bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single-Cell Analysis in Lung Adenocarcinoma Implicates RNA Editing in Cancer Innate Immunity and Patient Prognosis
Authors: Chan Tracey W. , Dodson Jack P. , Arbet Jaron , Boutros Paul C. , Xiao Xinshu 
Published: November 2022

Abstract

RNA editing modifies single nucleotides of RNAs, regulating primary protein structure and protein abundance. In recent years, the diversity of proteins and complexity of gene regulation associated with RNA editing dysregulation has been increasingly appreciated in oncology. Large-scale shifts in editing have been observed in bulk tumors across various cancer types. However, RNA editing in single cells and individual cell types within tumors has not been explored. By profiling editing in single cells from lung adenocarcinoma biopsies, we found that the increased editing trend of bulk lung tumors was unique to cancer cells. Elevated editing levels were observed in cancer cells resistant to targeted therapy, and editing sites associated with drug response were enriched. Consistent with the regulation of antiviral pathways by RNA editing, higher editing levels in cancer cells were associated with reduced antitumor innate immune response, especially levels of natural killer cell infiltration. In addition, the level of RNA editing in cancer cells was positively associated with somatic point mutation burden. This observation motivated the definition of a new metric, RNA editing load, reflecting the amount of RNA mutations created by RNA editing. Importantly, in lung cancer, RNA editing load was a stronger predictor of patient survival than DNA mutations. This study provides the first single cell dissection of editing in cancer and highlights the significance of RNA editing load in cancer prognosis.

Significance:
RNA editing analysis in single lung adenocarcinoma cells uncovers RNA mutations that correlate with tumor mutation burden and cancer innate immunity and reveals the amount of RNA mutations that strongly predicts patient survival.
See related commentary by Luo and Liang, p. 351
Elucidating the Genetic Landscape of Oral Leukoplakia to Predict Malignant Transformation
Authors: Wils Leon J. , Poell Jos B. , Brink Arjen , Evren Ilkay , Brouns Elisabeth R. , de Visscher Jan G.A.M. , Bloemena Elisabeth , Brakenhoff Ruud H. 
Published: November 2022

Abstract

Purpose:
Oral leukoplakia is the most common oral potentially malignant disorder with an annual malignant transformation rate of 1% to 5%. Consequently, oral leukoplakia patients have a 30% to 50% lifetime risk to develop oral squamous cell carcinoma. Although risk factors for malignant transformation of oral leukoplakia have been investigated, no definitive risk stratification model has been proposed. Next-generation sequencing can elucidate the genetic landscape of oral leukoplakia, which may be used to predict the risk for malignant transformation.

Experimental Design:
We investigated a retrospective cohort of 89 oral leukoplakia patients, and analyzed their oral leukoplakia lesions for the presence of genomic copy-number alterations and mutations in genes associated with oral squamous cell carcinoma.

Results:
In 25 of 89 (28%) patients, oral squamous cell carcinoma developed during follow-up. Seventy-nine of 89 (89%) oral leukoplakias harbored at least one genetic event. Copy-number alterations were present in 61 of 89 (69%) oral leukoplakias, most commonly gains of chromosome regions 8q24 (46%) and 20p11 (20%) and loss of 13q12 (19%). Mutations were present in 59 of 89 (66%) oral leukoplakias, most commonly in TP53 (28%), FAT1 (20%), and NOTCH1 (13%). Genetic data were combined with the presence of dysplasia to generate a prediction model, identifying three groups with a distinct risk for malignant transformation.

Conclusions:
We provide an extensive description of genetic alterations in oral leukoplakia and its relation to malignant transformation. On the basis of our data we provide a model for the prediction of malignant transformation of oral leukoplakia using dysplasia and genetic markers.
Cannabinoid Receptor 2-Centric Molecular Feedback Loop Drives Necroptosis in Diabetic Heart Injuries
Authors: Gao Pan , Cao Mengying , Jiang Xueli , Wang Xiaolin , Zhang Guoping , Tang Xinru , Yang Chunjie , Komuro Issei , Ge Junbo , Li Liliang , Zou Yunzeng 
Published: November 2022

Background:
Diabetic heart dysfunction is a common complication of diabetes. Cell death is a core event that leads to diabetic heart dysfunction. However, the time sequence of cell death pathways and the precise time to intervene of particular cell death type remain largely unknown in the diabetic heart. This study aims to identify the particular cell death type that is responsible for diabetic heart dysfunction and to propose a promising therapeutic strategy by intervening in the cell death pathway.

Methods:

Type 2 diabetes models were established using
db/db
leptin receptor–deficient mice and high-fat diet/streptozotocin–induced mice. The type 1 diabetes model was established in streptozotocin-induced mice. Apoptosis and programmed cell necrosis (necroptosis) were detected in diabetic mouse hearts at different ages. G protein–coupled receptor–targeted drug library was searched to identify potential receptors regulating the key cell death pathway. Pharmacological and genetic approaches that modulate the expression of targets were used. Stable cell lines and a homemade phosphorylation antibody were prepared to conduct mechanistic studies.

Results:

Necroptosis was activated after apoptosis at later stages of diabetes and was functionally responsible for cardiac dysfunction. Cannabinoid receptor 2 (CB2R) was a key regulator of necroptosis. Mechanically, during normal glucose levels, CB2R inhibited S6 kinase–mediated phosphorylation of BACH2 at serine 520, thereby leading to BACH2 translocation to the nucleus, where BACH2 transcriptionally repressed the necroptosis genes
Rip1
,
Rip3
, and
Mlkl
. Under hyperglycemic conditions, high glucose induced CB2R internalization in a β-arrestin 2–dependent manner; thereafter, MLKL (mixed lineage kinase domain-like), but not receptor-interacting protein kinase 1 or 3, phosphorylated CB2R at serine 352 and promoted CB2R degradation by ubiquitin modification. Cardiac re-expression of CB2R rescued diabetes-induced cardiomyocyte necroptosis and heart dysfunction, whereas cardiac knockout of
Bach2
diminished CB2R-mediated beneficial effects. In human diabetic hearts, both CB2R and BACH2 were negatively associated with diabetes-induced myocardial injuries.

Conclusions:
CB2R transcriptionally repressed necroptosis through interaction with BACH2; in turn, MLKL formed a negative feedback to phosphorylate CB2R. Our study provides the integrative view of a novel molecular mechanism loop for regulation of necroptosis centered by CB2R, which represents a promising alternative strategy for controlling diabetic heart dysfunction.
Amount of Pannexin 1 in Smooth Muscle Cells Regulates Sympathetic Nerve–Induced Vasoconstriction
Authors: Dunaway Luke S. , Billaud Marie , Macal Edgar , Good Miranda E. , Medina Christopher B. , Lorenz Ulrike , Ravichandran Kodi , Koval Michael , Isakson Brant E. 
Published: November 2022

Background:
Panx1 (pannexin 1) forms high conductance channels that secrete ATP upon stimulation. The role of Panx1 in mediating constriction in response to direct sympathetic nerve stimulation is not known. Additionally, it is unknown how the expression level of Panx1 in smooth muscle cells (SMCs) influences α-adrenergic responses. We hypothesized that the amount of Panx1 in SMCs dictates the levels of sympathetic constriction and blood pressure.

Methods:
To test this hypothesis, we used genetically modified mouse models enabling expression of Panx1 in vascular cells to be varied. Electrical field stimulation on isolated arteries and blood pressure were assessed.

Results:
Genetic deletion of SMC Panx1 prevented constriction by electric field stimulation of sympathetic nerves. Conversely, overexpression of Panx1 in SMCs using a ROSA26 transgenic model increased sympathetic nerve-mediated constriction. Connexin 43 hemichannel inhibitors did not alter constriction. Next, we evaluated the effects of altered SMC Panx1 expression on blood pressure. To do this, we created mice combining a global Panx1 deletion, with ROSA26-Panx1 under the control of an inducible SMC specific Cre (Myh11). This resulted in mice that could express only human Panx1, only in SMCs. After tamoxifen, these mice had increased blood pressure that was acutely decreased by the Panx1 inhibitor spironolactone. Control mice genetically devoid of Panx1 did not respond to spironolactone.

Conclusions:
These data suggest Panx1 in SMCs could regulate the extent of sympathetic nerve constriction and blood pressure. The results also show the feasibility humanized Panx1-mouse models to test pharmacological candidates.
A Retrospective Propensity‐Matched Analysis of Functional Outcomes for Carotid Puncture for Endovascular Thrombectomy
Authors: Yu Andrew T. , Knox Joey , Jiang Fei , Kim Anthony S. , Cooke Daniel 
Published: November 2022

Background
Endovascular thrombectomy is a well‐established therapy for patients with large‐vessel occlusion stroke but its success largely depends on minimizing time to reperfusion. Direct carotid puncture (DCP) is a technique that avoids difficult aortic arch anatomy, which may cause intraprocedural delays, but because DCP is typically used as rescue access, the poorer outcomes that some have observed may reflect differences in patients chosen for DCP rather than the impact of DCP itself. We performed a propensity score–matched case‐control study to try to address potential confounding by indication to better evaluate whether the DCP procedure itself is responsible for differences in functional outcomes.

Methods
We identified all DCP cases and non‐DCP endovascular thrombectomy controls that were performed under general anesthesia at 2 academic medical centers from 2015 to 2021. Baseline characteristics, workflow time metrics, aortic arch measurements, and 90‐day modified Rankin scale were abstracted from the electronic health record. We then matched patients with controls based on propensity scores, then performed a linear regression to evaluate the relationship between DCP and 90‐day modified Rankin scale.

Results

We identified 13 patients with DCP and 67 control patients for our final analysis. The mean age for DCP was 85.4 years compared with 73.8 years in the control group (
P
≤0.001). We used sex, age, National Institutes of Health Stroke Scale, and last seen normal‐to‐groin times to generate a propensity score to estimate each patient's likelihood of receiving DCP. After matching, we found no significant difference in mean modified Rankin scale associated with DCP (β=−0.231, standard error 0.545;
P
=0.676).

Conclusions
After propensity‐score matching, we found that DCP was not associated with a difference in functional outcomes of endovascular thrombectomy for large‐vessel occlusion stroke compared with non‐DCP access. Advances in algorithms to identify patients highly likely to require DCP and in devices for safer carotid closure are needed before wider adoption of DCP.
No Man is an Island: Reflections on the Battlefield Landscapes of the Falklands-Malvinas War
Authors: Pollard Tony 
Published: November 2022

Abstract
There were two sets of Falkland Islands fought over in 1982. To the British, including the islanders, they were of course the Falklands, but to the Argentines they were the Malvinas. Some in the British military thought the islands were off the coast of Scotland when they first heard of them, in most cases just before deployment. By way of contrast, Argentine troops had grown up believing they were part of their birth right stolen from them by British ‘pirates’. But how did troops on the ground view the islands when they were up close and personal with them, when the islands formed the battlefields over which they fought? During the Falklands-Malvinas War the surface of the land was bombed, it was shelled, it was picked apart and dug into to create fortifications, minefields and graves, and in places it still carries those scars. Drawing on the experience of four visits since 2012, eyewitness accounts and memoirs, military records and archaeological remains, this article explores the islands as both imaginary spaces and as an environment in which men strove to fight the elements and one another, and in doing so presents a fresh perspective on the relationship between people and places in time of war.
Studies on seasonal population fluctuations and feeding damage induced by Dolichotetranychus floridanus (Banks) (Acari: Tenuipalpidae) on areca palms of Kerala, India
Authors: PRABHEENA P. , RAMANI N. 
Published: November 2022

The state of Kerala is home to nearly 10,035 plant species as per the diversity scenario, thereby constituting 22% of the total plant diversity of India. Areca catechu L. (Arecales: Arecaceae) is an important plantation crop of Kerala with a multitude of economic utility and constitutes an important source of income for the people. The areca palms of Kerala are under the threat of many arthropod pests, of which tenuipalpid mites represent a major group causing severe damage to the foliage as well as the nuts. The present study reports a new host record for the tenuipalpid species viz Dolichotetranychus floridanus, which was found to infest the areca palms inducing severe damage to the developing nuts in various Areca plantations of Kerala. To understand the extent of damage induced by the species to its new host A. catechu, sampling was carried out monthly to collect nut samples from areca plantations distributed in two districts viz. Kozhikode and Malappuram of North Kerala, for a period of two years from 2013 and 2015. The collected nut samples were examined in the laboratory under a stereozoom microscope (MVNSZ-450) and data were collected on the population density of the mite as well as the qualitative aspects of feeding damage induced by the mite on the nuts. Results of population studies enabled to record peak population density of D. floridanus during July–August months. A positive correlation was found to exist between mite population and relative humidity and a negative correlation was recorded between mite population and temperature. The mean longevity of the females of this species at different temperatures and humidity conditions was recorded as 17.64 ± 0.17 days at 25 + 2oC & 80 + 5% RH, 13.64 ± 0.12 days at 30 + 2oC & 70 + 5% RH and 11.37 ± 0.12 days at 35 + 2oC & 60 + 5% RH. The feeding activity of the species was found to induce severe alterations, leading to the drying up of epidermal tissue, and formation of cracks at the affected region and the latter often served to permit the entry of fungal and bacterial pathogens, leading to tissue rot.
Delimiting the Dermanyssoidea
Authors: SHAW MATTHEW 
Published: November 2022

The Dermanyssoidea and the Eviphidoidea are two closely related diverse superfamilies within the mite order Mesostigmata. This diversity accrues from their remarkable ecological vagility. The Dermanyssoidea is particularly prone to evolve symbioses with larger animals. Our understanding of the relationships within and between these superfamilies remain unsatisfactory. Various currently-used characters used to recognise the Dermanyssoidea are plesiomorphies and cannot clearly unite this grouping or define it with respect to the Eviphidoidea. While integrated phylogeny will assist in resolving these issues, for key taxa there is a need to further refine available characters to render them usable as homology statements. Several phylogenetically useful characters are outlined. Key characters, when clearly defined, will help the search for natural groups. This will guide phylogenetic sampling and make subsequent tests of evolutionary ecological questions coherent. These needs persist despite widespread calls (coming from outside of acarology) to distil the number of characters used to describe taxa at the species level.
Three-Dimensional Structure of Subduction/Obduction in the North Pacific Ocean
Authors: Liu Ling Ling , Huang Rui Xin , Wang Fan 
Published: November 2022

Abstract
A new three-dimensional method is proposed for calculating the annual mean subduction and obduction rate in the ocean and applied to the North Pacific Ocean. Due to the beta spiral, the subducted/obducted water at a given station can spread over/come from a wide range with different densities in the subsurface ocean. This new method can provide the three-dimensional feature of subduction/obduction and more accurate distribution of the annual subduction/obduction rate in density space. The spatial patterns of annual subduction/obduction rate obtained from both the classical and new methods are similar, although at individual stations the rate can be different; however, the new 3D method can greatly improve the density structure of subducted/obducted water mass. In spite of the assumption of idealized fluid in most previous studies, our analysis showed that subducted water masses can change their density due to diapycnal mixing, especially for water masses subducted at relatively shallow depths. In the North Pacific, the subduction process mainly takes place for about 1–2 months in most of the subtropical basin, while the time window for obduction is ∼100 days in the major obduction regions. Based on the SODA monthly mean climatology, the subducted/obducted water in the North Pacific is primarily distributed at depths of 80–120 m.

Significance Statement
The annual mean subduction/obduction rate is a term quantifying the large-scale irreversible downward/upward water transport between the mixed layer and the permanent pycnocline; these processes are crucially important for climate and the biogeochemical cycle in the oceans. However, the widely used classical Lagrangian method for calculating the annual subduction/obduction rate does not take the three-dimensional structure of ocean currents into consideration, which may induce errors in the destinations/sources of subducted/obducted water masses and the associated water properties. This study is focused on refining the three-dimensional features of subduction/obduction and providing a more accurate distribution of the annual subduction/obduction rate in the density space. In addition, the time window for subduction/obduction and the distribution of subducted/obducted water in the ocean interior are explored based on the SODA monthly mean climatology.
Achieving weight loss through a community-based, telewellness programme: A randomised controlled trial
Authors: Backman Desiree R , Kohatsu Neal D , Padovani Andrew J , Dao Crystie , Ritley Dominique , Fleuret Julia E , McCracken Camlyn R 
Published: November 2022

Objectives: To (1) determine the weight-reducing effect of the Koa Family Program (KFP), a community-based, telewellness obesity intervention and (2) examine the impact of the KFP on improving weight-related health indicators. Design: Randomised controlled trial. Setting: Community-based in Sacramento, California, USA. Methods: Seventy women with overweight or obesity (25 ⩽ BMI < 40), aged 21–45 years and with low income (⩽ 185% of the US Federal Poverty Level) were randomly assigned to an intervention ( n = 34) or control ( n = 36) group. Data were collected by phone-administered questionnaire at weeks 0, 18 and 25. The intervention consisted of three components: (1) weekly, health coach-led, health education meetings on Zoom; (2) social media support through texting and private Facebook groups; and (3) a tree planting and stewardship campaign. The treatment effect on outcome measures (95% confidence intervals) was analysed with adjustment for variables including age, race/ethnicity, education and intake of fruit and vegetables. Results: The overall treatment effect of the KFP was weight loss at both Week 18 (–7.69 pounds [ p < .000; 95% confidence interval (CI) = −11.97 to −3.41]) and Week 25 (−7.72 pounds [ p = .002; 95% CI = −13.02 to −2.42]) of the study. KFP-associated improvements in diet, physical activity, stages of change and self-efficacy were also observed. Conclusions: The KFP resulted in weight loss significant at individual and population levels.
Associated risk factors for patients undergoing a unique or double Nuss bar placement for pectus excavatum
Authors: Chen Hei Yu Matthew , Cheng Wai Yeung Rechard , Chan Herman , Ng Wing Shun 
Published: November 2022

Background Pectus excavatum is the most common chest wall deformity. Surgical correction via Nuss Procedure is a common approach. Patients with long-segment sternal depression require more than one Nuss bar to be inserted. Complications of Nuss procedure include surgical site infection and bar migration which may necessitate surgical re-intervention. There has been conflicting evidence regarding the safety profile of inserting two Nuss bars. We aim to specifically review the safety profile of two Nuss bar insertion and its complications. Method 179 consecutive patients who had undergone Nuss procedure between November 2013 and November 2021 were identified. Data analysis was performed on patient's age at time of operation, gender, height, weight, Haller index, pre-existing medical conditions, indication for surgery, duration of operation, numbers of bars placed, length of stay, post-operative pneumothorax, bar migration, superficial and deep infections, need for surgical intervention and mortality. Result Patients receiving two Nuss bars were at a significantly higher risk of developing infective complications. Lower weight and Haller index increase the risk of surgical site infection and infection requiring re-operation in this group of patients. A cut-off of 50 kg has a specificity of 92.1% with a sensitivity of 68.8% in regards to surgical site infection. Conclusion Patients receiving two Nuss bars as a part of their Nuss procedure are at a significantly higher risk of developing infective complications. Selecting patients more than 50 kg to receive two Nuss bars appear to be a reasonable measure to reduce surgical site infection.
A randomized, crossover study to evaluate α-tocopherol bioavailability via a microemulsion gel or dry tablet delivery in healthy adults
Authors: Stefan Matthew W , Sharp Matthew H , Gheith Raad H , Lowery Ryan P , Wilson Jacob M 
Published: November 2022

Background Vitamin E (α-tocopherol) is an essential micronutrient for human health and optimal physiological function. Inadequacy may be common due to a lack of bioavailability. The use of dietary lipids alongside other emulsification agents may elicit more robust serum concentrations of α-tocopherol via improved bioavailability. Therefore, the aim of the study was to examine oral bioavailability of two delivery methods of α-tocopherol, (1) a microemulsion gel formula composed of dietary lipids and other emulsification agents and (2) a dry solid tablet over 12 hours. Methods Twelve participants (age  =  37.3  ±  9.6 years; height  =  173.4  ±  11.8 cm; body mass  =  71.2  ±  10.0 kg) participated in a double-blind, randomized, crossover trial comparing two delivery methods both dosed at 288 mg of α-tocopherol. Serum α-tocopherol concentrations were assessed from blood donated by participants at pre-consumption, 2-, 4-, 8-, and 12-hour post-consumption. Study conditions were separated by a 7-day washout. Results The microemulsion gel formula delivery demonstrated significantly greater area under the curve ( p < 0.001) and serum concentration maximums ( p  =  0.003) for serum α-tocopherol compared to the tablet delivery. No significant differences were detected between conditions for the time to reach concentration maximums ( p  =  0.375). Conclusion We conclude that a mixture of dietary lipids and emulsification agents in the form of a microemulsion gel formula was able to significantly improve bioavailability of serum α-tocopherol compared to a tablet by yielding higher serum α-tocopherol maximum concentrations and area under the curve over a 12-hour study period despite dosage being matched.