nadi (Aquitanian) and Chhasra (Burdigalian-Langian) representing a time span of ∼9 Ma (24.4 – 15 Ma).

Our collection of over 2000 individuals represents a total of 15 families and 61 morphospecies. The fossils are predominantly calcitic in nature and families of aragonitic composition are often preserved as molds indicating a potential negative effect of diagenesis. The taphonomic nature, however, does not vary substantially across shellbeds and hence, less likely produced a temporal pattern. The five most abundant species,Ostrea latimarginata, Ostrea angulata, Talochlamys articulata, Anomia primaevaandPlacuna lamellataoccur in all the formations. The species composition of the Maniyara Fort formation is substantially different from those of the younger formations implying the possible effect of biogeographic separation. Moreover, the absence of proto-Mediterranean taxa in Oligocene shellbeds support a limited faunal exchange as early as ∼24.4Ma (Chattian) ago. We observed a monotonic increase in the overall rarefied species richness and a decrease in evenness from the Maniyara Fort to the Chhasra Formation. However, shellbed analyses show a dominantly conservative behavior of diversity and body size without a strong directional trend through time. Although it is difficult to rule out the negative influence of taphonomy on the diversity of the studied fauna, Oligo-Miocene marine bivalve fauna of the Kutch Basin demonstrate little or no influence of the Tethyan closure and Himalayan upliftment.
Spinal reconsolidation engages non-ionotropic NMDA receptor signaling to reverse pain hypersensitivity
Authors: D’Souza Abigail J. , Rodriguez-Hernandez David , Zhang Hantao , He David , Zain Maham , Fung Samuel , Bennett Laura A. , Bonin Robert P.
Published: September 2021

Reconsolidation enables the activity-dependent modification of memory traces and has been used to reverse addiction, fear memory, and pain hypersensitivity in animal models. We demonstrate that non-ionotropic NMDA receptor signalling in the spinal dorsal horn is sufficient to reverse pain hypersensitivity and necessary for pain modulation by spinal reconsolidation. These findings reveal a key process by which reconsolidation disrupts memory traces that may be exploited in the treatment of pain and other disorders.
CaPTure: Calcium PeakToolbox for analysis of in vitro calcium imaging data
Authors: Tippani Madhavi , Pattie Elizabeth A. , Davis Brittany A. , Nguyen Claudia V. , Wang Yanhong , Sripathy Srinidhi Rao , Maher Brady J. , Martinowich Keri , Jaffe Andrew E. , Page Stephanie Cerceo
Published: September 2021

Background

Calcium imaging is a powerful technique for recording cellular activity across large populations of neurons. However, analysis methods capable of single-cell resolution in cultured neurons, especially for cultures derived from human induced pluripotent stem cells (hiPSCs), are lacking. Existing methods lack scalability to accommodate high-throughput comparisons between multiple lines, across developmental timepoints, or across pharmacological manipulations.

Results

We developed a scalable, automated Ca2+ imaging analysis pipeline called CaPTure (https://github.com/LieberInstitute/CaPTure). This method detects neurons, classifies and quantifies spontaneous activity, quantifies synchrony metrics, and generates cell- and network-specific metrics that facilitate phenotypic discovery. The method is compatible with parallel processing on computing clusters without requiring significant user input or parameter modification.

Conclusion

CaPTure allows for rapid assessment of neuronal activity in cultured cells at cellular resolution, rendering it amenable to high-throughput screening and phenotypic discovery. The platform can be applied to both human- and rodent-derived neurons and is compatible with many imaging systems.
Beyond traditional visual sleep scoring: massive feature extraction and unsupervised clustering of sleep time series
Authors: Decat Nicolas , Walter Jasmine , Koh Zhao H. , Sribanditmongkol Piengkwan , Fulcher Ben D. , Windt Jennifer M. , Andrillon Thomas , Tsuchiya Naotsugu
Published: September 2021

Sleep is classically measured with electrophysiological recordings, which are then scored based on guidelines tailored for the visual inspection of these recordings. As such, these rules reflect a limited range of features easily captured by the human eye and do not always reflect the physiological changes associated with sleep. Here we present a novel analysis framework that characterizes sleep using over 7700 time-series features from thehctsasoftware. We used clustering to categorize sleep epochs based on the similarity of their features, without relying on established scoring conventions. The resulting structure overlapped substantially with that defined by visual scoring and we report novel features that are highly discriminative of sleep stages. However, we also observed discrepancies ashctsafeatures unraveled distinctive properties within traditional sleep stages. Our framework lays the groundwork for a data-driven exploration of sleep and the identification of new signatures of sleep disorders and conscious sleep states.
Angicin, a novel bacteriocin of Streptococcus anginosus
Authors: Vogel Verena , Bauer Richard , Mauerer Stefanie , Schiffelholz Nicole , Haupt Christian , Seibold Gerd M. , Fändrich Marcus , Walther Paul , Spellerberg Barbara
Published: September 2021

As a conserved defense mechanism, many bacteria produce antimicrobial peptides, called bacteriocins, which give a colonization advantage in a multispecies environment. Here the first bacteriocin of Streptococcus anginosus, designated Angicin, is described. S. anginosus is commonly described as a commensal, however it also possesses a high pathogenic potential. Therefore, understanding factors contributing to its host colonization and persistence are important. A radial diffusion assay was used to identify S. anginosus BSU 1211 as a potent bacteriocin producer. By genetic mutagenesis the background of bacteriocin production and the bacteriocin gene itself were identified. Synthetic Angicin shows high activity against closely related streptococci, listeria and vancomycin resistant enterococci. It has a fast mechanism of action and causes a membrane disruption in target cells. Angicin, present in cell free supernatant, is insensitive to changes in temperature from −70 to 90 °C and pH values from 2-10, suggesting that it represents an interesting compound for potential applications in food preservation or clinical settings.
The X-linked splicing regulator MBNL3 has been co-opted to restrict placental growth in eutherians
Authors: Spruce Thomas , Plass Mireya , Gohr André , Ray Debashish , de Lagrán María Martínez , Rot Gregor , Nóvoa Ana , Burguera Demian , Permanyer Jon , Miret Marta , Zheng Hong , Swanson Maurice S. , Morris Quaid , Mallo Moises , Dierssen Mara , Hughes Timothy R. , Pernaute Barbara , Irimia Manuel
Published: September 2021

The eutherian placenta is a major site for parental genetic conflict. Here, we identify the X-linked Mbnl3 gene as a novel player in this dispute. Mbnl3 belongs to an RNA binding protein family whose members regulate alternative splicing and other aspects of RNA metabolism in association with cellular differentiation. We find that, in eutherians, Mbnl3 has become specifically expressed in placenta and has undergone accelerated sequence evolution leading to changes in its RNA binding specificities. Although its molecular roles are partly redundant with those of Mbnl2, Mbnl3 has also acquired novel biological functions. In particular, whereas Mbnl2;Mbnl3 double knockout mice display severe placental maturation defects leading to strong histological and functional abnormalities, Mbnl3 knockout alone results in increased placental growth and favors placental and fetal resource allocation during limiting conditions.
Benzyl isothiocyanate induces cardiomyocyte proliferation and heart regeneration
Authors: Sakaguchi Akane , Kawasaki Miwa , Saito Yuichi , Murata Kozue , Masumoto Hidetoshi , Kimura Wataru
Published: September 2021

Cardiomyocyte proliferation is an evolutionarily conserved mechanism that supports cardiac regeneration in vertebrates. Mammalian cardiomyocytes are arrested from the cell cycle shortly after birth, and therefore mammals lose the ability to regenerate injured myocardium for the rest of their lives. Pharmacological induction of cardiomyocyte proliferation has gained a lot of interest in recent years, as researchers strive to achieve heart tissue regeneration. Here we show that a small chemical, benzyl isothiocyanate (BITC), induced cardiomyocyte proliferation through activation of the cyclin-dependent kinase (CDK) pathway. BITC treatment also allowed heart regeneration in the infarcted neonatal heart, even after the regeneration period in mice. Furthermore, administration of BITC to adult mice in parallel with mild hypoxia (10% O2) induced cell cycle reentry and tissue regeneration in the adult heart. Our findings thus suggest that pharmacological activation of the CDK pathway using BITC, concurrently with the activation of hypoxia-related signaling pathways, may be a promising approach to inducing cardiac regeneration in patients with heart disease.
Polycomb group protein CBX7 represses cardiomyocyte proliferation via modulation of the TARDBP/Rbm38 axis
Authors: Cho Kyu-Won , Andrade Mark , Bae Seongho , Kim Sangsung , Kim Jin Eyun , Jang Er Yearn , Husain Ahsan , Sutliff Roy L. , Calvert John W. , Park Changwon , Yoon Young-sup
Published: September 2021

Cardiomyocyte (CM) proliferation notably decreases during the perinatal period. At present, regulatory mechanisms for this loss of proliferative capacity is poorly understood. CBX7, a polycomb group (PcG) protein, regulates the cell cycle but its role in CM proliferation is unknown. Here, we report that CBX7 inhibits proliferation of perinatal CMs by controlling TARDBP/Rbm38 pathway. Gene expression profiling demonstrated that CBX7 expression in the heart was low during the prenatal period, abruptly increased during the perinatal period, and sustained constantly throughout the adulthood. CBX7, when overexpressed via adenoviral transduction in neonatal CMs, reduced proliferation and promoted multinucleation of the CMs. Mutant mice carrying targeted inhibition of CBX7 in CMs exhibited cardiomegaly with increased proliferation of CMs at postnatal stages. Mechanistically, CBX7 interacted with TAR DNA-binding protein 43 (TARDBP) and positively regulated its downstream target, RNA Binding Motif Protein 38 (RBM38). Rbm38 was upregulated in the postnatal hearts and overexpression of RBM38 reduced proliferation of neonatal CMs. Together, this study provides a novel insight into the role of CBX7 in regulation of CM proliferation during the perinatal period.
Interleukin-6 Signaling Mediates Cartilage Degradation and Pain in Post-Traumatic Osteoarthritis
Authors: Liao Yihan , Ren Yinshi , Luo Xin , Long Jason T. , Mirando Anthony J. , Leinroth Abigail P. , Ji Ru-Rong , Hilton Matthew J.
Published: September 2021

Osteoarthritis (OA) and post-traumatic OA (PTOA) are prevalent joint disorders and leading causes of chronic pain. The disease pathology of OA/PTOA is caused by imbalanced catabolic and anabolic responses and pro-inflammatory changes; however, their connection to pain is not well studied. Since IL-6 is involved in cartilage degradation and conditions of inflammatory pain, we set out to identify whether IL-6 and IL-6 signaling mechanisms contribute to both PTOA-associated cartilage degradation and pain. We performed a modified destabilization of the medial meniscus (DMM) surgery, a model of PTOA, on conventional IL-6 KO and control mice and assessed both cartilage degradation and pain-associated phenotypes. Genetic removal ofIl6in males attenuates PTOA-associated cartilage catabolism, decreases innervation of soft tissues associated with the knee joint, and reduces nociceptive pain signaling, without improving subchondral bone sclerosis or chondrocyte apoptosis. We further demonstrate that specific downstream mediators of IL-6 signaling, the Janus kinases (JAKs), are critical in regulating both cartilage catabolism and pain signaling. We identified STAT3 as a key regulator of cartilage catabolism downstream of JAK; however, inhibition of STAT3 decreases cartilage anabolism while enhancing pain signals. ERK was found to be important for neurite outgrowth and pain signaling; however, inhibition of ERK was less effective in reducing cartilage catabolism. Therefore, our data demonstrate that IL-6 mediates both PTOA-associated cartilage degradation and pain, and provides critical details regarding the downstream mediators of IL-6 signaling as therapeutic targets for disease-modifying osteoarthritis drugs.

Single Sentence Summary

IL-6 mediates PTOA-associated cartilage degradation and pain via specific downstream signaling mechanisms in a gender specific manner.
Mct11 deficiency alters hepatic glucose metabolism and energy homeostasis
Authors: Ainbinder Alina , Zhao Liping , Glover Patricia , Gelinas-Roa Karen , Rusu Victor , Harney Alycen , Hoch Eitan , Deik Amy A. , Pierce Kerry A. , Bullock Kevin , Dennis Courtney , Jeanfavre Sarah , Krejci Jesse , Choi Jinyoung , Hollenberg Anthony N. , Centeno-Cruz Federico , Barajas-Olmos Francisco , Zerrweck Carlos , Orozco Lorena , Clish Clary B. , Lander Eric S. , Florez Jose C. , Jacobs Suzanne B. R.
Published: September 2021

Genetic variation at the SLC16A11 locus contributes to the disproportionate impact of type 2 diabetes (T2D) on Latino populations. We recently demonstrated that T2D risk variants reduce SLC16A11 liver expression and function of MCT11, the monocarboxylate transporter encoded by the SLC16A11 gene. Here, we show that SLC16A11 expression within the liver is primarily localized to the low oxygen pericentral region, and that T2D risk variants disrupt oxygen-regulated SLC16A11 expression in human hepatocytes. Under physiologic oxygen conditions, MCT11 deficiency alters hepatocyte glucose metabolism, resulting in elevated intracellular lactate and a metabolic shift toward triacylglycerol accumulation. We also demonstrate an impact of Mct11 deficiency on glucose and lipid metabolism in Slc16a11 knockout mice, which display physiological changes that are observed in individuals with T2D. Our findings provide mechanistic insight into how SLC16A11 disruption impacts hepatic energy metabolism and T2D risk, and highlight MCT11-mediated regulation of lactate levels as a potential therapeutic target.