bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluation of high-yielding wheat (Triticum aestivum L.) varieties under water limitation
Authors: Khan Mueen Alam , Faisal Umer Hafiz Muhammad , Iqbal Muhammad , Rehman Abdul , Chattha Waqas Shafqat
Published: April 2021

Drought tolerance is a highly complex trait and one of the important components of yield stability in wheat. An experiment was therefore conducted to study the drought tolerance status of 14 high-yielding wheat varieties based on morphological characteristics under a randomized complete block design following factorial arrangement with three replications. Variety × Treatment × Year interactions of wheat genotypes were studied for various morphological traits under normal and drought stress conditions for 2 years in plants grown in pots. Significant differences were observed among the 14 varieties of wheat. Sutlej-86 was found to be highly affected by drought, with maximum reductions in plant height, spike length and number of spikelets/spike. The variety with the maximum tolerance to drought was Bahawalpur-97; this variety also had the lowest reductions in the number of fertile tillers/plant, the number of spikelets/spike, spike weight, the number of grains/spike, 1000-grain weight, grain yield/spike, total biomass and stress susceptibility and tolerance indices. Stronger correlations among the studied attributes under drought stress over normal conditions further highlighted drought stress adversities. The studied traits are thus recognized as drought tolerance indicators for varietal selection, and varieties showing less reduction under drought could be used as a standard check in breeding programmes to identify lineages with drought tolerance and could be recommended for drought-stressed areas.
Suicide, self-harm and thoughts of suicide or self-harm in infectious disease epidemics: a systematic review and meta-analysis
Authors: Rogers J. P. , Chesney E. , Oliver D. , Begum N. , Saini A. , Wang S. , McGuire P. , Fusar-Poli P. , Lewis G. , David A. S.
Published: April 2021

Aims

Suicide accounts for 2.2% of all years of life lost worldwide. We aimed to establish whether infectious epidemics are associated with any changes in the incidence of suicide or the period prevalence of self-harm, or thoughts of suicide or self-harm, with a secondary objective of establishing the frequency of these outcomes.

Methods

In this systematic review and meta-analysis, MEDLINE, Embase, PsycINFO and AMED were searched from inception to 9 September 2020. Studies of infectious epidemics reporting outcomes of (a) death by suicide, (b) self-harm or (c) thoughts of suicide or self-harm were identified. A random-effects model meta-analysis for the period prevalence of thoughts of suicide or self-harm was conducted.

Results

In total, 1354 studies were screened with 57 meeting eligibility criteria, of which 7 described death by suicide, 9 by self-harm, and 45 thoughts of suicide or self-harm. The observation period ranged from 1910 to 2020 and included epidemics of Spanish Flu, severe acute respiratory syndrome, human monkeypox, Ebola virus disease and coronavirus disease 2019 (COVID-19). Regarding death by suicide, data with a clear longitudinal comparison group were available for only two epidemics: SARS in Hong Kong, finding an increase in suicides among the elderly, and COVID-19 in Japan, finding no change in suicides among children and adolescents. In terms of self-harm, five studies examined emergency department attendances in epidemic and non-epidemic periods, of which four found no difference and one showed a reduction during the epidemic. In studies of thoughts of suicide or self-harm, one large survey showed a substantial increase in period prevalence compared to non-epidemic periods, but smaller studies showed no difference. As a secondary objective, a meta-analysis of thoughts of suicide and self-harm found that the pooled prevalence was 8.0% overall (95% confidence interval (CI) 5.2–12.0%; 14 820 of 99 238 cases in 24 studies) over a time period of between seven days and six months. The quality assessment found 42 studies were of low quality, nine of moderate quality and six of high quality.

Conclusions

There is little robust evidence on the association of infectious epidemics with suicide, self-harm and thoughts of suicide or self-harm. There was an increase in suicides among the elderly in Hong Kong during SARS and no change in suicides among young people in Japan during COVID-19, but it is unclear how far these findings may be generalised. The development of up-to-date self-harm and suicide statistics to monitor the effect of the current pandemic is an urgent priority.
A High Resolution Ultraviolet Spectroradiometer and its Application in Solar Radiation Measurement
Authors: Yin Bangsheng , Min Qilong , Berndt Jerry , Harrison Lee , Zhu Lei
Published: April 2021

A recent laboratory study suggests that water vapor displays structured absorption features over the 290–350 nm region, with maximum and minimum cross‐sections of 8.4 × 10−25 and 1.4 × 10−25 cm2/molecule at room temperature (Pei et al. 2019, https://doi.org/10.1029/2019jd030724; Du et al., 2013, https://doi.org/10.1002/grl.50935). To observe water vapor absorption features in the ultraviolet (UV) region in the atmosphere, a United States Department of Agriculture reference spectroradiometer was upgraded with a new fore‐optical module, enabling it to measure direct solar beam and sky radiance at given azimuth and elevation angles. This double Czerny‐Turner spectroradiometer enables wavelength scanning from 290 to 410 nm, with a nominal bandwidth of 0.1 nm. It can operate with a step‐size of 0.0005 nm and a full width at half maximum of 0.1 nm. It has an out‐of‐band rejection ratio of approximately 10−10. This high resolution spectroradiometer can be used as a reference instrument for UV radiation measurements and for monitoring atmospheric gases such as O3, SO2, and NO2. A series of field observations were made using this spectroradiometer in the University at Albany campus. A residual analysis method is developed to analyze absorption by atmospheric components and to retrieve atmospheric optical depth. The residual optical depth was calculated by subtracting the optical depths of Rayleigh scattering, aerosol extinction, and absorption of typical atmospheric gases such as O3, SO2, and NO2 from the retrieved total optical depth. Multiple case studies show that residual optical depth from the observed UV spectra is sensitive to the atmospheric water vapor amount. The greater the water vapor path, the larger the magnitude of residual optical depth. The ozone amount was inferred from the residual analysis; it is comparable to the satellite measurements. For example, in a case with water vapor path of 13 mm on October 24, 2019, the inferred ozone amount from residual analysis is 2.7% lower than retrievals from the Ozone Monitoring Instrument‐Total Ozone Mapping Spectrometer.
Phonon imaging in 3D with a fibre probe
Authors: La Cavera Salvatore , Pérez-Cota Fernando , Smith Richard J. , Clark Matt
Published: April 2021

We show for the first time that a single ultrasonic imaging fibre is capable of simultaneously accessing 3D spatial information and mechanical properties from microscopic objects. The novel measurement system consists of two ultrafast lasers that excite and detect high-frequency ultrasound from a nano-transducer that was fabricated onto the tip of a single-mode optical fibre. A signal processing technique was also developed to extract nanometric in-depth spatial measurements from GHz frequency acoustic waves, while still allowing Brillouin spectroscopy in the frequency domain. Label-free and non-contact imaging performance was demonstrated on various polymer microstructures. This singular device is equipped with optical lateral resolution, 2.5 μm, and a depth-profiling precision of 45 nm provided by acoustics. The endoscopic potential for this device is exhibited by extrapolating the single fibre to tens of thousands of fibres in an imaging bundle. Such a device catalyses future phonon endomicroscopy technology that brings the prospect of label-free in vivo histology within reach.
Do side effects of antidepressants impact efficacy estimates based on the Hamilton Depression Rating Scale? A pooled patient-level analysis
Authors: Hieronymus Fredrik , Lisinski Alexander , Eriksson Elias , Østergaard Søren Dinesen
Published: April 2021

The Hamilton Depression Rating Scale (HDRS-17) measures symptoms that may overlap with common antidepressant side effects (e.g., sexual dysfunction), thus making it possible that side effects of antidepressant treatment are erroneously rated as symptoms of depression, and vice versa. This study uses patient-level data from previously conducted antidepressant treatment trials to assess whether side effect ratings co-vary with HDRS-17 ratings. Data from all HDRS-17-rated, industry-sponsored pre- and post-marketing trials (n = 4647) comparing the serotonin and noradrenaline reuptake inhibitor, duloxetine, to placebo and/or to a selective serotonin reuptake inhibitor were pooled; three studies, which utilised sub-therapeutic doses, did not have symptom-level ratings available and could not be included. Severity was assessed for side effects related to sleep, somatic anxiety, gastrointestinal function, and sexual dysfunction. Analysis of covariance was used to assess the relation between these side effects and ratings of relevant HDRS-17-derived outcome parameters. Side effects related to sleep, somatic anxiety and sexual dysfunction significantly and exclusively associated with higher scores on HDRS-17 items measuring the corresponding domains. Side effects related to gastrointestinal function associated with higher HDRS-17 item scores on all assessed domains. Treatment outcome was significantly related to side effect severity when assessed using HDRS-17-sum (beta 0.32 (0.074), p < 0.001), but not when the HDRS-6-sum-score (beta 0.035 (0.043), p = 0.415) or the depressed mood item (beta 0.007 (0.012), p = .527) were used as effect parameters. That some HDRS-17 items co-vary with common antidepressant side effects suggests some of these adverse events are counted twice, potentially leading to an underestimation of antidepressant efficacy.
Cell-type-specific expression quantitative trait loci associated with Alzheimer disease in blood and brain tissue
Authors: Patel Devanshi , Zhang Xiaoling , Farrell John J. , Chung Jaeyoon , Stein Thor D. , Lunetta Kathryn L. , Farrer Lindsay A.
Published: April 2021

Because regulation of gene expression is heritable and context-dependent, we investigated AD-related gene expression patterns in cell types in blood and brain. Cis-expression quantitative trait locus (eQTL) mapping was performed genome-wide in blood from 5257 Framingham Heart Study (FHS) participants and in brain donated by 475 Religious Orders Study/Memory & Aging Project (ROSMAP) participants. The association of gene expression with genotypes for all cis SNPs within 1 Mb of genes was evaluated using linear regression models for unrelated subjects and linear-mixed models for related subjects. Cell-type-specific eQTL (ct-eQTL) models included an interaction term for the expression of “proxy” genes that discriminate particular cell type. Ct-eQTL analysis identified 11,649 and 2533 additional significant gene-SNP eQTL pairs in brain and blood, respectively, that were not detected in generic eQTL analysis. Of note, 386 unique target eGenes of significant eQTLs shared between blood and brain were enriched in apoptosis and Wnt signaling pathways. Five of these shared genes are established AD loci. The potential importance and relevance to AD of significant results in myeloid cell types is supported by the observation that a large portion of GWS ct-eQTLs map within 1 Mb of established AD loci and 58% (23/40) of the most significant eGenes in these eQTLs have previously been implicated in AD. This study identified cell-type-specific expression patterns for established and potentially novel AD genes, found additional evidence for the role of myeloid cells in AD risk, and discovered potential novel blood and brain AD biomarkers that highlight the importance of cell-type-specific analysis.
The N-terminus of an Ustilaginoidea virens Ser-Thr-rich glycosylphosphatidylinositol-anchored protein elicits plant immunity as a MAMP
Authors: Song Tianqiao , Zhang You , Zhang Qi , Zhang Xiong , Shen Danyu , Yu Junjie , Yu Mina , Pan Xiayan , Cao Huijuan , Yong Mingli , Qi Zhongqiang , Du Yan , Zhang Rongsheng , Yin Xiaole , Qiao Junqing , Liu Youzhou , Liu Wende , Sun Wenxian , Zhang Zhengguang , Wang Yuanchao , Dou Daolong , Ma Zhenchuan , Liu Yongfeng
Published: April 2021

Many pathogens infect hosts through specific organs, such as Ustilaginoidea virens, which infects rice panicles. Here, we show that a microbe-associated molecular pattern (MAMP), Ser-Thr-rich Glycosyl-phosphatidyl-inositol-anchored protein (SGP1) from U. virens, induces immune responses in rice leaves but not panicles. SGP1 is widely distributed among fungi and acts as a proteinaceous, thermostable elicitor of BAK1-dependent defense responses in N. benthamiana. Plants specifically recognize a 22 amino acid peptide (SGP1 N terminus peptide 22, SNP22) in its N-terminus that induces cell death, oxidative burst, and defense-related gene expression. Exposure to SNP22 enhances rice immunity signaling and resistance to infection by multiple fungal and bacterial pathogens. Interestingly, while SGP1 can activate immune responses in leaves, SGP1 is required for U. virens infection of rice panicles in vivo, showing it contributes to the virulence of a panicle adapted pathogen.
The ANTsX ecosystem for quantitative biological and medical imaging
Authors: Tustison Nicholas J. , Cook Philip A. , Holbrook Andrew J. , Johnson Hans J. , Muschelli John , Devenyi Gabriel A. , Duda Jeffrey T. , Das Sandhitsu R. , Cullen Nicholas C. , Gillen Daniel L. , Yassa Michael A. , Stone James R. , Gee James C. , Avants Brian B.
Published: April 2021

The Advanced Normalizations Tools ecosystem, known as ANTsX, consists of multiple open-source software libraries which house top-performing algorithms used worldwide by scientific and research communities for processing and analyzing biological and medical imaging data. The base software library, ANTs, is built upon, and contributes to, the NIH-sponsored Insight Toolkit. Founded in 2008 with the highly regarded Symmetric Normalization image registration framework, the ANTs library has since grown to include additional functionality. Recent enhancements include statistical, visualization, and deep learning capabilities through interfacing with both the R statistical project (ANTsR) and Python (ANTsPy). Additionally, the corresponding deep learning extensions ANTsRNet and ANTsPyNet (built on the popular TensorFlow/Keras libraries) contain several popular network architectures and trained models for specific applications. One such comprehensive application is a deep learning analog for generating cortical thickness data from structural T1-weighted brain MRI, both cross-sectionally and longitudinally. These pipelines significantly improve computational efficiency and provide comparable-to-superior accuracy over multiple criteria relative to the existing ANTs workflows and simultaneously illustrate the importance of the comprehensive ANTsX approach as a framework for medical image analysis.
Molecular mechanism of lateral bud differentiation of Pinus massoniana based on high-throughput sequencing
Authors: Chen Hu , Tan Jianhui , Liang Xingxing , Tang Shengsen , Jia Jie , Yang Zhangqi
Published: April 2021

Knot-free timber cultivation is an important goal of forest breeding, and lateral shoots affect yield and stem shape of tree. The purpose of this study was to analyze the molecular mechanism of lateral bud development by removing the apical dominance of Pinus massoniana young seedlings through transcriptome sequencing and identify key genes involved in lateral bud development. We analyzed hormone contents and transcriptome data for removal of apical dominant of lateral buds as well as apical and lateral buds of normal development ones. Data were analyzed using an comprehensive approach of pathway- and gene-set enrichment analysis, Mapman visualization tool, and gene expression analysis. Our results showed that the contents of auxin (IAA), Zea and strigolactone (SL) in lateral buds significantly increased after removal of apical dominance, while abscisic acid (ABA) decreased. Gibberellin (GA) metabolism, cytokinin (CK), jasmonic acid, zeatin pathway-related genes positively regulated lateral bud development, ABA metabolism-related genes basically negatively regulated lateral bud differentiation, auxin, ethylene, SLs were positive and negative regulation, while only A small number of genes of SA and BRASSINOSTEROID, such as TGA and TCH4, were involved in lateral bud development. In addition, it was speculated that transcription factors such as WRKY, TCP, MYB, HSP, AuxIAA, and AP2 played important roles in the development of lateral buds. In summary, our results provided a better understanding of lateral bud differentiation and lateral shoot formation of P. massoniana from transcriptome level. It provided a basis for molecular characteristics of side branch formation of other timber forests, and contributed to knot-free breeding of forest trees.
ALK inhibition activates LC3B-independent, protective autophagy in EML4-ALK positive lung cancer cells
Authors: Schläfli Anna M. , Tokarchuk Igor , Parejo Sarah , Jutzi Susanne , Berezowska Sabina , Engedal Nikolai , Tschan Mario P.
Published: April 2021

ALK inhibitors effectively target EML4-ALK positive non-small cell lung cancer, but their effects are hampered by treatment resistance. In the present study, we asked whether ALK inhibition affects autophagy, and whether this may influence treatment response. Whereas the impact of targeted therapies on autophagic activity previously have been assessed by surrogate marker proteins such as LC3B, we here thoroughly examined effects on functional autophagic activity, i.e. on the sequestration and degradation of autophagic cargo, in addition to autophagic markers. Interestingly, the ALK inhibitor Ceritinib decreased mTOR activity and increased GFP-WIPI1 dot formation in H3122 and H2228 EML4-ALK+ lung cancer cells, suggesting autophagy activation. Moreover, an mCherry-EGFP-LC3B based assay indicated elevated LC3B carrier flux upon ALK inhibition. In accordance, autophagic cargo sequestration and long-lived protein degradation significantly increased upon ALK inhibition. Intriguingly, autophagic cargo flux was dependent on VPS34 and ULK1, but not LC3B. Co-treating H3122 cells with Ceritinib and a VPS34 inhibitor or Bafilomycin A1 resulted in reduced cell numbers. Moreover, VPS34 inhibition reduced clonogenic recovery of Ceritinib-treated cells. In summary, our results indicate that ALK inhibition triggers LC3B-independent macroautophagic flux in EML4-ALK+ cells to support cancer cell survival and clonogenic growth.
Mitochondrial DNA impact on joint damaged process in a conplastic mouse model after being surgically induced with osteoarthritis
Authors: Scotece Morena , Rego-Pérez Ignacio , Lechuga-Vieco Ana Victoria , Cortés Alberto Centeno , Jiménez-Gómez María Concepción , Filgueira-Fernández Purificación , Vaamonde-García Carlos , Enríquez José Antonio , Blanco Francisco J.
Published: April 2021

It has been suggested that mitochondrial dysfunction and mtDNA variations may contribute to osteoarthritis (OA) pathogenesis. However, the causative link to support this claim is lacking. Here, we surgically-induced OA in conplastic mice in order to evaluate the functional consequences of mtDNA haplotypes in their joint degeneration. BL/6NZB strain was developed with C57BL/6JOlaHsd nuclear genome and NZB/OlaHsdmtDNA while BL/6C57, which is the original, was developed with C57BL/6JOlaHsd nuclear genome and C57/OlaHsdmtDNA for comparison. The surgical DMM OA model was induced in both strains. Their knees were processed and examined for histopathological changes. Cartilage expression of markers of autophagy, apoptosis, oxidative stress and senescence were also analyzed by immunohistochemistry. The joints of BL/6NZB mice that were operated presented more cellularity together with a reduced OARSI histopathology score, subchondral bone, menisci score and synovitis compared to those of BL/6C57 mice. This was accompanied with higher autophagy and a lower apoptosis in the cartilage of BL/6NZB mice that were operated. Therefore, the study demonstrates the functional impact of non-pathological variants of mtDNA on OA process using a surgically-induced OA model. Conplastic (BL/6NZB ) mice develop less severe OA compared to the BL/6C57original strain. These findings demonstrate that mitochondria and mtDNA are critical targets for potential novel therapeutic approaches to treat osteoarthritis.
Early loss of Scribble affects cortical development, interhemispheric connectivity and psychomotor activity
Authors: Ezan Jerome , Moreau Maité M. , Mamo Tamrat M. , Shimbo Miki , Decroo Maureen , Richter Melanie , Peyroutou Ronan , Rachel Rivka , Tissir Fadel , de Anda Froylan Calderon , Sans Nathalie , Montcouquiol Mireille
Published: April 2021

Neurodevelopmental disorders arise from combined defects in processes including cell proliferation, differentiation, migration and commissure formation. The evolutionarily conserved tumor-suppressor protein Scribble (Scrib) serves as a nexus to transduce signals for the establishment of apicobasal and planar cell polarity during these processes. Human SCRIB gene mutations are associated with neural tube defects and this gene is located in the minimal critical region deleted in the rare Verheij syndrome. In this study, we generated brain-specific conditional cKO mouse mutants and assessed the impact of the Scrib deletion on brain morphogenesis and behavior. We showed that embryonic deletion of Scrib in the telencephalon leads to cortical thickness reduction (microcephaly) and partial corpus callosum and hippocampal commissure agenesis. We correlated these phenotypes with a disruption in various developmental mechanisms of corticogenesis including neurogenesis, neuronal migration and axonal connectivity. Finally, we show that Scrib cKO mice have psychomotor deficits such as locomotor activity impairment and memory alterations. Altogether, our results show that Scrib is essential for early brain development due to its role in several developmental cellular mechanisms that could underlie some of the deficits observed in complex neurodevelopmental pathologies.
HDAC2 targeting stabilizes the CoREST complex in renal tubular cells and protects against renal ischemia/reperfusion injury
Authors: Aufhauser David D. , Hernandez Paul , Concors Seth J. , O’Brien Ciaran , Wang Zhonglin , Murken Douglas R. , Samanta Arabinda , Beier Ulf H. , Krumeich Lauren , Bhatti Tricia R. , Wang Yanfeng , Ge Guanghui , Wang Liqing , Cheraghlou Shayan , Wagner Florence F. , Holson Edward B. , Kalin Jay H. , Cole Philip A. , Hancock Wayne W. , Levine Matthew H.
Published: April 2021

Histone/protein deacetylases (HDAC) 1 and 2 are typically viewed as structurally and functionally similar enzymes present within various co-regulatory complexes. We tested differential effects of these isoforms in renal ischemia reperfusion injury (IRI) using inducible knockout mice and found no significant change in ischemic tolerance with HDAC1 deletion, but mitigation of ischemic injury with HDAC2 deletion. Restriction of HDAC2 deletion to the kidney via transplantation or PAX8-controlled proximal renal tubule-specific Cre resulted in renal IRI protection. Pharmacologic inhibition of HDAC2 increased histone acetylation in the kidney but did not extend renal protection. Protein analysis demonstrated increased HDAC1-associated CoREST protein in HDAC2-/- versus WT cells, suggesting that in the absence of HDAC2, increased CoREST complex occupancy of HDAC1 can stabilize this complex. In vivo administration of a CoREST inhibitor exacerbated renal injury in WT mice and eliminated the benefit of HDAC2 deletion. Gene expression analysis of endothelin showed decreased endothelin levels in HDAC2 deletion. These data demonstrate that contrasting effects of HDAC1 and 2 on CoREST complex stability within renal tubules can affect outcomes of renal IRI and implicate endothelin as a potential downstream mediator.
Sensory feedback-dependent coding of arm position in local field potentials of the posterior parietal cortex
Authors: VanGilder Paul , Shi Ying , Apker Gregory , Buneo Christopher A.
Published: April 2021

Although multisensory integration is crucial for sensorimotor function, it is unclear how visual and proprioceptive sensory cues are combined in the brain during motor behaviors. Here we characterized the effects of multisensory interactions on local field potential (LFP) activity obtained from the superior parietal lobule (SPL) as non-human primates performed a reaching task with either unimodal (proprioceptive) or bimodal (visual-proprioceptive) sensory feedback. Based on previous analyses of spiking activity, we hypothesized that evoked LFP responses would be tuned to arm location but would be suppressed on bimodal trials, relative to unimodal trials. We also expected to see a substantial number of recording sites with enhanced beta band spectral power for only one set of feedback conditions (e.g. unimodal or bimodal), as was previously observed for spiking activity. We found that evoked activity and beta band power were tuned to arm location at many individual sites, though this tuning often differed between unimodal and bimodal trials. Across the population, both evoked and beta activity were consistent with feedback-dependent tuning to arm location, while beta band activity also showed evidence of response suppression on bimodal trials. The results suggest that multisensory interactions can alter the tuning and gain of arm position-related LFP activity in the SPL.
Estimating, monitoring, and forecasting COVID-19 epidemics: a spatiotemporal approach applied to NYC data
Authors: Albani Vinicius V. L. , Velho Roberto M. , Zubelli Jorge P.
Published: April 2021

We propose a susceptible-exposed-infective-recovered-type (SEIR-type) meta-population model to simulate and monitor the (COVID-19) epidemic evolution. The basic model consists of seven categories, namely, susceptible (S), exposed (E), three infective classes, recovered (R), and deceased (D). We define these categories for n age and sex groups in m different spatial locations. Therefore, the resulting model contains all epidemiological classes for each age group, sex, and location. The mixing between them is accomplished by means of time-dependent infection rate matrices. The model is calibrated with the curve of daily new infections in New York City and its boroughs, including census data, and the proportions of infections, hospitalizations, and deaths for each age range. We finally obtain a model that matches the reported curves and predicts accurate infection information for different locations and age classes.
Association of blood biomarkers and autoimmunity with immune related adverse events in patients with cancer treated with immune checkpoint inhibitors
Authors: Michailidou Despina , Khaki Ali Raza , Morelli Maria Pia , Diamantopoulos Leonidas , Singh Namrata , Grivas Petros
Published: April 2021

Patients with cancer treated with immune checkpoint inhibitors (ICIs) develop immune related adverse events (irAEs), however biomarkers are lacking. We hypothesized that clinicopathologic and laboratory factors would be associated with irAE risk and overall survival (OS) in this population. In a retrospective study of patients treated with ICIs we collected clinicopathologic, laboratory, irAEs and outcomes data. The association between baseline blood biomarkers, clinicopathologic features and irAEs was assessed by logistic regression adjusting for age, sex, smoking, cancer type, performance status, concomitant other systemic therapy, history of autoimmune disease (AD), chronic infection and pre-existing systemic steroid use (regardless of dose). Optimal cutoff values of biomarkers were identified by recursive partitioning analysis. 470 patients were identified; 156 (33%) developed irAEs, which were associated with baseline absolute lymphocyte count > 2.6 k/ul (adjusted [a]OR: 4.30), absolute monocyte count > 0.29 k/ul (aOR: 2.34) and platelet count > 145 k/ul (aOR: 2.23), neutrophil to lymphocyte ratio (NLR) ≤ 5.3 (aOR: 2.07) and monocyte to lymphocyte ratio (MLR) ≤ 0.73 (aOR: 2.96), as well as platelet to lymphocyte ratio ≤ 534 (aOR: 5.05). Patients with pre-existing AD (aOR: 2.57), family history of AD (aOR: 5.98), and ICI combination (aOR: 2.00) had higher odds of irAEs. Baseline NLR ≤ 5.3 (aHR: 0.68), MLR ≤ 0.73 (aHR: 0.43), PLT > 145 (aHR: 0.48) and PLR ≤ 534 (aHR: 0.48) were associated with longer OS. irAEs were associated with autoimmune history, ICI combination and baseline laboratory measurements. Lower NLR, MLR and PLR may have favorable prognostic value. Our hypothesis-generating findings require validation in larger prospective studies.
PTEN is a predictive biomarker of trastuzumab resistance and prognostic factor in HER2-overexpressing gastroesophageal adenocarcinoma
Authors: Yokoyama Daiju , Hisamori Shigeo , Deguchi Yasunori , Nishigori Tatsuto , Okabe Hiroshi , Kanaya Seiichiro , Manaka Dai , Kadokawa Yoshio , Hata Hiroaki , Minamiguchi Sachiko , Tsunoda Shigeru , Obama Kazutaka , Sakai Yoshiharu
Published: April 2021

Poor trastuzumab (Tmab) response of patients with human epidermal growth factor receptor 2-overexpressing gastric or gastroesophageal junction adenocarcinoma (HER2-GEA) is associated with the inhibition of phosphatase and tensin homolog (PTEN) expression. In this multicenter, retrospective observational study, pathological samples of patients with HER2-GEA receiving Tmab-combined chemotherapy were immunohistochemically analyzed for PTEN expression. The primary endpoints were disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). We assessed the effect of conventional chemotherapy and Tmab alone or combined with PI3K pathway inhibitors in vitro in HER2-GEA cells with or without PTEN expression. Twenty-nine and 116 patients were in the PTEN-loss and PTEN-positive groups, respectively. In patients with the target region, DCR was significantly lower in PTEN-loss patients than in PTEN-positive patients (67% and 87%, respectively, p = 0.049). The multivariate analysis demonstrated that PTEN loss was significantly associated with shorter PFS (HR = 1.63, p = 0.035) and OS (HR = 1.83, p = 0.022). PTEN knockdown did not affect the cytostatic effect of 5-FU and cisplatin, whereas Tmab combined with the PI3K/mTOR inhibitor NPV-BEZ235 suppressed PTEN-knockdown cell proliferation. In patients with HER2-GEA, PTEN loss is a predictive biomarker of Tmab resistance and prognostic factor. Molecular-targeted therapy with a PI3K/mTOR inhibitor would be effective for HER2-GEA with PTEN loss.
Transcriptional signatures in prefrontal cortex confer vulnerability versus resilience to food and cocaine addiction-like behavior
Authors: Navandar Mohit , Martín-García Elena , Maldonado Rafael , Lutz Beat , Gerber Susanne , Ruiz de Azua Inigo
Published: April 2021

Addiction is a chronic relapsing brain disease characterized by compulsive reward-seeking despite harmful consequences. The mechanisms underlying addiction are orchestrated by transcriptional reprogramming in the reward system of vulnerable subjects. This study aims at revealing gene expression alterations across different types of addiction. We analyzed publicly available transcriptome datasets of the prefrontal cortex (PFC) from a palatable food and a cocaine addiction study. We found 56 common genes upregulated in the PFC of addicted mice in these two studies, whereas most of the differentially expressed genes were exclusively linked to either palatable food or cocaine addiction. Gene ontology analysis of shared genes revealed that these genes contribute to learning and memory, dopaminergic synaptic transmission, and histone phosphorylation. Network analysis of shared genes revealed a protein–protein interaction node among the G protein-coupled receptors (Drd2, Drd1, Adora2a, Gpr6, Gpr88) and downstream targets of the cAMP signaling pathway (Ppp1rb1, Rgs9, Pde10a) as a core network in addiction. Upon extending the analysis to a cell-type specific level, some of these common molecular players were selectively expressed in excitatory neurons, oligodendrocytes, and endothelial cells. Overall, computational analysis of publicly available whole transcriptome datasets provides new insights into the molecular basis of addiction-like behaviors in PFC.
An efficient alpha helix model and simulation framework for stationary electrostatic interaction force estimation
Authors: Butcher Guy G. , Harwin William S. , Jones Chris I.
Published: April 2021

The alpha-helix coiled-coils within talin’s rod domain have mechanical and signalling functions through their unfolding and refolding dynamics. A better understanding of talin unfolding events and the forces that are involved should allow better prediction of talin signalling. To overcome the current limitations of force measuring in molecular dynamics simulations, a new simulation framework was developed which operated directly within the force domain. Along with a corresponding alpha-helix modelling method, the simulation framework was developed drawing on robotic kinematics to specifically target force interactions. Coordinate frames were used efficiently to compartmentalise the simulation structures and static analysis was applied to determine the propagation of forces and torques through the protein structure. The results of the electrostatic approximation using Coulomb’s law shows a simulated force interaction within the physiological relevant range of 5–40 pN for the rod sub-domains of talin. This covers the range of forces talin operates in and is 2–3 orders of magnitude closer to experimentally measured values than the compared all-atom and coarse-grained molecular dynamics. This targeted, force-based simulation is, therefore, able to produce more realistic forces values than previous simulation methods.
Whole-brain mapping of monosynaptic inputs to midbrain cholinergic neurons
Authors: Huerta-Ocampo Icnelia , Dautan Daniel , Gut Nadine K. , Khan Bakhtawer , Mena-Segovia Juan
Published: April 2021

The cholinergic midbrain is involved in a wide range of motor and cognitive processes. Cholinergic neurons of the pedunculopontine (PPN) and laterodorsal tegmental nucleus (LDT) send long-ranging axonal projections that target sensorimotor and limbic areas in the thalamus, the dopaminergic midbrain and the striatal complex following a topographical gradient, where they influence a range of functions including attention, reinforcement learning and action-selection. Nevertheless, a comprehensive examination of the afferents to PPN and LDT cholinergic neurons is still lacking, partly due to the neurochemical heterogeneity of this region. Here we characterize the whole-brain input connectome to cholinergic neurons across distinct functional domains (i.e. PPN vs LDT) using conditional transsynaptic retrograde labeling in ChAT::Cre male and female rats. We reveal that input neurons are widely distributed throughout the brain but segregated into specific functional domains. Motor related areas innervate preferentially the PPN, whereas limbic related areas preferentially innervate the LDT. The quantification of input neurons revealed that both PPN and LDT receive similar substantial inputs from the superior colliculus and the output of the basal ganglia (i.e. substantia nigra pars reticulata). Notably, we found that PPN cholinergic neurons receive preferential inputs from basal ganglia structures, whereas LDT cholinergic neurons receive preferential inputs from limbic cortical areas. Our results provide the first characterization of inputs to PPN and LDT cholinergic neurons and highlight critical differences in the connectome among brain cholinergic systems thus supporting their differential roles in behavior.
CpG-ODN induced antimicrobial immunity in neonatal chicks involves a substantial shift in serum metabolic profiles
Authors: Goonewardene Kalhari Bandara , Karu Naama , Ahmed Khawaja Ashfaque , Popowich Shelly , Chow-Lockerbie Betty , Ayalew Lisanework E. , Karunarathna Ruwani , Gunawardana Thushari , Liu Mengying , Tikoo Suresh K. , Foldvari Marianna , Willson Philip , Mandal Rupasri , Wishart David S. , Gomis Susantha
Published: April 2021

Synthetic CpG-ODNs can promote antimicrobial immunity in neonatal chicks by enriching immune compartments and activating immune cells. Activated immune cells undergo profound metabolic changes to meet cellular biosynthesis and energy demands and facilitate the signaling processes. We hypothesize that CpG-ODNs induced immune activation can change the host’s metabolic demands in neonatal chicks. Here, we used NMR-based metabolomics to explore the potential of immuno-metabolic interactions in the orchestration of CpG-ODN-induced antimicrobial immunity. We administered CpG-ODNs to day-old broiler chicks via intrapulmonary (IPL) and intramuscular (IM) routes. A negative control group was administered IPL distilled water (DW). In each group (n = 60), chicks (n = 40) were challenged with a lethal dose of Escherichia coli, two days post-CpG-ODN administration. CpG-ODN administered chicks had significantly higher survival (P < 0.05), significantly lower cumulative clinical scores (P < 0.05), and lower bacterial loads (P < 0.05) compared to the DW control group. In parallel experiments, we compared NMR-based serum metabolomic profiles in neonatal chicks (n = 20/group, 24 h post-treatment) treated with IM versus IPL CpG-ODNs or distilled water (DW) control. Serum metabolomics revealed that IM administration of CpG-ODN resulted in a highly significant and consistent decrease in amino acids, purines, betaine, choline, acetate, and a slight decrease in glucose. IPL CpG-ODN treatment resulted in a similar decrease in purines and choline but less extensive decrease in amino acids, a stronger decrease in acetate, and a considerable increase in 2-hydroxybutyrate, 3-hydroxybutyrate, formic acid and a mild increase in TCA cycle intermediates (all P < 0.05 after FDR adjustment). These perturbations in pathways associated with energy production, amino acid metabolism and nucleotide synthesis, most probably reflect increased uptake of nutrients to the cells, to support cell proliferation triggered by the innate immune response. Our study revealed for the first time that CpG-ODNs change the metabolomic landscape to establish antimicrobial immunity in neonatal chicks. The metabolites highlighted in the present study can help future targeted studies to better understand immunometabolic interactions and pinpoint the key molecules or pathways contributing to immunity.
High sensitivity sanger sequencing detection of BRAF mutations in metastatic melanoma FFPE tissue specimens
Authors: Cheng Lauren Y. , Haydu Lauren E. , Song Ping , Nie Jianyi , Tetzlaff Michael T. , Kwong Lawrence N. , Gershenwald Jeffrey E. , Davies Michael A. , Zhang David Yu
Published: April 2021

Mutations in the BRAF gene at or near the p. V600 locus are informative for therapy selection, but current methods for analyzing FFPE tissue DNA generally have a limit of detection of 5% variant allele frequency (VAF), or are limited to the single variant (V600E). These can result in false negatives for samples with low VAFs due to low tumor content or subclonal heterogeneity, or harbor non-V600 mutations. Here, we show that Sanger sequencing using the NuProbe VarTrace BRAF assay, based on the Blocker Displacement Amplification (BDA) technology, is capable of detecting BRAF V600 mutations down to 0.20% VAF from FFPE lymph node tissue samples. Comparison experiments on adjacent tissue sections using BDA Sanger, immunohistochemistry (IHC), digital droplet PCR (ddPCR), and NGS showed 100% concordance among all 4 methods for samples with BRAF mutations at ≥ 1% VAF, though ddPCR did not distinguish the V600K mutation from the V600E mutation. BDA Sanger, ddPCR, and NGS (with orthogonal confirmation) were also pairwise concordant for lower VAF mutations down to 0.26% VAF, but IHC produced a false negative. Thus, we have shown that Sanger sequencing can be effective for rapid detection and quantitation of multiple low VAF BRAF mutations from FFPE samples. BDA Sanger method also enabled detection and quantitation of less frequent, potentially actionable non-V600 mutations as demonstrated by synthetic samples.
Phosphopeptide interactions of the Nbs1 N-terminal FHA-BRCT1/2 domains
Authors: Kim Kyungmin , Kirby Thomas W. , Perera Lalith , London Robert E.
Published: April 2021

Human Nbs1, a component of the MRN complex involved in DNA double strand break repair, contains a concatenated N-terminal FHA-BRCT1/2 sequence that supports interaction with multiple phosphopeptide binding partners. MDC1 binding localizes Nbs1 to the damage site, while binding of CDK-phosphorylated CtIP activates additional ATM-dependent CtIP phosphorylation, modulating substrate-dependent resection. We have investigated the phosphopeptide binding characteristics of Nbs1 BRCT1/2 based on a molecular modeling approach that revealed structural homology with the tandem TopBP1 BRCT7/8 domains. Relevance of the model was substantiated by the ability of TopBP1-binding FANCJ phosphopeptide to interact with hsNbsBRCT1/2, albeit with lower affinity. The modeled BRCT1/2 is characterized by low pSer/pThr selectivity, preference for a cationic residue at the + 2 position, and an inter-domain binding cleft selective for hydrophobic residues at the + 3/ + 4 positions. These features provide insight into the basis for interaction of SDT motifs with the BRCT1/2 domains and allowed identification of CtIP pSer347- and pThr847-containing phosphopeptides as high and lower affinity ligands, respectively. Among other binding partners considered, rodent XRCC1 contains an SDT sequence in the second linker consistent with high-affinity Nbs1 binding, while human XRCC1 lacks this motif, but contains other phosphorylated sequences that exhibit low-affinity binding.
Hedgehog interacting protein (HHIP) represses airway remodeling and metabolic reprogramming in COPD-derived airway smooth muscle cells
Authors: Li Yan , Zhang Li , Polverino Francesca , Guo Feng , Hao Yuan , Lao Taotao , Xu Shuang , Li Lijia , Pham Betty , Owen Caroline A. , Zhou Xiaobo
Published: April 2021

Although HHIP locus has been consistently associated with the susceptibility to COPD including airway remodeling and emphysema in genome-wide association studies, the molecular mechanism underlying this genetic association remains incompletely understood. By utilizing Hhip+/- mice and primary human airway smooth muscle cells (ASMCs), here we aim to determine whether HHIP haploinsufficiency increases airway smooth muscle mass by reprogramming glucose metabolism, thus contributing to airway remodeling in COPD pathogenesis. The mRNA levels of HHIP were compared in normal and COPD-derived ASMCs. Mitochondrial oxygen consumption rate and lactate levels in the medium were measured in COPD-derived ASMCs with or without HHIP overexpression as readouts of glucose oxidative phosphorylation and aerobic glycolysis rates. The proliferation rate was measured in healthy and COPD-derived ASMCs treated with or without 2-DG. Smooth muscle mass around airways was measured by immunofluorescence staining for α-smooth muscle actin (α-SMA) in lung sections from Hhip+/- mice and their wild type littermates, Hhip+/+ mice. Airway remodeling was assessed in Hhip+/- and Hhip+/- mice exposed to 6 months of cigarette smoke. Our results show HHIP inhibited aerobic glycolysis and represses cell proliferation in COPD-derived ASMCs. Notably, knockdown of HHIP in normal ASMCs increased PKM2 activity. Importantly, Hhip+/- mice demonstrated increased airway remodeling and increased intensity of α-SMA staining around airways compared to Hhip+/+ mice. In conclusion, our findings suggest that HHIP represses aerobic glycolysis and ASMCs hyperplasia, which may contribute to the increased airway remodeling in Hhip+/- mice.
Low serum klotho concentration is associated with worse cognition, psychological components of frailty, dependence, and falls in nursing home residents
Authors: Sanz Begoña , Arrieta Haritz , Rezola-Pardo Chloe , Fernández-Atutxa Ainhoa , Garin-Balerdi Jon , Arizaga Nagore , Rodriguez-Larrad Ana , Irazusta Jon
Published: April 2021

Serum alpha-klotho (s-klotho) protein has been linked with lifespan, and low concentrations of s-klotho have been associated with worse physical and cognitive outcomes. Although its significance in aging remains unclear, s-klotho has been proposed as a molecular biomarker of frailty and dependence. This study is a secondary analysis of data from a clinical trial performed in a population of 103 older individuals living in 10 nursing homes in Gipuzkoa (Spain). We aimed to elucidate associations between s-klotho (as measured by enzyme-linked immunosorbent assay) and body composition, physical fitness, and cognition, as well as frailty and dependence (determined using validated tests and scales). In addition, we investigated the association of s-klotho concentration with falls in the six months following the initial assessment. Low s-klotho levels were associated with a lower score in the psychological component of the Tilburg Frailty Indicator, a worse score in the Coding Wechsler Adult Intelligence Scale, and a greater dependence in activities of daily living. Moreover, participants with lower s-klotho concentrations suffered more falls during the 6 months after the assessment. Future translational research should aim to validate klotho’s putative role as a biomarker that could identify the risk of aging-related adverse events in clinical practice.