bluuebunny/crossref_metadata_2025 huggingface dataset:
Future fire risk under climate change and deforestation scenarios in tropical Borneo
Authors: Davies-Barnard Taraka , Catto Jennifer L , Harper Anna B , Imron Muhammad Ali , Frank van Veen F J
Published: January 2023

Fire in the tropical peatland forests of Borneo is an environmental issue interactioning with climate change and deforestation, and the consequences have local and global implications. While research has shown that fire severity and frequency are expected to increase with climate change, there is conflicting model and observational data as to the effect of deforestation on precipitation, which is a key metric for fire risk. To better understand the changes in fire risk from deforestation and climate change we ran simulations of the climate scenario RCP8.5 with and without total deforestation using regional climate model RegCM4. The output was then used for calculations of the fire weather index. We find that annual temperature change from deforestation at elevations above 500 m is 53% of the change over the 21st century in RCP8.5. Fire risk is significantly affected by both climate change and deforestation, despite some increases in precipitation from deforestation. While the multi model dry season (June–August) mean increases in fire risk are larger from elevated atmospheric carbon dioxide, the increases in maximum fire risk are larger from deforestation. The altitude is a good predictor of fire risk change, with larger increases at more densely populated lower elevations where the peatlands are concentrated and smaller increases at higher elevations. Therefore, while deforestation generally causes a smaller increase in climate-related fire risk than climate change, its local control and heterogeneous effects compared to global carbon emissions makes it critical for climate mitigation policy. These high-resolution simulations provide a guide to the most vulnerable areas of Borneo from climatic increases in fire risk.
Tipping point in North American Arctic-Boreal carbon sink persists in new generation Earth system models despite reduced uncertainty
Authors: Braghiere Renato K , Fisher Joshua B , Miner Kimberley R , Miller Charles E , Worden John R , Schimel David S , Frankenberg Christian
Published: January 2023

Estimating the impacts of climate change on the global carbon cycle relies on projections from Earth system models (ESMs). While ESMs currently project large warming in the high northern latitudes, the magnitude and sign of the future carbon balance of Arctic-Boreal ecosystems are highly uncertain. The new generation of increased complexity ESMs in the Intergovernmental Panel on Climate Change Sixth Assessment Report (IPCC AR6) is intended to improve future climate projections. Here, we benchmark the Coupled Model Intercomparison Project (CMIP) 5 and 6 (8 CMIP5 members and 12 CMIP6 members) with the International Land Model Benchmarking (ILAMB) tool over the region of NASA’s Arctic-Boreal vulnerability experiment (ABoVE) in North America. We show that the projected average net biome production (NBP) in 2100 from CMIP6 is higher than that from CMIP5 in the ABoVE domain, despite the model spread being slightly narrower. Overall, CMIP6 shows better agreement with contemporary observed carbon cycle variables (photosynthesis, respiration, biomass) than CMIP5, except for soil carbon and turnover time. Although both CMIP ensemble members project the ABoVE domain will remain a carbon sink by the end of the 21st century, the sink strength in CMIP6 increases with CO2 emissions. CMIP5 and CMIP6 ensembles indicate a tipping point defined here as a negative inflection point in the NBP curve by 2050–2080 independently of the shared socioeconomic pathway (SSP) for CMIP6 or representative concentration pathway (RCP) for CMIP5. The model ensembles therefore suggest that, if the carbon sink strength keeps declining throughout the 21st century, the Arctic-Boreal ecosystems in North America may become a carbon source over the next century.
Effects of Comprehensive Background-Check Policies on Firearm Fatalities in 4 States
Authors: Kagawa Rose , Charbonneau Amanda , McCort Christopher , McCourt Alexander , Vernick Jon , Webster Daniel , Wintemute Garen
Published: January 2023

Despite promising results from individual-level studies, state-level studies of the effectiveness of comprehensive background-check (CBC) policies in reducing firearm fatalities have yielded null results in multiple states. These prior studies focused on CBC laws adopted in the 1990s, when record keeping was far less complete. We estimated the effect of the implementation of CBC policies on state-level firearm homicide and suicide rates in states implementing CBC policies from 2013 to 2015 (Colorado, Delaware, Oregon, and Washington). We compared age-adjusted firearm homicide and suicide rates, measured annually from 15 years prior to policy implementation until 2019, in each treated state to rates in control groups constructed using the synthetic control group method. Differences in firearm homicide rates for Colorado, Oregon, and Washington post treatment were all small (0.09 to 0.18 per 100,000 residents per year) and not well distinguished from natural variation. Oregon had on average 0.80 per 100,000 fewer firearm suicides per year than did synthetic Oregon post treatment. However, these results were inconsistent across modeling approaches and not well distinguished from natural variation. Our models produced poor fit for Delaware. Coupled with previous null results from Indiana, California, Maryland, Pennsylvania, and Tennessee, the present results suggest that extending background check requirements to private transfers alone and implementing these policies as is currently done is not sufficient to achieve significant state-level reductions in firearm fatalities.
Invited Commentary: Stop Analyzing Suicides, Drug-Related Deaths, and Alcohol-Related Deaths Together
Authors: Tilstra Andrea M
Published: January 2023

In the accompanying article, Spark et al. (Am J Epidemiol. 2023;192(5):720–731) estimate the undercounting of deaths due to suicide, drug use, and alcohol use in a Colorado veteran population and argue for a standardized case definition for the 3 causes of mortality. Use of a case definition for these 3 causes of death combined implies that they should be analyzed together. This is problematic, given the disparate trends in and historical contexts behind these 3 different causes of death.
Invited Commentary: Algorithmic Dementia Classification—Promises and Challenges
Authors: Mayeda Elizabeth Rose , Shaw Crystal
Published: January 2023

Dementia is a complex, progressive syndrome characterized by cognitive decline and disability. Gold-standard dementia diagnosis requires several hours of cognitive and clinical assessment and review by a panel of clinicians and is infeasible in large population-based cohort studies. Alternatively, algorithmic dementia classification methods, which use models that take into account measures of cognition and functional limitations or cognitive and functional-limitation score cutoffs, have been developed to predict dementia status for participants in large studies. Developing accurate dementia classification algorithms is crucial for high-quality studies of the distribution and determinants of dementia. The accompanying article by Nichols et al. (Am J Epidemiol. 2023;192(4):520–534) assesses differences in associations of measures of cognition and functional limitations with prevalent dementia versus incident dementia and discusses implications for algorithmic dementia classification in research studies. This work highlights important opportunities for tailoring measures of cognition and functional limitations to study goals by selecting optimal measures and developing and validating algorithms specific to study needs. Combining efficient, high-quality assessments of cognition and functional limitations with innovative study designs will facilitate collection of higher-quality measurements in larger samples and support future development of accurate dementia classifications, ultimately leading to more impactful epidemiologic studies.
Impacts of Cold-Stress Stimulation On Mice Pregnancy
Authors: Pan Zhengjun , Zhuang Juan , Zhu Chuankun , Li Caisheng , Zhao Haitao , Ding Huaiyu
Published: January 2023

Background

Animals exposed to cold stress develop hypertension; however, the effects of cold-induced hypertension on pregnancy remain unclear. We therefore, aimed to investigate the impacts of cold-stress stimulation on mice pregnancy.

Methods

Four groups of mice were used in the study: non-pregnant control group (NN), non-pregnant cold-stress group (NC), pregnant control group (PN) and pregnant cold-stress group (PC). control groups were kept at 25℃, and the cold-stress groups were kept in a room for cold-stress stimulation (4 ± 2℃) for 4 hours (then back to 25℃) every day from the 1st to the 18th day.

Results

The blood pressure of the PC was the highest among the four groups, and the hypertensive percentage of the PC was significantly increased. However, plasma angiotensinⅡ levels of the PC were the lowest. The weights of the foetus and placenta in the PC were significantly decreased compared to the PN. More apparent changes in kidneys and placenta were observed in the PC compared to the PN. The blood pressure of pregnant mice showed no difference between the PN and PC groups 50 days after delivery.

Conclusions

Intermittent cold-stress stimulation had significantly adverse effects on the pregnant mice, leading to maternal hypertension, renal and placental lesions, body weight and placenta reduction in offspring. The study results may offer a non-invasive method to establish an animal model of hypertensive disorders in pregnancy. Cold-stress stimulation may be one of the inducible factors of pregnancy-induced hypertension.

Cold-stress stimulation may be one of the inducible factors of pregnancy-induced hypertension.
Inhibition of P21-activated Kinase 1 Promotes Vascular Smooth Muscle Cells Apoptosis Through Reduction of Phosphorylation of Bad
Authors: Jiao Lin , Yi Wenjuan , Chang Yu-Rong , Cheng Wen-Lin , Cao Jian-Lei , Chao Sheng-Ping , Zhao Fang , Lu Zhibing
Published: January 2023

Background

P21-activated kinase 1 (Pak1) has an effect on cell apoptosis and has recently been reported to play an important role in various cardiovascular diseases, in which vascular smooth muscle cell (VSMC) apoptosis is a key process. Thus, we hypothesized that Pak1 may be a novel target to regulate VSMC behaviors.

Methods and Results

In the present study, we found that the expression of Pak1 was dramatically upregulated in vascular smooth muscle cells (VSMCs) on H2O2 administration and was dependent on stimulation time. Through a loss-of-function approach, Pak1 knockdown increased apoptosis of VSMCs, as tested by TUNEL (TdT-mediated dUTP Nick-End Labeling) immunofluorescence staining, whereas it inhibited the proliferation of VSMCs examined by EdU staining. Moreover, we also noticed that Pak1 silencing promoted the mRNA and protein levels of pro-apoptosis genes but decreased anti-apoptosis marker expression. Importantly, we showed that Pak1 knockdown reduced the phosphorylation of Bad. Moreover, increased Pak1 expression was also noticed in carotid arteries on the wire jury.

Conclusions

Our study identified that Pak1 acted as a novel regulator of apoptosis of VSMCs partially through phosphorylation of Bad.
Just DOAC: Use of direct-acting oral anticoagulants in pediatrics
Authors: Mills Kimberly , Hill Carolyn , King Morgan , Pauley Jennifer L , Cober M Petrea , Fenn Norman E , Omecene Nicole E , Smith Tara , Sierra Caroline M
Published: January 2023

Purpose

The aim of this article is to provide an overview of the current literature for direct-acting oral anticoagulant (DOAC) use in pediatric patients and summarize ongoing trials.

In treatment of venous thromboembolism (VTE) in pediatric patients, evidence supports use of both dabigatran and rivaroxaban. Dabigatran has been shown to be noninferior to standard of care (SOC) in terms of efficacy, with similar bleeding rates. Similarly, treatment with rivaroxaban in children with acute VTE resulted in a low recurrence risk and reduced thrombotic burden, without increased risk of bleeding, compared to SOC. Treatment of pediatric cerebral venous thrombosis as well as central venous catheter–related VTE with rivaroxaban appeared to be both safe and efficacious and similar to that with SOC. Dabigatran also has a favorable safety profile for prevention of VTE, and rivaroxaban has a favorable safety profile for VTE prevention in children with congenital heart disease. Many studies with several different DOACs are ongoing to evaluate both safety and efficacy in unique patient populations, as well as VTE prevention.

Conclusion

The literature regarding pediatric VTE treatment and prophylaxis is growing, but the need for evidence-based pediatric guidelines remains. Additional long-term, postauthorization studies are warranted to further elucidate safety and efficacy in clinical scenarios excluded in clinical trials. Additional data on safety, efficacy, and dosing strategies for reversal agents are also necessary, especially as the use of DOACs becomes more common in the pediatric population.
Sodium Oxybate for Alcohol Dependence: A Network Meta-Regression Analysis Considering Population Severity at Baseline and Treatment Duration
Authors: Guiraud Julien , Addolorato Giovanni , Aubin Henri-Jean , Bachelot Sylvie , Batel Philippe , de Bejczy Andrea , Benyamina Amine , Caputo Fabio , Couderc Monique , Dematteis Maurice , Goudriaan Anna E , Gual Antoni , Lecoustey Sylvie , Lesch Otto-Michael , Maremmani Icro , Nutt David J , Paille François , Perney Pascal , Rehm Jürgen , Rolland Benjamin , Scherrer Bruno , Simon Nicolas , Söderpalm Bo , Somaini Lorenzo , Sommer Wolfgang H , Spanagel Rainer , Walter Henriette , van den Brink Wim
Published: January 2023

Aims

The estimated effect of sodium oxybate (SMO) in the treatment of alcohol dependence is heterogeneous. Population severity and treatment duration have been identified as potential effect modifiers. Population severity distinguishes heavy drinking patients with <14 days of abstinence before treatment initiation (high-severity population) from other patients (mild-severity population). Treatment duration reflects the planned treatment duration. This study aimed to systematically investigate the effect of these potential effect moderators on SMO efficacy in alcohol-dependent patients.

Methods

Network meta-regression allows for testing potential effect modifiers. It was selected to investigate the effect of the above factors on SMO efficacy defined as continuous abstinence (abstinence rate) and the percentage of days abstinent (PDA). Randomized controlled trials for alcohol dependence with at least one SMO group conducted in high-severity and mild-severity populations were assigned to a high-severity and mild-severity group of studies, respectively.

Results

Eight studies (1082 patients) were retained: four in the high-severity group and four in the mild-severity group. The high-severity group was associated with larger SMO effect sizes than the mild-severity group: abstinence rate risk ratio (RR) 3.16, P = 0.004; PDA +26.9%, P < 0.001. For PDA, longer treatment duration was associated with larger SMO effect size: +11.3% per extra month, P < 0.001. In the high-severity group, SMO showed benefit: abstinence rate RR 2.91, P = 0.03; PDA +16.9%, P < 0.001. In the mild-severity group, SMO showed benefit only in PDA for longer treatment duration: +23.9%, P < 0.001.

Conclusions

In the retained studies with alcohol-dependent patients, high-severity population and longer treatment duration were associated with larger SMO effect sizes.
How do Effort, Reward, and Their Combined Effects Predict Burnout, Self-rated Health, and Work-family Conflict Among Permanent and Fixed-term Faculty?
Authors: Tanimoto Anna Sofia , Richter Anne , Lindfors Petra
Published: January 2023

Employment conditions and psychosocial factors have been linked to various health-related outcomes in different occupational groups, but few studies focus on the conditions in academia. This study explores the effects of effort, reward, and their interaction to explain health-related outcomes, namely burnout, self-rated health, and work-family conflict among academic faculty in Sweden. We also explore these effects among those with permanent and fixed-term employment contracts. Questionnaire data, collected online in 2016, came from 2335 employees (57% women) with a doctoral degree, working at a Swedish higher education institution. Latent moderation analysis combined with multi-group analysis was conducted. Main effects of effort were found for all health-related outcomes revealing that effort was associated with higher burnout, poorer self-rated health, and greater work-family conflict. Reward was negatively associated with burnout and self-rated health revealing that reward reduced burnout and improved self-rated health. The interaction between effort and reward was significantly associated with all outcomes among permanent contract employees, but was non-significant among those with fixed-term contracts. This may suggest that fixed-term faculty are less affected by the presence or lack of reward. Overall, the findings emphasize the importance of the psychosocial work environment to understand health-related consequences for permanent and fixed-term faculty with a doctoral degree.
CAM plants: their importance in epiphyte communities and prospects with global change
Authors: Zotz Gerhard , Andrade José Luis , Einzmann Helena J R
Published: January 2023

Background and Scope

The epiphytic life form characterizes almost 10 % of all vascular plants. Defined by structural dependence throughout their life and their non-parasitic relationship with the host, the term epiphyte describes a heterogeneous and taxonomically diverse group of plants. This article reviews the importance of crassulacean acid metabolism (CAM) among epiphytes in current climatic conditions and explores the prospects under global change.

Results and Conclusions

We question the view of a disproportionate importance of CAM among epiphytes and its role as a ‘key innovation’ for epiphytism but do identify ecological conditions in which epiphytic existence seems to be contingent on the presence of this photosynthetic pathway. Possibly divergent responses of CAM and C3 epiphytes to future changes in climate and land use are discussed with the help of experimental evidence, current distributional patterns and the results of several long-term descriptive community studies. The results and their interpretation aim to stimulate a fruitful discussion on the role of CAM in epiphytes in current climatic conditions and in altered climatic conditions in the future.
New Child and Adolescent Memory Profile Embedded Performance Validity Test
Authors: Brooks Brian L , Fay-McClymont Taryn B , MacAllister William S , Vasserman Marsha , Mish Sandra , Sherman Elisabeth M S
Published: January 2023

Objective

It is essential to interpret performance validity tests (PVTs) that are well-established and have strong psychometrics. This study evaluated the Child and Adolescent Memory Profile (ChAMP) Validity Indicator (VI) using a pediatric sample with traumatic brain injury (TBI).

Method

A cross-sectional sample of N = 110 youth (mean age = 15.1 years, standard deviation [SD] = 2.4 range = 8–18) on average 32.7 weeks (SD = 40.9) post TBI (71.8% mild/concussion; 3.6% complicated mild; 24.6% moderate-to-severe) were administered the ChAMP and two stand-alone PVTs. Criterion for valid performance was scores above cutoffs on both PVTs; criterion for invalid performance was scores below cutoffs on both PVTs. Classification statistics were used to evaluate the existing ChAMP VI and establish a new VI cutoff score if needed.

Results

There were no significant differences in demographics or time since injury between those deemed valid (n = 96) or invalid (n = 14), but all ChAMP scores were significantly lower in those deemed invalid. The original ChAMP VI cutoff score was highly specific (no false positives) but also highly insensitive (sensitivity [SN] = .07, specificity [SP] = 1.0). Based on area under the curve (AUC) analysis (0.94), a new cutoff score was established using the sum of scaled scores (VI-SS). A ChAMP VI-SS score of 32 or lower achieved strong SN (86%) and SP (92%). Using a 15% base rate, positive predictive value was 64% and negative predictive value was 97%.

Conclusions

The originally proposed ChAMP VI has insufficient SN in pediatric TBI. However, this study yields a promising new ChAMP VI-SS, with classification metrics that exceed any other current embedded PVT in pediatrics.
Blueberry stem extract and stem active components prevent blue light-emitting diode light-induced retinal photoreceptor cell damagein vitro
Authors: Ogawa Kenjirou , Urata Karin , Suzuki Yosuke , Sugamoto Kazuhiro , Goto Yo , Nakayama Takayuki , Nishiyama Kazuo , Kunitake Hisato , Yamasaki Masao
Published: January 2023

Blue light causes retinal damage that can lead to ocular diseases such as age-related macular degeneration. In this study, we determined the protective effect of blueberry stem extract (BStEx) and active components on blue light-emitting diode (LED) light-induced retinal photoreceptor cell damage in vitro. Photoreceptor cells cultured in the presence of BStEx or components were exposed to blue light to induce cell damage. BStEx, fractions of BStEx containing proanthocyanidins, chlorogenic acid, catechin, and epicatechin prevented the cell damage and/or inhibited the generation of reactive oxygen species (ROS). Furthermore, BStEx reduced apoptosis and cell death, and inhibited the phosphorylation of p38 mitogen-activated protein kinase and c-Jun N-terminal kinase leading to cellular apoptosis induced by blue light exposure. These findings suggest that BStEx and components exert a protective effect against blue light-induced photoreceptor cell damage through the inhibition of MAPK phosphorylation and ROS production.
The effect of heterospecific and conspecific competition on inter-individual differences in tungara frog tadpole (Engystomops pustulosus) behavior
Authors: Beyts Cammy , Cella Maddalena , Colegrave Nick , Downie Roger , Martin Julien G A , Walsh Patrick
Published: January 2023

Repeated social interactions with conspecifics and/or heterospecifics during early development may drive the differentiation of behavior among individuals. Competition is a major form of social interaction and its impacts can depend on whether interactions occur between conspecifics or heterospecifics and the directionality of a response could be specific to the ecological context that they are measured in. To test this, we reared tungara frog tadpoles (Engystomops pustulosus) either in isolation, with a conspecific tadpole or with an aggressive heterospecific tadpole, the whistling frog tadpole (Leptodactylus fuscus). In each treatment, we measured the body size and distance focal E. pustulosus tadpoles swam in familiar, novel and predator risk contexts six times during development. We used univariate and multivariate hierarchical mixed effect models to investigate the effect of treatment on mean behavior, variance among and within individuals, behavioral repeatability and covariance among individuals in their behavior between contexts. There was a strong effect of competition on behavior, with different population and individual level responses across social treatments. Within a familiar context, the variance in the distance swam within individuals decreased under conspecific competition but heterospecific competition caused more variance in the average distance swam among individuals. Behavioral responses were also context specific as conspecific competition caused an increase in the distance swam within individuals in novel and predator risk contexts. The results highlight that the impact of competition on among and within individual variance in behavior is dependent on both competitor species identity and context.
Liquidhope: methylome and genomic profiling from very limited quantities of plasma-derived DNA
Authors: Trinidad Eva María , Vidal Enrique , Coronado Esther , Esteve-Codina Anna , Castel Victoria , Cañete Adela , Gut Marta , Heath Simon , Font de Mora Jaime
Published: January 2023

Analysis of the methylome of tumor cell-free deoxyribonucleic acid (DNA; cfDNA) has emerged as a powerful non-invasive technique for cancer subtyping and prognosis. However, its application is frequently hampered by the quality and total cfDNA yield. Here, we demonstrate the feasibility of very low-input cfDNA for whole-methylome and copy-number profiling studies using enzymatic conversion of unmethylated cysteines [enzymatic methyl-seq (EM-seq)] to better preserve DNA integrity. We created a model for predicting genomic subtyping and prognosis with high accuracy. We validated our tool by comparing whole-genome CpG sequencing with in situ cohorts generated with bisulfite conversion and array hybridization, demonstrating that, despite the different techniques and sample origins, information on cfDNA methylation is comparable with in situ cohorts. Our findings support use of liquid biopsy followed by EM-seq to assess methylome of cancer patients, enabling validation in external cohorts. This advance is particularly relevant for rare cancers like neuroblastomas where liquid-biopsy volume is restricted by ethical regulations in pediatric patients.
Structure-preserved dimension reduction using joint triplets sampling for multi-batch integration of single-cell transcriptomic data
Authors: Xu Xinyi , Li Xiangjie
Published: January 2023

Dimension reduction (DR) plays an important role in single-cell RNA sequencing (scRNA-seq), such as data interpretation, visualization and other downstream analysis. A desired DR method should be applicable to various application scenarios, including identifying cell types, preserving the inherent structure of data and handling with batch effects. However, most of the existing DR methods fail to accommodate these requirements simultaneously, especially removing batch effects. In this paper, we develop a novel structure-preserved dimension reduction (SPDR) method using intra- and inter-batch triplets sampling. The constructed triplets jointly consider each anchor’s mutual nearest neighbors from inter-batch, k-nearest neighbors from intra-batch and randomly selected cells from the whole data, which capture higher order structure information and meanwhile account for batch information of the data. Then we minimize a robust loss function for the chosen triplets to obtain a structure-preserved and batch-corrected low-dimensional representation. Comprehensive evaluations show that SPDR outperforms other competing DR methods, such as INSCT, IVIS, Trimap, Scanorama, scVI and UMAP, in removing batch effects, preserving biological variation, facilitating visualization and improving clustering accuracy. Besides, the two-dimensional (2D) embedding of SPDR presents a clear and authentic expression pattern, and can guide researchers to determine how many cell types should be identified. Furthermore, SPDR is robust to complex data characteristics (such as down-sampling, duplicates and outliers) and varying hyperparameter settings. We believe that SPDR will be a valuable tool for characterizing complex cellular heterogeneity.
slORFfinder: a tool to detect open reading frames resulting from trans-splicing of spliced leader sequences
Authors: Song Bo , Li Hao , Jiang Mengyun , Gao Zhongtian , Wang Suikang , Gao Lei , Chen Yunsheng , Li Wujiao
Published: January 2023

Trans-splicing of a spliced leader (SL) to the 5′ ends of mRNAs is used to produce mature mRNAs in several phyla of great importance to human health and the marine ecosystem. One of the consequences of the addition of SL sequences is the change or disruption of the open reading frames (ORFs) in the recipient transcripts. Given that most SL sequences have one or more of the trinucleotide NUG, including AUG in flatworms, trans-splicing of SL sequences can potentially supply a start codon to create new ORFs, which we refer to as slORFs, in the recipient mRNAs. Due to the lack of a tool to precisely detect them, slORFs were usually neglected in previous studies. In this work, we present the tool slORFfinder, which automatically links the SL sequences to the recipient mRNAs at the trans-splicing sites identified from SL-containing reads of RNA-Seq and predicts slORFs according to the distribution of ribosome-protected footprints (RPFs) on the trans-spliced transcripts. By applying this tool to the analyses of nematodes, ascidians and euglena, whose RPFs are publicly available, we find wide existence of slORFs in these taxa. Furthermore, we find that slORFs are generally translated at higher levels than the annotated ORFs in the genomes, suggesting they might have important functions. Overall, this study provides a tool, slORFfinder (https://github.com/songbo446/slORFfinder), to identify slORFs, which can enhance our understanding of ORFs in taxa with SL machinery.
Learning from small medical data—robust semi-supervised cancer prognosis classifier with Bayesian variational autoencoder
Authors: Hsu Te-Cheng , Lin Che
Published: January 2023

Motivation

Cancer is one of the world’s leading mortality causes, and its prognosis is hard to predict due to complicated biological interactions among heterogeneous data types. Numerous challenges, such as censorship, high dimensionality and small sample size, prevent researchers from using deep learning models for precise prediction.

Results

We propose a robust Semi-supervised Cancer prognosis classifier with bAyesian variational autoeNcoder (SCAN) as a structured machine-learning framework for cancer prognosis prediction. SCAN incorporates semi-supervised learning for predicting 5-year disease-specific survival and overall survival in breast and non-small cell lung cancer (NSCLC) patients, respectively. SCAN achieved significantly better AUROC scores than all existing benchmarks (81.73% for breast cancer; 80.46% for NSCLC), including our previously proposed bimodal neural network classifiers (77.71% for breast cancer; 78.67% for NSCLC). Independent validation results showed that SCAN still achieved better AUROC scores (74.74% for breast; 72.80% for NSCLC) than the bimodal neural network classifiers (64.13% for breast; 67.07% for NSCLC). SCAN is general and can potentially be trained on more patient data. This paves the foundation for personalized medicine for early cancer risk screening.

Availability and implementation

The source codes reproducing the main results are available on GitHub: https://gitfront.io/r/user-4316673/36e8714573f3fbfa0b24690af5d1a9d5ca159cf4/scan/.

Supplementary information

Supplementary data are available at Bioinformatics Advances online.
Efficient querying of genomic reference databases with gget
Authors: Luebbert Laura , Pachter Lior
Published: January 2023

Motivation

A recurring challenge in interpreting genomic data is the assessment of results in the context of existing reference databases. With the increasing number of command line and Python users, there is a need for tools implementing automated, easy programmatic access to curated reference information stored in a diverse collection of large, public genomic databases.

Results

gget is a free and open-source command line tool and Python package that enables efficient querying of genomic reference databases, such as Ensembl. gget consists of a collection of separate but interoperable modules, each designed to facilitate one type of database querying required for genomic data analysis in a single line of code.

Availability and implementation

The manual and source code are available at https://github.com/pachterlab/gget.

Supplementary information

Supplementary data are available at Bioinformatics online.
Actin-related protein ACTL7B ablation leads to OAT with multiple morphological abnormalities of the flagellum and male infertility in mice
Authors: Clement Tracy M , Geyer Christopher B , Willis William D , Goulding Eugenia H , Upadhyay Srijana , Eddy Edward M
Published: January 2023

The formation of fertilisation-competent sperm requires spermatid morphogenesis (spermiogenesis), a poorly understood program that involves complex coordinated restructuring and specialised cytoskeletal structures. A major class of cytoskeletal regulators are the actin-related proteins (ARPs), which include conventional actin variants, and related proteins that play essential roles in complexes regulating actin dynamics, intracellular transport, and chromatin remodeling. Multiple testis-specific ARPs are well conserved among mammals, but their functional roles are unknown. One of these is actin-like 7b (Actl7b) that encodes an orphan ARP highly similar to the ubiquitously expressed beta actin (ACTB). Here we report ACTL7B is expressed in human and mouse spermatids through the elongation phase of spermatid development. In mice, ACTL7B specifically localises to the developing acrosome, within the nucleus of early spermatids, and to the flagellum connecting region. Based on this localisation pattern and high level of sequence conservation in mice, humans, and other mammals, we examined the requirement for ACTL7B in spermiogenesis by generating and characterising the reproductive phenotype of male Actl7b KO mice. KO mice were infertile, with severe and variable oligoteratozoospermia (OAT) and multiple morphological abnormalities of the flagellum (MMAF) and sperm head. These defects phenocopy human OAT and MMAF, which are leading causes of idiopathic male infertility. In conclusion, this work identifies ACTL7B as a key regulator of spermiogenesis that is required for male fertility.
BBOX1-AS1 mediates trophoblast cells dysfunction via regulating hnRNPK/GADD45A axis
Authors: Li Yali , Zhao Hui , Li Ning , Yuan Chao , Dong Nana , Wen Jin , Li Zihui , Wang Qun , Wang Lina , Mao Haiting
Published: January 2023

Recurrent pregnancy loss (RPL) is a common pathological problem during pregnancy, and its clinical etiology is complex and unclear. Dysfunction of trophoblasts may cause a series of pregnancy complications, including preeclampsia, fetal growth restriction, and RPL. Recently, lncRNAs have been found to be closely related to the occurrence and regulation of pregnancy-related diseases, but few studies have focused on their role in RPL. In this study, we identified a novel lncRNA BBOX1-AS1 that was significantly upregulated in villous tissues and serum of RPL patients. Functionally, BBOX1-AS1 inhibited proliferation, migration, invasion, tube formation and promoted apoptosis of trophoblast cells. Mechanistically, overexpression of BBOX1-AS1 activated the p38 and JNK MAPK signaling pathways by upregulating GADD45A expression. Further studies indicated that BBOX1-AS1 could increase the stability of GADD45A mRNA by binding hnRNPK and ultimately cause abnormal trophoblast function. Collectively, our study highlights that the BBOX1-AS1/hnRNPK/GADD45A axis plays an important role in trophoblast-induced RPL and that BBOX1-AS1 may serve as a potential target for the diagnosis of RPL.
Evaluation Options for Wildlife Management and Strengthening of Causal Inference
Authors: Hone Jim , Drake V Alistair , Krebs Charles J
Published: January 2023

Wildlife management aims to halt and then reverse the decline of threatened species, to sustainably harvest populations, and to control undesirable impacts of some species. We describe a unifying framework of three feasible options for evaluation of wildlife management, including conservation, and discuss their relative strengths of statistical and causal inference. The first option is trends in abundance, which can provide strong evidence a change has occurred (statistical inference) but does not identify the causes. The second option assesses population outcomes relative to management efforts, which provides strong evidence of cause and effect (causal inference) but not the trend. The third option combines the first and second options and therefore provides both statistical and causal inferences in an adaptive framework. We propose that wildlife management needs to explicitly use causal criteria and inference to complement adaptive management. We recommend incorporating these options into management plans.
Making Desistance Recognizable: How Ex-Offenders Can Signal Their Desistance From Crime to Employers by Strategic Design
Authors: Reich Suzanne E
Published: January 2023

One of the primary concerns employers hold about hiring an ex-offender is the potential reoffending risk they pose. However, criminological literature shows that an ex-offender may be able to mitigate employers’ concerns by signalling their desistance from crime. Less understood is how ex-offenders can signal their desistance to (a) make desistance recognizable and (2) communicate desistance signals that employers value. This article draws on the results from the second phase of an Explanatory Sequential Mixed Methods study with a sample of Australian employers who participated in semi-structured interviews (n = 43). The findings show desistance signals can be communicated to employers via strategic design. These findings along with the theoretical and policy implications are then discussed.
A Disproportionate Risk of Being Executed: Why Pakistani Migrants Are Vulnerable to Capital Punishment in Saudi Arabia
Authors: Hoyle Carolyn , Hutton Jocelyn , Harry Lucy
Published: January 2023

Many labour migrants in the Arab Gulf countries are from South Asia. Necessary to local economies, they enjoy few rights and protections from host states, particularly when accused of serious crimes. Our original empirical data suggests a disproportionate number of Pakistanis sentenced to death and executed in Saudi Arabia and we explore explanations within a wider discussion of the place and experiences of South Asian migrants in the Gulf. Our data suggest that drug laws and penal policies leave migrant workers particularly susceptible to capital punishment, with the administration of migrant employment recruitment processes exposing Pakistanis to coercion into drug trafficking such that some could be regarded not as criminally liable but as victims of human trafficking.
Association of metformin use and survival in patients with cutaneous melanoma and diabetes
Authors: Krakowski Isabelle , Häbel Henrike , Nielsen Kari , Ingvar Christian , Andersson Therese M L , Girnita Ada , Smedby Karin E , Eriksson Hanna
Published: January 2023

Background

Metformin use has been associated with improved survival in patients with different types of cancer, but research regarding the effect of metformin on cutaneous melanoma (CM) survival is sparse and inconclusive.

Objectives

To investigate the association between metformin use and survival among patients with CM and diabetes.

Methods

All adult patients with a primary invasive CM between 2007 and 2014 were identified in the Swedish Melanoma Registry and followed until death, or end of follow-up on 31 December 2017 in this population-based cohort study. Patients with both CM and type 2 diabetes mellitus were assessed further. Overall survival (OS) and melanoma-specific survival (MSS) were the primary endpoints. Cox proportional hazard models estimating crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were used comparing peridiagnostic use vs. nonuse of metformin. Dose response was evaluated based on defined daily doses.

Results

Among a total of 23 507 patients, 1162 patients with CM and type 2 diabetes mellitus were included in the final cohort, with a median follow-up time of 4.1 years (interquartile range 2.4–6.1). Peridiagnostic metformin use was associated with a significantly decreased risk of death by any cause (HR 0.68, 95% CI 0.57–0.81). Cumulative pre- and postdiagnostic metformin use was also associated with improved OS: the HR for prediagnostic use was 0.90 (95% CI 0.86–0.95) for every 6 months of use and the HR for postdiagnostic use ranged from 0.98 (95% CI 0.97–0.98) for 0–6 months to 0.59 (0.49–0.70) for 24–30 months of use. No association was found for metformin use and MSS.

Conclusions

Metformin use was associated with improved OS in patients with CM and diabetes regardless of timing (pre-, post- or peridiagnostic use) and followed a dose–response pattern. However, further research regarding the underlying mechanisms is warranted.
Insights into atopic dermatitis pathogenesis lead to newly approved systemic therapies
Authors: Trier Anna M , Kim Brian S
Published: January 2023

Atopic dermatitis (AD) is a common inflammatory skin disease characterized by scaly, oozing skin and itch. In moderate-to-severe AD, treatment options have been historically very limited and off-label use has been a common method for disease management. For decades, ciclosporin A was the only systemic immunosuppressive drug approved in most European countries to address this major unmet medical need. However, increased understanding of the pathophysiology of AD has led to a revolution in the treatment of this potentially debilitating disease. Following the approval of the first biological therapy for AD in 2017, there has been a rapid expansion of compounds under development and four additional systemic therapies have been approved in Europe and the USA within the past 3 years alone. In this review, we underscore how key breakthroughs have transformed the therapeutic landscape of AD, leading to a major expansion of type 2 immunity-targeted biological therapies, exploration of neuroimmune modulatory agents, and interest in Janus kinase inhibition.
Safety and efficacy of bimekizumab through 2 years in patients with moderate-to-severe plaque psoriasis: longer-term results from the BE SURE randomized controlled trial and the open-label extension from the BE BRIGHT trial
Authors: Thaçi Diamant , Vender Ron , de Rie Menno A , Conrad Curdin , Pariser David M , Strober Bruce , Vanvoorden Veerle , Wang Maggie , Madden Cynthia , de Cuyper Dirk , Kimball Alexa B
Published: January 2023

Background

BE SURE 1-year results demonstrated the superior efficacy of bimekizumab compared with adalimumab with no unexpected safety findings.

Objectives

To provide efficacy and safety data over 2 years of bimekizumab treatment compared with adalimumab from BE SURE and the BE BRIGHT open-label extension (OLE) in patients with moderate-to-severe plaque psoriasis.

Methods

The 56-week double-blinded BE SURE phase III randomized controlled trial randomized patients 1 : 1 : 1 to bimekizumab 320 mg every 4 weeks (Q4W), bimekizumab 320 mg Q4W to week 16 then every 8 weeks (Q8W), or adalimumab 40 mg every 2 weeks to week 24 then bimekizumab 320 mg Q4W. After completing BE SURE, patients could enter the ongoing BE BRIGHT OLE, with possible dosing adjustments based on Psoriasis Area and Severity Index (PASI). The primary outcome in BE BRIGHT was incidence of treatment-emergent adverse events (TEAEs); safety data are reported by study period through week 104. Efficacy data are reported for the intention-to-treat population through week 104 by initial randomization group, with ≥ 90% improvement from baseline PASI (PASI 90) and 100% improvement (PASI 100) as key outcomes.

Results

Of the patients randomized to bimekizumab, 158 were assigned to Q4W, and 161 to Q4W/Q8W. At week 104, PASI 90 was achieved by 91.2% and 89.7%, and PASI 100 was achieved by 72.3% and 68.1%, for Q4W and Q4W/Q8W, respectively; comparable to week 16 results. Among the 159 patients randomized to adalimumab, responses rapidly and substantially increased after the week 24 bimekizumab switch; at week 104, 96.9% and 70.2% of patients achieved PASI 90 and PASI 100 respectively. Through weeks 24–104, the three most common TEAEs in any bimekizumab-treated group were nasopharyngitis, oral candidiasis and upper respiratory tract infection. Rates of serious TEAEs were low.

Conclusions

Clinical responses observed through week 16 of BE SURE in patients randomized to bimekizumab were sustained through 104 weeks of treatment, regardless of Q4W or Q8W maintenance dosing. Response rates were also sustained through week 104 in patients who switched from adalimumab to bimekizumab at week 24, and were similar to those observed in the bimekizumab groups. Bimekizumab was well tolerated with no new safety signals.
Integrated safety analysis of baricitinib in adults with severe alopecia areata from two randomized clinical trials
Authors: King Brett , Mostaghimi Arash , Shimomura Yutaka , Zlotogorski Abraham , Choi Gwang-Seong , Blume-Peytavi Ulrike , Passeron Thierry , Holzwarth Katrin , Dutronc Yves , McCollam Jill , Yang Fan Emily , Stanley Sarah , Wu Wen-Shuo , Sinclair Rodney
Published: January 2023

Background

Baricitinib, an oral, selective, reversible Janus kinase (JAK)1/JAK2 inhibitor, is an approved treatment for adults with severe alopecia areata (AA) in the USA, European Union and Japan.

Objectives

To report safety data for baricitinib in patients with severe AA from two clinical trials including long-term extension periods.

Methods

This analysis includes pooled patient-level safety data from two trials, an adaptive phase II/III trial (BRAVE-AA1) and a phase III trial (BRAVE-AA2) (ClinicalTrials.gov, NCT03570749 and NCT03899259). Data are reported in three datasets: (i) the placebo-controlled dataset (up to week 36): baricitinib 2 mg and 4 mg vs. placebo; (ii) the extended dataset (up to the data cutoff): patients remaining on continuous treatment with baricitinib 2 mg or 4 mg from baseline; and (iii) the all-baricitinib dataset (all-BARI, up to the data cutoff): all patients receiving any dose of baricitinib at any time during the trials. Safety outcomes include treatment-emergent adverse events (TEAEs), adverse events of special interest and abnormal laboratory changes. Proportions of patients with events and incidence rates (IR) were calculated.

Results

Data were collected for 1303 patients who were given baricitinib, reflecting 1868 patient-years of exposure (median 532 days). The most frequently reported TEAEs during the placebo-controlled period (based on the baricitinib 4-mg group) were upper respiratory tract infection, nasopharyngitis, headache, acne and elevated blood creatine phosphokinase (CPK). During the placebo-controlled period, the frequency of acne was higher with baricitinib than placebo, and elevated CPK was higher with baricitinib 4 mg than placebo and baricitinib 2 mg. In all-BARI, the IR of serious infections was low (n = 16, IR 0.8). There was one opportunistic infection (IR 0.1), and 34 cases of herpes zoster (IR 1.8). There was one positively adjudicated major adverse cardiovascular event (myocardial infarction) (IR 0.1), one pulmonary embolism (IR 0.1), three malignancies other than nonmelanoma skin cancer (IR 0.2) and one gastrointestinal perforation (IR 0.1). No deaths were reported.

Conclusions

This integrated safety analysis in patients with severe AA is consistent with the overall safety profile of baricitinib. Some differences with atopic dermatitis were noted that may be attributable to the disease characteristics of AA.