bluuebunny/crossref_metadata_2025 huggingface dataset:
The Use of Natural Language Processing to Assess Social Support in Patients With Advanced Cancer
Authors: Bhatt Sunil , Johnson P Connor , Markovitz Netana H , Gray Tamryn , Nipp Ryan D , Ufere Nneka , Rice Julia , Reynolds Matthew J , Lavoie Mitchell W , Clay Madison A , Lindvall Charlotta , El-Jawahri Areej
Published: November 2022

Background

Data examining associations among social support, survival, and healthcare utilization are lacking in patients with advanced cancer.

Methods

We conducted a cross-sectional secondary analysis using data from a prospective longitudinal cohort study of 966 hospitalized patients with advanced cancer at Massachusetts General Hospital from 2014 through 2017. We used NLP to identify extent of patients’ social support (limited versus adequate as defined by NLP-aided review of the Electronic Health Record (EHR)). Two independent coders achieved a Kappa of 0.90 (95% CI: 0.84-1.00) using NLP. Using multivariable regression models, we examined associations of social support with: 1) OS; 2) death or readmission within 90 days of hospital discharge; 3) time to readmission within 90 days; and 4) hospital length of stay (LOS).

Results

Patients’ median age was 65 (range: 21-92) years, and a plurality had gastrointestinal (GI) cancer (34.3%) followed by lung cancer (19.5%). 6.2% (60/966) of patients had limited social support. In multivariable analyses, limited social support was not significantly associated with OS (HR = 1.13, P = 0.390), death or readmission (OR = 1.18, P = 0.578), time to readmission (HR = 0.92, P = 0.698), or LOS (β = −0.22, P = 0.726). We identified a potential interaction suggesting cancer type (GI cancer versus other) may be an effect modifier of the relationship between social support and OS (interaction term P = 0.053). In separate unadjusted analyses, limited social support was associated with lower OS (HR = 2.10, P = 0.008) in patients with GI cancer but not other cancer types (HR = 1.00, P = 0.991).

Conclusion

We used NLP to assess the extent of social support in patients with advanced cancer. We did not identify significant associations of social support with OS or healthcare utilization but found cancer type may be an effect modifier of the relationship between social support and OS. These findings underscore the potential utility of NLP for evaluating social support in patients with advanced cancer.
Natural variation in CRABS CLAW contributes to fruit length divergence in cucumber
Authors: Che Gen , Pan Yupeng , Liu Xiaofeng , Li Min , Zhao Jianyu , Yan Shuangshuang , He Yuting , Wang Zhongyi , Cheng Zhihua , Song Weiyuan , Zhou Zhaoyang , Wu Tao , Weng Yiqun , Zhang Xiaolan
Published: November 2022

Fruit length is a key domestication trait that affects crop yield and appearance. Cucumber (Cucumis sativus) fruits vary from 5 to 60 cm in length. Despite the identification of several regulators and multiple quantitative trait loci (QTLs) underlying fruit length, the natural variation, and molecular mechanisms underlying differences in fruit length are poorly understood. Through map-based cloning, we identified a nonsynonymous polymorphism (G to A) in CRABS CLAW (CsCRC) as underlying the major-effect fruit size/shape QTL FS5.2 in cucumber. The short-fruit allele CsCRCA is a rare allele that has only been found in round-fruited semi-wild Xishuangbanna cucumbers. A near-isogenic line (NIL) homozygous for CsCRCA exhibited a 34∼39% reduction in fruit length. Introducing CsCRCG into this NIL rescued the short-fruit phenotype, and knockdown of CsCRCG resulted in shorter fruit and smaller cells. In natural cucumber populations, CsCRCG expression was positively correlated with fruit length. Further, CsCRCG, but not CsCRCA, targets the downstream auxin-responsive protein gene CsARP1 to regulate its expression. Knockout of CsARP1 produced shorter fruit with smaller cells. Hence, our work suggests that CsCRCG positively regulates fruit elongation through transcriptional activation of CsARP1 and thus enhances cell expansion. Using different CsCRC alleles provides a strategy to manipulate fruit length in cucumber breeding.
Wheat TaSnRK2.10 phosphorylates TaERD15 and TaENO1 and confers drought tolerance when overexpressed in rice
Authors: Zhang Yanfei , Wang Jingyi , Li Yuying , Zhang Zihui , Yang Lili , Wang Min , Zhang Yining , Zhang Jie , Li Chaonan , Li Long , Reynolds Matthew P , Jing Ruilian , Wang Chenyang , Mao Xinguo
Published: November 2022

Wheat (Triticum aestivum) is particularly susceptible to water deficit at the jointing stage of its development. Sucrose non-fermenting 1-related protein kinase 2 (SnRK2) acts as a signaling hub in the response to drought stress, but whether SnRK2 helps plants cope with water deficit via other mechanisms is largely unknown. Here, we cloned and characterized TaSnRK2.10, which was induced by multiple abiotic stresses and phytohormones. Ectopic expression of TaSnRK2.10 in rice (Oryza sativa) conferred drought tolerance, manifested by multiple improved physiological indices, including increased water content, cell membrane stability, and survival rates, as well as decreased water loss and accumulation of H2O2 and malonaldehyde. TaSnRK2.10 interacted with and phosphorylated early responsive to dehydration 15 (TaERD15) and enolase 1 (TaENO1) in vivo and in vitro. TaERD15 phosphorylated by TaSnRK2.10 was prone to degradation by the 26S proteasome, thereby mitigating its negative effects on drought tolerance. Phosphorylation of TaENO1 by TaSnRK2.10 may account for the substantially increased levels of phosphoenolpyruvate (PEP), a key metabolite of primary and secondary metabolism, in TaSnRK2.10-overexpressing rice, thereby enhancing its viability under drought stress. Our results demonstrate that TaSnRK2.10 not only regulated stomatal aperture and the expression of drought-responsive genes, but also enhanced PEP supply and promoted the degradation of TaERD15, all of which enhanced drought tolerance.
PICLN modulates alternative splicing and light/temperature responses in plants
Authors: Mateos Julieta L , Sanchez Sabrina E , Legris Martina , Esteve-Bruna David , Torchio Jeanette C , Petrillo Ezequiel , Goretti Daniela , Blanco-Touriñán Noel , Seymour Danelle K , Schmid Markus , Weigel Detlef , Alabadí David , Yanovsky Marcelo J
Published: November 2022

Plants undergo transcriptome reprograming to adapt to daily and seasonal fluctuations in light and temperature conditions. While most efforts have focused on the role of master transcription factors, the importance of splicing factors modulating these processes is now emerging. Efficient pre-mRNA splicing depends on proper spliceosome assembly, which in plants and animals requires the methylosome complex. Ion Chloride nucleotide-sensitive protein (PICLN) is part of the methylosome complex in both humans and Arabidopsis (Arabidopsis thaliana), and we show here that the human PICLN ortholog rescues phenotypes of Arabidopsis picln mutants. Altered photomorphogenic and photoperiodic responses in Arabidopsis picln mutants are associated with changes in pre-mRNA splicing that partially overlap with those in PROTEIN ARGININE METHYL TRANSFERASE5 (prmt5) mutants. Mammalian PICLN also acts in concert with the Survival Motor Neuron (SMN) complex component GEMIN2 to modulate the late steps of UsnRNP assembly, and many alternative splicing events regulated by PICLN but not PRMT5, the main protein of the methylosome, are controlled by Arabidopsis GEMIN2. As with GEMIN2 and SM PROTEIN E1/PORCUPINE (SME1/PCP), low temperature, which increases PICLN expression, aggravates morphological and molecular defects of picln mutants. Taken together, these results establish a key role for PICLN in the regulation of pre-mRNA splicing and in mediating plant adaptation to daily and seasonal fluctuations in environmental conditions.
Sequence patterns and signatures: Computational and experimental discovery of amyloid-forming peptides
Authors: Xiao Xingqing , Robang Alicia S , Sarma Sudeep , Le Justin V , Helmicki Michael E , Lambert Matthew J , Guerrero-Ferreira Ricardo , Arboleda-Echavarria Johana , Paravastu Anant K , Hall Carol K
Published: November 2022

Screening amino acid sequence space via experiments to discover peptides that self-assemble into amyloid fibrils is challenging. We have developed a computational peptide assembly design (PepAD) algorithm that enables the discovery of amyloid-forming peptides. Discontinuous molecular dynamics (DMD) simulation with the PRIME20 force field combined with the FoldAmyloid tool is used to examine the fibrilization kinetics of PepAD-generated peptides. PepAD screening of ∼10,000 7-mer peptides resulted in twelve top-scoring peptides with two distinct hydration properties. Our studies revealed that eight of the twelve in silico discovered peptides spontaneously form amyloid fibrils in the DMD simulations and that all eight have at least five residues that the FoldAmyloid tool classifies as being aggregation-prone. Based on these observations, we re-examined the PepAD-generated peptides in the sequence pool returned by PepAD and extracted five sequence patterns as well as associated sequence signatures for the 7-mer amyloid-forming peptides. Experimental results from Fourier transform infrared spectroscopy (FTIR), thioflavin T (ThT) fluorescence, circular dichroism (CD), and transmission electron microscopy (TEM) indicate that all the peptides predicted to assemble in silico assemble into antiparallel β-sheet nanofibers in a concentration-dependent manner. This is the first attempt to use a computational approach to search for amyloid-forming peptides based on customized settings. Our efforts facilitate the identification of β-sheet-based self-assembling peptides, and contribute insights towards answering a fundamental scientific question: “What does it take, sequence-wise, for a peptide to self-assemble?”
Reduced homotopic interhemispheric connectivity in psychiatric disorders: evidence for both transdiagnostic and disorder specific features
Authors: Yao Shuxia , Kendrick Keith M
Published: November 2022

There is considerable interest in the significance of structural and functional connections between the two brain hemispheres in terms of both normal function and in relation to psychiatric disorders. In recent years, many studies have used voxel mirrored homotopic connectivity analysis of resting state data to investigate the importance of connectivity between homotopic regions in the brain hemispheres in a range of neuropsychiatric disorders. The current review summarizes findings from these voxel mirrored homotopic connectivity studies in individuals with autism spectrum disorder, addiction, attention deficit hyperactivity disorder, anxiety and depression disorders, and schizophrenia, as well as disorders such as Alzheimer's disease, mild cognitive impairment, epilepsy, and insomnia. Overall, other than attention deficit hyperactivity disorder, studies across psychiatric disorders report decreased homotopic resting state functional connectivity in the default mode, attention, salience, sensorimotor, social cognition, visual recognition, primary visual processing, and reward networks, which are often associated with symptom severity and/or illness onset/duration. Decreased homotopic resting state functional connectivity may therefore represent a transdiagnostic marker for general psychopathology. In terms of disorder specificity, the extensive decreases in homotopic resting state functional connectivity in autism differ markedly from attention deficit hyperactivity disorder, despite both occurring during early childhood and showing extensive co-morbidity. A pattern of more posterior than anterior regions showing reductions in schizophrenia is also distinctive. Going forward, more studies are needed to elucidate the functions of these homotopic functional connections in both health and disorder and focusing on associations with general psychopathology, and not only on disorder specific symptoms.
Advances in neuroimaging studies of alcohol use disorder (AUD)
Authors: Xie Ji-Yu , Li Rui-Hua , Yuan Wei , Du Jiang , Zhou Dong-Sheng , Cheng Yu-Qi , Xu Xue-Ming , Liu Heng , Yuan Ti-Fei
Published: November 2022

Alcohol use disorder (AUD) is a worldwide problem and the most common substance use disorder. Chronic alcohol consumption may have negative effects on the body, the mind, the family, and even society. With the progress of current neuroimaging methods, an increasing number of imaging techniques are being used to objectively detect brain impairment induced by alcoholism and serve a vital role in the diagnosis, prognosis, and treatment assessment of AUD. This article organizes and analyzes the research on alcohol dependence concerning the main noninvasive neuroimaging methods, structural magnetic resonance imaging, functional magnetic resonance imaging, and electroencephalography, as well as the most common noninvasive brain stimulation – transcranial magnetic stimulation, and intersperses the article with joint intra- and intergroup studies, providing an outlook on future research directions.
Quantifying conjugacy separability in wreath products of groups
Authors: Ferov Michal , Pengitore Mark
Published: November 2022

We study generalizations of conjugacy separability in restricted wreath products of groups. We provide an effective upper bound for $\mathcal{C}$-conjugacy separability of a wreath product $A \wr B$ in terms of the $\mathcal{C}$-conjugacy separability of A and B, the growth of $\mathcal{C}$-cyclic subgroup separability of B and the $\mathcal{C}$-residual girth of $B.$ As an application, we provide a characterization of when $A \wr B$ is p-conjugacy separable. We use this characterization to provide for each prime p an example of a wreath product with infinite base group that is p-conjugacy separable. We also provide asymptotic upper bounds for conjugacy separability for wreath products of nilpotent groups, which include the lamplighter groups and provide asymptotic upper bounds for conjugacy separability of the free metabelian groups.
CLASSIC IL-6 SIGNALING IS ASSOCIATED WITH POOR OUTCOMES IN BURN PATIENTS
Authors: Rehou Sarah , Abdullahi Abdikarim , Jeschke Marc G.
Published: November 2022

Background: Interleukin (IL)-6 is a multifunctional cytokine with both a proinflammatory and anti-inflammatory role. In many studies, IL-6 increases rapidly after burn injury and is associated with poor outcomes. However, there are two aspects to IL-6; it can signal via its soluble IL-6 receptor (sIL-6R), which is referred to as trans-signaling and is regarded as the proinflammatory pathway. The role of sIL-6R postburn injury has yet to be explored in its entirety. We hypothesized that patients with a lower ratio of IL-6 to sIL-6R would have worse outcomes. Methods: Patients admitted to our burn center within 7 days of injury were included in this study. Patients were divided into two groups based on IL-6 and sIL-6R levels measured within the first 7 days postburn injury. Patients were in the high ratio group if their IL-6/sIL-6R ratio was ≥0.185. Clinical outcomes included organ biomarkers, morbidities, and hospital length of stay. Groups were compared using Student's t test, Mann-Whitney U, and Fisher's exact test as appropriate; a P value of <0.05 was considered statistically significant. Results: We studied 86 patients with a median age of 50 years (36–66 years) and a median total body surface area burn of 18% (10–31). There were 40 patients categorized with a low IL-6/sIL-6R ratio and 46 patients with a high IL-6/sIL-6R ratio. Patients in the high IL-6/sIL-6R ratio group had a significantly greater total body surface area burn (P < 0.001) and a significantly greater proportion of patients with inhalation injury (P = 0.001). Levels of IL-6 were significantly higher in patients with a high IL-6/sIL-6R ratio (P < 0.0001). However, levels of sIL-6R were not significantly different among the low and high groups (P = 0.965). Mortality was significantly greater in the high IL-6/sIL-6R ratio group (3% vs. 26%; P = 0.002). Conclusions: Interestingly, patients with a higher ratio of IL-6/sIL-6R had significantly greater mortality. Using sIL-6R as a marker for the proinflammatory immune response, we expected patients with a lower IL-6/sIL-6R ratio to have poor outcomes, typically associated with a hyperinflammatory or exaggerated immune response. However, the absolute value of sIL-6R did not differ. This suggests that classical signaling of IL-6 via its membrane-bound receptor, with an anti-inflammatory function, is important.
POSTHEMORRHAGIC SHOCK MESENTERIC LYMPH IMPAIRS SPLENIC DENDRITIC CELL FUNCTION IN MICE
Authors: Liu Hua , Li Jian-Feng , Zhang Li-Min , Wang Huai-Huai , Wang Xu-Qing , Liu Gui-Qing , Du Hui-Bo , Jin Yu-Jie , Xing Li-Qiang , Zhao Zi-Gang , Niu Chun-Yu
Published: November 2022

Dendritic cell (DC)–mediated immune dysfunction is involved in the process of severe hemorrhagic shock that leads to sepsis. Although post–hemorrhagic shock mesenteric lymph (PHSML) induces immune organs injuries and apoptosis, whether PHSML exerts adverse effects on splenic DCs remains unknown. In this study, we established a hemorrhagic shock model (40 ± 2 mm Hg for 60 min) followed by fluid resuscitation with the shed blood and equal Ringer's solution and drained the PHSML after resuscitation. At 3 h after resuscitation, we harvested the splenic tissue to isolate DCs using anti-CD11c immunomagnetic beads and then detected the necrotic and apoptotic rates in splenocytes and splenic DCs. We also detected the levels of TNF-α, IL-10, and IL-12 in the culture supernatants and surface marker expressions of MHC-II, CD80, and CD86 of splenic DCs following LPS stimulation for 24 h. Second, we purified the DCs from splenocytes of normal mice to investigate the effects of PHSML treatment on cytokine production and surface marker expression following LPS stimulation. The results showed that PHSML drainage attenuated LPS-induced cell death of splenocytes and DCs. Meanwhile, PHSML drainage enhanced the DC percentage in splenocytes and increased the TNF-α and IL-12 production by DCs and the expressions of CD80, CD86, and MHCII of DCs treated by LPS. Furthermore, PHSML treatment reduced the productions of TNF-α, IL-10, and IL-12 and the expressions of CD80 and CD86 in normal DCs after treatment with LPS. In summary, the current investigation demonstrated that PHSML inhibited the cytokine production and surface marker expressions of DCs stimulated by LPS, suggesting that PHSML plays an important role in hemorrhagic shock–induced immunosuppression through the impairment of DC function and maturation.
Predicting and Interpreting Protein Developability via Transfer of Convolutional Sequence Representation
Authors: Golinski Alexander W. , Schmitz Zachary D. , Nielsen Gregory H. , Johnson Bryce , Saha Diya , Appiah Sandhya , Hackel Benjamin J. , Martiniani Stefano
Published: November 2022

Engineered proteins have emerged as novel diagnostics, therapeutics, and catalysts. Often, poor protein developability – quantified by expression, solubility, and stability – hinders utility. The ability to predict protein developability from amino acid sequence would reduce the experimental burden when selecting candidates. Recent advances in screening technologies enabled a high-throughput developability dataset for 105of 1020possible variants of protein ligand scaffold Gp2. In this work, we evaluate the ability of neural networks to learn a developability representation from a high-throughput dataset and transfer this knowledge to predict recombinant expression beyond observed sequences. The model convolves learned amino acid properties to predict expression levels 44% closer to the experimental variance compared to a non-embedded control. Analysis of learned amino acid embeddings highlights the uniqueness of cysteine, the importance of hydrophobicity and charge, and the unimportance of aromaticity, when aiming to improve the developability of small proteins. We identify clusters of similar sequences with increased developability through nonlinear dimensionality reduction and we explore the inferred developability landscape via nested sampling. The analysis enables the first direct visualization of the fitness landscape and highlights the existence of evolutionary bottlenecks in sequence space giving rise to competing subpopulations of sequences with different developability. The work advances applied protein engineering efforts by predicting and interpreting protein scaffold developability from a limited dataset. Furthermore, our statistical mechanical treatment of the problem advances foundational efforts to characterize the structure of the protein fitness landscape and the amino acid characteristics that influence protein developability.

Significance statement

Protein developability prediction and understanding constitutes a critical limiting step in biologic discovery and engineering due to limited experimental throughput. We demonstrate the ability of a machine learning model to learn sequence-developability relationships first through the use of high-throughput assay data, followed by the transfer of the learned developability representation to predict the true metric of interest, recombinant yield in bacterial production. Model performance is 44% better than a model not pre-trained using the high-throughput assays. Analysis of model behavior reveals the importance of cysteine, charge, and hydrophobicity to developability, as well as of an evolutionary bottleneck that greatly limited sequence diversity above 1.3 mg/L yield. Experimental characterization of model predicted candidates confirms the benefit of this transfer learning and in-silico evolution approach.
Enhancing Mitochondrial Functions by Optogenetic Clustering
Authors: Qiu Kangqiang , Zou Weiwei , Tian Zhiqi , Huang Taosheng , Tsai Nien-Pei , Zhang Kai , Diao Jiajie
Published: November 2022

Known as the powerhouses of cells, mitochondria and its dynamics are important for their functions in cells. Herein, an optogenetic method that controlling mitochondria to form the clusters was developed. The plasmid named CRY2PHR-mCherry-Miro1TM was designed for the optogenetic system. The photoactivable protein CRY2PHR was anchored to mitochondria, via the specific organelle-targeting transmembrane domain Miro1TM. Under blue light illumination, CRY2PHR can form the oligomerization, called puncta. With the illuminated time extended, the puncta can interact, and the mitochondria were found to form clustering with reversibility and spatiotemporal controllability. The mitochondrial functions were found to enhance after the formation of optogenetic mitochondrial clusters. This method presented here provides a way to control mitochondrial clustering and raise mitochondrial functions up.
Bayesian network modelling to identify on-ramps to childhood obesity
Authors: Zhu Wanchuang , Marchant Roman , Morris Richard W , Baur Louise A , Simpson Stephen J , Cripps Sally
Published: November 2022

Background

When tackling complex public health challenges such as childhood obesity, interventions focused on immediate causes, such as poor diet and physical inactivity, have had limited success, largely because upstream root causes remain unresolved. A priority is to develop new modelling frameworks to infer the causal structure of complex chronic disease networks, allowing disease “on-ramps” to be identified and targeted.

Methods

The system surrounding childhood obesity was modelled as a Bayesian Network, using data from The Longitudinal Study of Australian Children. The existence and direction of the dependencies between factors represent possible causal pathways for childhood obesity and were encoded in directed acyclic graphs (DAGs). The posterior distribution of the DAGs was estimated using Partition Markov chain Monte Carlo.

Results

We have implemented structure learning for each dataset. For each wave and cohort, socio-economic status was central to the DAGs, implying that socio-economic status drives the system regarding childhood obesity. Furthermore, the causal pathway socio-economic status and/or parental high school levels → parental body mass index (BMI) → child’s BMI existed in over 99.99% of posterior DAG samples across all waves and cohorts. For children under the age of 8y, the most influential proximate causal factors explaining child BMI were birth weight and parents’ BMI. After age 8y, free time activity became an important driver of obesity, while the upstream factors influencing free time activity for boys compared with girls were different.

Conclusions

Childhood obesity is largely a function of socio-economic status, which is manifest through numerous downstream factors. Parental high school levels entangle with socio-economic status, hence are on-ramp to childhood obesity. The strong and independent causal relationship between birth weight and childhood BMI suggests a biological link. Our study implies that interventions that improve socio-economic status, including through increasing high school completion rates, may be effective in reducing childhood obesity prevalence.
Plasmodium vivaxrelapse, reinfection and recrudescence estimation using genetic data
Authors: Taylor Aimee R , Foo Yong See , White Michael T
Published: November 2022

Malaria is a major public health concern. Among the two most important causes of human malaria,Plasmodium vivaxis the hardest to eliminate, owing largely to its ability to relapse (cause recurrent blood-stage infection following the activation of dormant liver-stage parasites called hypnozoites). Recurrent vivax malaria can also follow a failure to treat a preceding blood-stage infection (recrudescence) and, in endemic settings, a new infectious mosquito bite (reinfection). Understanding the cause of recurrent vivax malaria is critical for disease control efforts, e.g., to estimate the efficacy of a hypnozoiticidal drug, relapse needs to be separated from reinfection and recrudescence. In this report we describe the Pv3R statistical model designed to estimate usingP. vivaxgenetic data the probability that a recurrentP. vivaxblood-stage infection is a relapse, reinfection or recrudescence (thePv3Rs).
Vitamin D and the preclinical Alzheimer cognitive composite cognition (PACC) score: a two-sample mendelian randomization study
Authors: Ilboudo Yann , Yoshiji Satoshi , Lu Tianyuan , Butler-Laporte Guillaume , Zhou Sirui , Richards J. Brent
Published: November 2022

Objective

Observational studies on cognition found that vitamin D supplementation is associated with improved cognition. Further, recent Mendelian randomization (MR) studies have shown that increased vitamin D levels, as measured by 25-hydroxyvitamin D [25(OH)D], may protect against Alzheimer’s disease. Thus, it is possible that 25OHD may protect against Alzheimer’s disease by improving cognition.

Methods

To evaluate this hypothesis, we began by performing an observational study by testing the association of 25OHD levels with 5 cognitive outcomes related to memory and executive function, adjusting for age, sex, BMI, smoking status and nutritional risk index in 26,787 older individuals (median age 62). Since such observational analyses can be biased by confounding, we next performed two-sample mendelian randomization (MR) analyses testing the effect of 25(OH)D on cognitive outcomes, since this method helps to protect against bias from confounding.

Results

Observational studies suggested a strong protective association between 25(OH)D and cognitive measures. However, in MR analyses, we found no estimated effect of 25(OH)D on these outcomes.

Conclusion

These findings suggest that associations between 25(OH)D levels and cognition are likely to be biased by confounding and that the relationship between 25(OH)D levels and Alzheimer’s disease is not due to the effect of 25(OH)D on cognition.
Substance use, psychiatric symptoms, personal mastery, and social support among COVID-19 long haulers: A compensatory model
Authors: Tam Cheuk Chi , Qiao Shan , Garrett Camryn , Zhang Ran , Aghaei Atefeh , Aggarwal Abhishek , Li Xiaoming
Published: November 2022

Background

Substance use has become a critical health concern during the COVID-19 pandemic, and emerging attention has been paid to people with the persistent symptoms of COVID-19 (COVID-19 long haulers) due to their high vulnerability. However, scant research has investigated their substance use and relevant psychosocial factors. The current study was to (1) examine substance use behaviors (i.e., legal drug use, illicit drug use, and non-medical use of prescription drugs); and (2) assessed their associations with psychiatric symptoms (i.e., depression, anxiety, and post-traumatic stress disorder) and psychosocial factors (i.e., personal mastery and social support) among COVID-19 long haulers.

Methods

In January – March 2022, 460 COVID-19 long haulers (50% female), with an average age of 32, completed online surveys regarding their demographics, substance use, psychiatric symptoms, and psychosocial factors.

Results

In the past three months, the most commonly used or non-medically used substances were tobacco (82%) for legal drugs, cocaine (53%) for illicit drugs, and prescription opioids (67%) for prescription drugs. Structural equation modeling suggested that psychiatric symptoms were positively associated with substance use behaviors (βs = .38 to .68,ps < .001), while psychosocial factors were negatively associated with substance use behaviors (βs = -.61 to -.43,ps < .001).

Conclusion

Substance use is common in COVID-19 long haulers and psychiatric symptoms are the risk factors. Personal mastery and social support appear to offer protection offsetting the psychiatric influences. Substance use prevention and mental health services for COVID-19 long haulers should attend to personal mastery and social support.
Predicting Lung Cancer in Korean Never-Smokers with Polygenic Risk Scores
Authors: Kim Juyeon , Park Young Sik , Kim Jin Hee , Hong Yun-Chul , Kim Young-Chul , Oh In-Jae , Jee Sun Ha , Ahn Myung-Ju , Kim Jong-Won , Yim Jae-Joon , Won Sungho
Published: November 2022

In the last few decades, genome-wide association studies (GWAS) with more than 10,000 subjects have identified several loci associated with lung cancer. Hence, recently, genetic data have been used to develop novel risk prediction tools for cancer. The present study aimed to establish a lung cancer prediction model for Korean never-smokers using polygenic risk scores (PRSs). PRSs were calculated using a thresholding-pruning-based approach based on 11 genome-wide significant single nucleotide polymorphisms (SNPs). Overall, the odds ratios tended to increase as PRSs were larger, with the odds ratio of the top 5% PRSs being 1.71 (95% confidence interval: 1.31−2.23), and the area under the curve (AUC) of the prediction model being of 0.76 (95% confidence interval: 0.747−0.774). The receiver operating characteristic (ROC) curves of the prediction model with and without PRSs as covariates were compared using DeLong’s test, and a significant difference was observed. Our results suggest that PRSs can be valuable tools for predicting the risk of lung cancer.
Heterotopic reduction of forelimb progenitors underpins development of the vestigial emu wing; implications for vertebrate limb evolution
Authors: Newton Axel H , Williams Sarah M , Phipson Belinda , Pask Andrew J , Major Andrew T , Smith Craig A
Published: November 2022

The tetrapod limb has evolved a broad diversity of form and function, enabling vertebrates to adapt to a wide range of environments. One of the most striking examples of this is the evolution of powered flight in birds. However, during the avian radiation, flightless ratites (Paleognathae) secondarily evolved multiple instances of wing reductions, utilizing distinct molecular mechanisms, and displaying heterochrony with flighted birds (Neoaves). Among ratites, the emu displays the most marked reduction of wing anatomy, developing a small wing with a single clawed digit. This major divergence from the typical avian pattern provides a robust model to determine the mechanisms underpinning developmental plasticity in the tetrapod limb. To interrogate the ontogenetic origins of vestigial wing development, we applied comparative single cell transcriptomics of the embryonic emu forelimb field with the chicken, as it possess a typical wing. Stunted wing development in the emu occurs through a heterotopic reduction of lateral plate mesoderm (LPM)-derived limb progenitor cells, and accompanying downregulation of genes associated with LPM development and early limb initiation. Here, forelimb bud initiation and outgrowth is altered by changes to the specification and allocation of limb progenitor cells, acting as an underlying template for pre- and post-patterning mechanisms. These findings provide novel insights into the evolution of limb development in tetrapods, and emphasizes an important, yet underappreciated role for heterotopy as major driver of limb disparity.

Significance statement

Animals exhibit a striking variety of morphologies, yet our understanding of how these forms evolve and arise during development are lagging. The emu is a large, flightless bird which has evolved a vestigial wing. This model allows detailed interrogations into the mechanisms which underlie evolution and development of a distinct morphological structure. Through application of comparative single cell transcriptomics between the emu and chicken, we identify an early embryological mechanism, heterotopy, underlying the evolution and vestigial development of the emu wing. This mechanism features reduced allocation of limb bud progenitor cells in the lateral plate mesoderm (LPM). This data provides new information on the mechanisms that underpin evolutionary diversity in morphological features.
Monitoring the intestinal magnetic field with optically pumped atomic magnetometers
Authors: Sun Chenxi , Zhao Biying , Wu Teng , Zhang Jianwei , Leng Yuxin , Guo Hong ,   CREAM Bioelectromagnetism Group
Published: November 2022

Research has shown the potential of magnetoenterography (MENG) for detecting intestinal diseases noninvasively by superconducting quantum interference devices (SQUIDs). Nevertheless, these devices need to operate under a cytogenetic environment maintained by liquid helium. In this paper, we record the intestinal magnetic field of a rabbit with optically pumped magnetometers (OPMs) at room temperature. It demonstrates that the OPM-based system has sufficient sensitivity to measure the intestinal magnetic fields of the rabbit, and can be potentially developed into a cost-effective and flexible MENG system.
Accurate prediction of cohesin-mediated 3D genome organization from 2D chromatin features
Authors: Abbas Ahmed , Chandratre Khyati , Gao Yunpeng , Yuan Jiapei , Zhang Michael Q. , Mani Ram S.
Published: November 2022

The three-dimensional (3D) genome organization influences diverse nuclear processes. Chromatin interaction analysis by paired-end tag sequencing (ChIA-PET) and Hi-C are powerful methods to study the 3D genome organization. However, ChIA-PET and Hi-C experiments are expensive, time-consuming, require tens to hundreds of millions of cells, and are challenging to optimize and analyze. Predicting ChIA-PET/Hi-C data using cheaper ChIP-Seq data and other easily obtainable features could be a useful alternative. It is well-established that the cohesin protein complex is a key determinant of 3D genome organization. Here we present Chromatin Interaction Predictor (ChIPr), a suite of regression models based on deep neural networks (DNN), random forest, and gradient boosting, respectively, to predict cohesin-mediated chromatin interaction strength between any two loci in the genome. Comprehensive tests on four cell lines show that the predictions of ChIPr correlate well with the original ChIA-PET data at the peak-level resolution and bin sizes of 25 and 5 Kbp. In addition, ChIPr can accurately capture most of the cell-type-dependent loops identified by ChIA-PET and Hi-C data. Rigorous feature testing indicated that genomic distance and RAD21 (a cohesin component) ChIP-Seq signals are the most important inputs for ChIPr in determining chromatin interaction strength. The standard ChIPr model requires three experimental inputs: ChIP-Seq signals for RAD21, H3K27ac (enhancer/active chromatin mark) and H3K27me3 (inactive chromatin mark). The minimal ChIPr model performs comparably and requires a single experimental input: ChIP-Seq signals for RAD21. Integrative analysis revealed novel insights into the role of CTCF motif, its orientation, and CTCF binding on the prevalence and strength of cohesin-mediated chromatin interactions. These studies outline the general features of genome folding and open new avenues to analyze spatial genome organization in specimens with limited cell numbers.
Accelerating cryptic pocket discovery using AlphaFold
Authors: Meller Artur , Bhakat Soumendranath , Solieva Shahlo , Bowman Gregory R.
Published: November 2022

Cryptic pockets, or pockets absent in ligand-free, experimentally determined structures, hold great potential as drug targets. However, cryptic pocket opening is often beyond the reach of conventional biomolecular simulations because certain cryptic pocket openings involve slow motions. Here, we investigate whether AlphaFold can be used to accelerate cryptic pocket discovery either by generating structures with open pockets directly or generating structures with partially open pockets that can be used as starting points for simulations. We use AlphaFold to generate ensembles for 10 known cryptic pocket examples, including 5 that were deposited after AlphaFold’s training data was extracted from the PDB. We find that in 6 out of 10 cases AlphaFold samples the open state. For plasmepsin II, an aspartic protease from the causative agent of malaria, AlphaFold only captures partial pocket opening. As a result, we ran simulations from an ensemble of AlphaFold-generated structures and show that this strategy samples cryptic pocket opening, even though an equivalent amount of simulations launched from a ligand-free experimental structure fails to do so. Markov state models (MSMs) constructed from the AlphaFold-seeded simulations quickly yield a free energy landscape of cryptic pocket opening that is in good agreement with the same landscape generated with well-tempered metadynamics. Taken together, our results demonstrate that AlphaFold has a useful role to play in cryptic pocket discovery but that many cryptic pockets may remain difficult to sample using AlphaFold alone.
Does the Ice Age legacy end in Central Europe? The shrinking distributions of glacial relict crustaceans
Authors: Arbačiauskas Kęstutis , Smith Carl , Audzijonyte Asta
Published: November 2022

Glacial relict mysid and amphipod crustaceans are characterised by their affinity for cold and well-oxygenated waters and inability to disperse upstream or by external agents. These crustaceans occur in large and deep lakes of Northern and Central Europe and North America, their distributions shaped by glaciation events. In Europe, along the southern edge of their distribution (Germany, Poland, Lithuania, Belarus), glacial relict crustaceans are threatened by eutrophication and global warming.

This study assesses the status of three glacial relict malacostracan species in Lithuania; the amphipodsMonoporeia affinisandPallaseopsis quadrispinosa, and mysidMysis relicta, and models their abundance as a function of environmental variables and the presence of invasive Ponto-Caspian mysids and amphipods.

Our results revealed thatM. affinisis likely extinct in the country, whereasM. relictawas found in only 9 out of 16 locations from which it was previously recorded. The distribution ofP. quadrispinosaappears to be shrinking.

Lake depth and water flowthrough intensity were significantly and positively associated with the relative abundance of relict mysids and amphipods, but no association was found with lake size or the presence of invasive Ponto-Caspian crustaceans.

We conclude that urgent action to mitigate the effects of nutrient run-off is needed to improve the status of glacial relict and other species that require good water quality. We also propose the re-introduction of glacial relict species in Lake Drūkšiai, where they went extinct during the operation of the Ignalina nuclear power plant that heated the lake, but where deep-water environmental conditions have improved following the powerplant closure in 2010.
The intracellular amastigote ofTrypanosoma cruzimaintains an actively beating flagellum
Authors: Won Madalyn M. , Krüger Timothy , Engstler Markus , Burleigh Barbara A.
Published: November 2022

Throughout its complex life cycle, the uniflagellate parasitic protist,Trypanosoma cruzi, adapts to different host environments by transitioning between elongated motile extracellular forms and non-motile intracellular amastigote forms that replicate in the cytoplasm of mammalian host cells. Despite their name, intracellularT. cruziamastigotes retain a short flagellum that extends beyond the opening of the flagellar pocket with access to the extracellular milieu. Contrary to the long-held view that theT. cruziamastigote flagellum is inert, we now report that this organelle is motile and displays quasiperiodic beating inside mammalian host cells. Kymograph analysis determined an average flagellar beat frequency of ~0.7 Hz for intracellular amastigotes. Similar beat frequencies were measured in extracellular amastigotes following their isolation from host cells. Inhibitor studies reveal roles for parasite mitochondrial respiration and intracellular calcium availability in modulating flagellar beat inT. cruziamastigotes. Together, these findings demonstrate that flagellar motility is an intrinsic property ofT. cruziamastigotes and suggest that this organelle may play an active role in the parasite infection process. To our knowledge, this is the first record of an intracellular eukaryotic flagellum beating within another eukaryotic cell.
An FcRn-targeted mucosal vaccine against SARS-CoV-2 infection and transmission
Authors: Li Weizhong , Wang Tao , Rajendrakumar Arunraj M. , Acharya Gyanada , Miao Zizhen , Varghese Berin P. , Yu Hailiang , Dhakal Bibek , LeRoith Tanya , Tuo Wenbin , Zhu Xiaoping
Published: November 2022

SARS-CoV-2 and its variants cause COVID-19, which is primarily transmitted through droplets and airborne aerosols. To prevent viral infection and reduce viral spread, vaccine strategies must elicit protective immunity in the airways. FcRn transfers IgG across epithelial barriers; we explore FcRn-mediated respiratory delivery of SARS-CoV-2 spike (S). A monomeric IgG Fc was fused to a stabilized S protein; the resulting S-Fc bound to S-specific antibodies (Ab) and FcRn. A significant increase in Ab responses was observed following the intranasal immunization of mice with S-Fc formulated in CpG as compared to the immunization with S alone or PBS. Furthermore, we intranasally immunize adult or aged mice and hamsters with S-Fc. A significant reduction of virus replication in nasal turbinate, lung, and brain was observed following nasal challenges with SARS-CoV-2, including Delta and Omicron variants. Intranasal immunization also significantly reduced viral transmission between immunized and naive hamsters. Protection was mediated by nasal IgA, serum-neutralizing Abs, tissue-resident memory T cells, and bone marrow S-specific plasma cells. Hence FcRn delivers an S-Fc antigen effectively into the airway and induces protection against SARS-CoV-2 infection and transmission. Based on these findings, FcRn-targeted non-invasive respiratory immunizations are superior strategies for preventing highly contagious respiratory viruses from spreading.
CYRI-B mediated macropinocytosis drives metastasis via lysophosphatidic acid receptor uptake
Authors: Nikolaou Savvas , Juin Amelie , Whitelaw Jamie A. , Paul Nikki R. , Fort Loic , Nixon Colin , Spence Heather J. , Bryson Sheila , Machesky Laura M.
Published: November 2022

Pancreatic ductal adenocarcinoma carries a dismal prognosis, with high rates of metastasis and few treatment options. Hyperactivation of KRAS in almost all tumours drives RAC1 activation, conferring enhanced migratory and proliferative capacity as well as macropinocytosis. Macropinocytosis is well understood as a nutrient scavenging mechanism, but little is known about its functions in trafficking of signaling receptors. We find that CYRI-B is highly expressed in pancreatic tumours in a mouse model of KRAS and p53- driven pancreatic cancer. Deletion of CYRI-B accelerates tumourigenesis, leading to enhanced ERK and JNK-induced proliferation in precancerous lesions, indicating a role as a buffer of RAC1 hyperactivation in early stages. However, as disease progresses, loss of CYRI-B inhibits metastasis. CYRI-B depleted tumour cells show reduced chemotactic responses to lysophosphatidic acid, a major driver of tumour spread, due to impaired macropinocytic uptake of LPAR1 receptor. Overall, we implicate CYRI-B as a mediator of growth and signaling in pancreatic cancer, providing new insights into pathways controlling metastasis.
Semisynthesis reveals Apoptin as a tumour-selective protein prodrug that causes cytoskeletal collapse
Authors: Wyatt Jasmine , Tavassoli Mahvash , Müller Manuel M.
Published: November 2022

Apoptin is a small viral protein capable of inducing cell death selectively in cancer cells. Despite its potential as an anticancer agent, relatively little is known about its mechanism of toxicity and cancer-selectivity. Previous experiments suggest that cancer-selective phosphorylation modulates Apoptin toxicity, although a lack of chemical tools has hampered the dissection of underlying mechanisms. Here, we describe structure-function studies with site-specifically phosphorylated Apoptin (Apoptin-T108ph) in living cells which revealed that Thr108 phosphorylation is the selectivity switch for Apoptin toxicity. Mechanistic investigations link T108ph to actin binding, cytoskeletal disruption and downstream inhibition of anoikis-resistance as well as cancer cell invasion. These results establish Apoptin as a protein pro-drug, selectively activated in cancer cells by phosphorylation, which disrupts the cytoskeleton and promotes cell death. We anticipate that this mechanism provides a framework for the design of next generation anticancer proteins with enhanced selectivity and potency.
Multiscale Effects of Excitatory-Inhibitory Homeostasis in Lesioned Cortical Networks: A Computational Study
Authors: Páscoa dos Santos Francisco , Vohryzek Jakub , Verschure Paul F.M.J.
Published: November 2022

Stroke-related disruptions in functional connectivity (FC) often spread beyond lesioned areas and, given the localized nature of lesions, it is unclear how the recovery of FC is orchestrated on a global scale. Since recovery is accompanied by long-term changes in excitability, we propose excitatory-inhibitory (E-I) homeostasis as a driving mechanism. We present a large-scale model of the neocortex, with synaptic scaling of local inhibition, showing how E-I homeostasis can drive the post-lesion restoration of FC and linking it to changes in excitability. We show that functional networks could reorganize to recover disrupted modularity and small-worldness, but not network dynamics, suggesting the need to consider forms of plasticity beyond synaptic scaling of inhibition. On average, we observed widespread increases in excitability, with the emergence of complex lesion-dependent patterns related to biomarkers of relevant side effects of stroke, such as epilepsy, depression and chronic pain. In summary, our results show that the effects of E-I homeostasis extend beyond local E-I balance, driving the restoration of global properties of FC, and relating to post-stroke symptomatology. Therefore, we suggest the framework of E-I homeostasis as a relevant theoretical foundation for the study of stroke recovery and for understanding the emergence of meaningful features of FC from local dynamics.