bluuebunny/crossref_metadata_2025 huggingface dataset:
Endocervical Adenocarcinoma, Gross Examination, and Processing, Including Intraoperative Evaluation: Recommendations From the International Society of Gynecological Pathologists
Authors: Parra-Herran Carlos , Malpica Anais , Oliva Esther , Zannoni Gian Franco , Ramirez Pedro T. , Rabban Joseph T.
Published: February 2021

The International Society of Gynecological Pathologists (ISGyP) Endocervical Adenocarcinoma Project aims to provide evidence-based guidance for the pathologic evaluation, classification, and reporting of endocervical adenocarcinoma. This review presents the recommendations pertaining to gross evaluation and intraoperative consultation of specimens obtained from patients in the setting of cervical cancer. The recommendations are the product of review of published peer-reviewed evidence, international guidelines and institutional grossing manuals, as well as deliberation within this working group. The discussion presented herein details the approach to the different specimen types encountered in practice: loop electrosurgical excision procedure, cone, trachelectomy, radical hysterectomy, pelvic exenteration, and lymphadenectomy specimens. Guidelines for intraoperative evaluation of trachelectomy and sentinel lymph node specimens are also addressed. Correlation with ISGyP recommendations on cancer staging, which appear as a separate review in this issue, is also included when appropriate. While conceived in the framework of endocervical adenocarcinoma, most of the discussion and recommendations can also be applied to other cervical malignancies.
The Role of Predictive Biomarkers in Endocervical Adenocarcinoma: Recommendations From the International Society of Gynecological Pathologists
Authors: Bosse Tjalling , Lax Sigurd , Abu-Rustum Nadeem , Matias-Guiu Xavier
Published: February 2021

To review the scientific evidence related to predictive biomarkers in cervical adenocarcinoma (ADC). The authors reviewed the literature regarding predictive biomarkers in cervical ADC. There were several limitations: (1) there is an overlap between predictive and prognostic biomarkers, as the vast majority of patients are treated with anticancer strategies; (2) in many studies and clinical trials, cervical ADC patients are included in a large series of patients predominantly composed of cervical squamous cell carcinomas; and (3) in most of the studies, and clinical trials, there is no distinction between human papillomavirus (HPV)-associated and HPV-independent cervical ADCs, or between various histologic subtypes. Results obtained from a small group of studies confirm that cervical ADCs exhibit distinct molecular features as compared with squamous carcinomas, and that there are different molecular features between different types of cervical ADCs. Promising areas of interest include ERBB2 (HER2) mutations and PD-L1 expression as predictive biomarkers for anti-HER2 treatment and immunotherapy, respectively. To date, no definitive data can be obtained from the literature regarding predictive biomarkers for cervical ADC. Clinical trials specifically designed for endocervical ADC patients are required to elucidate the predictive value of HER2 mutations and PD-L1 expression. The distinction between HPV-associated and HPV-independent cervical ADCs as well as early involvement of pathologists in the design of future clinical trials are needed to identify new predictive biomarkers in cervical ADC.
Viroselect: A novel SARS-CoV-2 detection assay to resolve inconclusive samples
Authors: Jawade Ketki , Sinha Akhauri Yash , Bhagat Sharad , Bhowmick Shilpa , Chauhan Bhagyashree , Kaginkar Snehal , Palav Harsha , Kasarpalkar Nandini , Devadiga Pratik , Karandikar Kalyani , Agarwal Sachee , Shastri Jayanthi , Munne Kiran , Bhor Vikrant M , Mahale Smita D , Bhowmik Subhanjan , Jagtap Dhanashree , Patel Vainav
Published: February 2021

Background

India bears the second largest burden of SARS-CoV-2 infection. A multitude of RT-PCR detection assays with disparate gene targets including automated high throughput platforms are available. Varying concordance and interpretation of diagnostic results in this setting can result in significant reporting delays leading to suboptimal disease management. Here, we report the development of a novel ORF-1a based SARS-CoV-2 RT-PCR assay, Viroselect, showing high concordance with conventional assays and the ability to resolve inconclusive results generated during the peak of the epidemic in Mumbai, India.

Methods

We identified a unique target region within SARS-CoV-2 ORF1a, non-structural protein (nsp3), that was used to design and develop our assay. This hypervariable region (1933-3956) between SARS-CoV-2, SARS-CoV, and MERS-COV was utilized to design our primers and probe for RT-PCR assay. We further evaluated concordance of our assay with commonly used EUA (USFDA) manual kits as well as an automated high throughput testing platform. Further, a retrospective analysis using Viroselect on samples reported as ‘inconclusive’ during April-October 2020 was carried out.

Results

A total of 701 samples were tested. Concordance analysis of 477 samples demonstrated high overall agreement of Viroselect assay with both manual (87.6%; 95% CI) as well as automated (84.7%; 95% CI) testing assays. Also, in the retrospective analysis of 224 additional samples reported as ‘inconclusive’, Viroselect was able to resolve 100% (19/19) and 93.7% (192/205) samples which were termed inconclusive by manual and automated high throughput platform respectively.

Conclusion

We show that Viroselect had high concordance with conventional assays, both manual and automated, as well as highlight its potential in resolving inconclusive samples.
ParticleChromo3D: A Particle Swarm Optimization Algorithm for Chromosome and Genome 3D Structure Prediction from Hi-C Data
Authors: Vadnais David , Middleton Michael , Oluwadare Oluwatosin
Published: February 2021

The three-dimensional (3D) structure of chromatin has a massive effect on its function. Because of this, it is desirable to have an understanding of the 3D structural organization of chromatin. To gain greater insight into the spatial organization of chromosomes and genomes and the functions they perform, chromosome conformation capture techniques, particularly Hi-C, have been developed. The Hi-C technology is widely used and well-known because of its ability to profile interactions for all read pairs in an entire genome. The advent of Hi-C has greatly expanded our understanding of the 3D genome, genome folding, gene regulation and has enabled the development of many 3D chromosome structure reconstruction methods. Here, we propose a novel approach for 3D chromosome and genome structure reconstruction from Hi-C data using Particle Swarm Optimization approach called ParticleChromo3D. This algorithm begins with a grouping of candidate solution locations for each chromosome bin, according to the particle swarm algorithm, and then iterates its position towards a global best candidate solution. While moving towards the optimal global solution, each candidate solution or particle uses its own local best information and a randomizer to choose its path. Using several metrics to validate our results, we show that ParticleChromo3D produces a robust and rigorous representation of the 3D structure for input Hi-C data. We evaluated our algorithm on simulated and real Hi-C data in this work. Our results show that ParticleChromo3D is more accurate than most of the existing algorithms for 3D structure reconstruction. Our results also show that constructed ParticleChromo3D structures are very consistent, hence indicating that it will always arrive at the global solution at every iteration. The source code for ParticleChromo3D, the simulated and real Hi-C datasets, and the models generated for these datasets are available here:https://github.com/OluwadareLab/ParticleChromo3D
Rheb-mTOR Activation Rescues Amyloid Beta-Induced Cognitive Impairment and Memory Function by Restoring miR-146 Activity in Glial Cells
Authors: De Dipayan , Mukherjee Ishita , Guha Subhalakshmi , Paidi Ramesh Kumar , Chakrabarti Saikat , Biswas Subhas C. , Bhattacharyya Suvendra N.
Published: February 2021

Deposition of amyloid beta plaques in adult rat or human brain is associated with increased production of proinflammatory cytokines by associated glial cells that are responsible for degeneration of the diseased tissue. The expression of these cytokines is usually under check and is controlled at post-transcriptional level via several microRNAs. Computational analysis of gene expression profiles of cortical regions of Alzheimer’s disease patients brain suggests ineffective target cytokine mRNA suppression by existing microRNPs in diseased brain. Exploring the mechanism of amyloid beta induced cytokine expression, we have identified how the inactivation of the repressive miR-146 microRNPs causes increased production of cytokines in amyloid beta exposed glial cells. In exploration of the cause of miRNP inactivation, we have noted amyloid beta oligomer induced sequestration of mTORC1 complex to early endosomes that results in decreased Ago2 phosphorylation, limited Ago2-miRNA uncoupling and retarded Ago2-cytokine mRNA interaction in rat astrocyte cells. Interestingly, constitutive activation of mTORC1 by Rheb activator restricts proinflammatory cytokine production by reactivating miR-146 microRNPs in amyloid beta exposed glial cells to rescue the disease phenotype in thein vivorat model of Alzheimer’s disease.
Charting the human amygdala development across childhood and adolescence: Manual and automatic segmentation
Authors: Zhou Quan , Liu Siman , Jiang Chao , He Ye , Zuo Xi-Nian
Published: February 2021

The developmental pattern of the amygdala throughout childhood and adolescence has been inconsistently reported in previous neuroimaging studies. Given the relatively small size of the amygdala on full brain MRI scans, discrepancies may be partly due to methodological differences in amygdalar segmentation. To investigate the impact of volume extraction methods on amygdala volume, we comparedFreeSurfer, FSLandvolBrainsegmentation measurements with those obtained by manual tracing. The manual tracing method, which we used as the ‘gold standard’, exhibited almost perfect intra- and inter-rater reliability. We observed systematic differences in amygdala volumes between automatic (FreeSurferandvolBrain) and manual methods. Specifically, compared with the manual tracing,FreeSurferestimated larger amygdalae, andvolBrainproduced smaller amygdalae whileFSLdemonstrated a mixed pattern. The tracing bias was not uniform, but higher for smaller amygdalae. We further modeled amygdalar growth curves using accelerated longitudinal cohort data from the Chinese Color Nest Project. Trajectory modeling and statistical assessments of the manually traced amygdalae revealed linearly increasing and parallel developmental patterns for both girls and boys, although the amygdalae of boys were larger than those of girls. Compared to these trajectories, the shapes of developmental curves were similar when using thevolBrainderived volumes.FreeSurferderived trajectories had more nonlinearities and appeared flatter.FSLderived trajectories demonstrated an inverted U shape and were significantly different from those derived from manual tracing method. The use of amygdala volumes adjusted for total gray-matter volumes, but not intracranial volumes, resolved the shape discrepancies and led to reproducible growth curves curves between manual tracing and the automatic methods (exceptFSL). Our findings revealed steady growth of the human amygdala, mirroring its functional development across the school age. Methodological improvements are warranted for current automatic tools to achieve more accurate tracing of the amygdala at school age, calling for next generation tools.
COVID-19-related symptoms 6 months after the infection - Update on a prospective cohort study in Germany
Authors: Rauch Barbara , Kern-Matschilles Stefanie , Haschka Stefanie J. , Sacco Vanessa , Potzel Anne L. , Banning Friederike , Benz Irina , Meisel Mandy , Seissler Jochen , Gar Christina , Lechner Andreas
Published: February 2021

Objective

Many anecdotal reports indicate the presence of ‘long COVID’ – COVID-19-related symptoms weeks to months after the acute illness. However, frequency and symptom-pattern of ‘long COVID’ in relation to acute disease severity are uncertain. As part of an ongoing, prospective cohort study we therefore conducted an online survey among adults 6 months after acute COVID-19.

Methods

The prospective online study Life&Covid is ongoing in Germany since May 2020. Participants were recruited 0 to 4 months after their SARS-CoV-2 infection und followed up by subsequent surveys. The survey 6 months after the infection was completed by 127 out of 148 individuals invited by email (86%). All grades of acute disease severity were included and 91% of the participants had been treated as outpatients during their acute illness.

Results

Six months after the infection, 67% of the study participants reported at least one symptom as a consequence of COVID-19. Exertional dyspnea (30% of participants), fatigue (25%) and diminished sense of taste/smell (19%) were the most common individual symptoms. At least one symptom, exertional dyspnea, and fatigue were reported more often after a severe acute illness, but diminished sense of taste/smell was unrelated to acute severity. Age group and sex did not associate with the frequency of symptoms at 6 months.

Conclusions

Based on this study, the prevalence of COVID-19-related symptoms 6 months after the infection is high. Some bias for overestimation may have affected this result. Nevertheless, ‘long COVID’ requires attention in medical care and a better scientific understanding.
An alternative approach for bioanalytical assay development for wastewater-based epidemiology of SARS-CoV-2
Authors: Tim Boogaerts , Jacobs Lotte , De Roeck Naomi , Van den Bogaert Siel , Aertgeerts Bert , Lahousse Lies , van Nuijs Alexander L.N. , Delputte Peter
Published: February 2021

Wastewater-based epidemiology could be applied to track down SARS-CoV-2 outbreaks at high spatio-temporal resolution and could potentially be used as an early-warning for emergence of SARS-CoV-2 circulation in the general population. Epidemiological surveillance of SARS-CoV-2 could play a role in monitoring the spread of the virus in the population and controlling possible outbreaks. However, sensitive sample preparation and detection methods are necessary to detect trace levels of SARS-CoV-2 RNA in influent wastewater (IWW).

Unlike predecessors, method development of a SARS-CoV-2 RNA concentration and detection procedure was performed with IWW samples with high viral SARS-CoV-2 loads (in combination with seeding IWW with a surrogate coronavirus). This is of importance since the SARS-CoV-2 genome in IWW might have already been subject to in-sewer degradation into smaller genome fragments or might be present in a different form (e.g. cell debris,…). Centricon Plus-70 (100 kDa) centrifugal filter devices resulted in the lowest and most reproducible Ct-values for SARS-CoV-2 RNA. Lowering pore sizes did not improve our limit of detection and quantification. Real-time polymerase chain reaction (qPCR) was employed for the amplification of the N1, N2, N3 and E_Sarbeco-gene.

This is one of the first studies to apply digital polymerase chain reaction (dPCR) for the detection of SARS-CoV-2 RNA in IWW. Interestingly, qPCR results were comparable with dPCR results suggesting that qPCR is a valid method. In this study, dPCR was also used as a proxy to assess the precision of qPCR. In this light, dPCR showed high variability at low concentration levels (100 copies/µL), indicating that variability in bioanalytical assays for SARS-CoV-2 RNA might be substantial.

On average, the N2-gene showed high in-sample stability in IWW for 10 days of storage at 4 °C. Between-sample variability was substantial due to the low native concentrations in IWW. Additionally, the E-gene proved to be less stable compared to the N2-gene and showed higher variability. Freezing the IWW samples resulted in a 10-fold decay of loads of the N2- and E-gene in IWW.

Although WBE can already aid in filling some knowledge gaps in the epidemiological surveillance of SARS-CoV-2, future WBE studies should aim to further validate and standardize bioanalytical assays, especially with regards to methodological limitations.

Highlights

Development of an analytical procedure for detection of SARS-CoV-2 RNA in wastewater

Extraction recovery was evaluated in influent wastewater

Precision measured with dPCR used as a proxy for qPCR

qPCR of the N2 gene fragment showed high in-sample stability of SARS-CoV-2 on average
Emergence in late 2020 of multiple lineages of SARS-CoV-2 Spike protein variants affecting amino acid position 677
Authors: Hodcroft Emma B. , Domman Daryl B. , Snyder Daniel J. , Oguntuyo Kasopefoluwa Y. , Van Diest Maarten , Densmore Kenneth H. , Schwalm Kurt C. , Femling Jon , Carroll Jennifer L. , Scott Rona S. , Whyte Martha M. , Edwards Michael W. , Hull Noah C. , Kevil Christopher G. , Vanchiere John A. , Lee Benhur , Dinwiddie Darrell L. , Cooper Vaughn S. , Kamil Jeremy P.
Published: February 2021

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S) plays critical roles in host cell entry. Non-synonymous substitutions affecting S are not uncommon and have become fixed in a number of SARS-CoV-2 lineages. A subset of such mutations enable escape from neutralizing antibodies or are thought to enhance transmission through mechanisms such as increased affinity for the cell entry receptor, angiotensin-converting enzyme 2 (ACE2). Independent genomic surveillance programs based in New Mexico and Louisiana contemporaneously detected the rapid rise of numerous clade 20G (lineage B.1.2) infections carrying a Q677P substitution in S. The variant was first detected in the US on October 23, yet between 01 Dec 2020 and 19 Jan 2021 it rose to represent 27.8% and 11.3% of all SARS-CoV-2 genomes sequenced from Louisiana and New Mexico, respectively. Q677P cases have been detected predominantly in the south central and southwest United States; as of 03 Feb 2021, GISAID data show 499 viral sequences of this variant from the USA. Phylogenetic analyses revealed the independent evolution and spread of at least six distinct Q677H sub-lineages, with first collection dates ranging from mid-August to late November 2020. Four 677H clades from clade 20G (B.1.2), 20A (B.1.234), and 20B (B.1.1.220, and B.1.1.222) each contain roughly 100 or fewer sequenced cases, while a distinct pair of clade 20G clusters are represented by 754 and 298 cases, respectively. Although sampling bias and founder effects may have contributed to the rise of S:677 polymorphic variants, the proximity of this position to the polybasic cleavage site at the S1/S2 boundary are consistent with its potential functional relevance during cell entry, suggesting parallel evolution of a trait that may confer an advantage in spread or transmission. Taken together, our findings demonstrate simultaneous convergent evolution, thus providing an impetus to further evaluate S:677 polymorphisms for effects on proteolytic processing, cell tropism, and transmissibility.
Anaerobic oxidation of methane in sediments of a nitrate-rich, oligo-mesotrophic boreal lake
Authors: Rissanen Antti J , Jilbert Tom , Simojoki Asko , Mangayil Rahul , Aalto Sanni L , Peura Sari , Jäntti Helena
Published: February 2021

The identity of electron acceptors in promoting anaerobic oxidation of methane (AOM) in the sediments of boreal lakes is currently unknown. Here, we studied the AOM rate of sediment slurries collected from three profundal stations of a nitrate-rich, oligo-mesotrophic, boreal lake (Lake Pääjärvi, Finland), under varying nitrate concentrations using13C-labelling. Furthermore, vertical profiles of the sediment and porewater geochemistry, and the microbial communities (16S rRNA gene and shotgun metagenomic sequencing) were analyzed. Despite geochemical data indicating that simultaneous consumption of nitrate and methane took place at the sediment layers chosen for incubations, AOM rate was not enhanced by nitrate amendments at either of the stations. AOM rate was much higher at the shallow Station 1 (0.9-6.8 nmol C cm-3d-1) with high contents of labile phytoplankton-derived organic matter, than at the deeper stations, Station 2 (0-0.3 nmol C cm-3d-1) and 3 (0-0.2 nmol C cm-3d-1). Accordingly, a higher relative abundance of methanotrophic archaea (CandidatusMethanoperedens) and bacteria (Methylococcales) were observed in the layers chosen for incubations at Station 1 than at the other stations. Besides nitrate, the geochemical profiles indicated that AOM was potentially coupled with iron or sulfate reduction at all stations. Furthermore, putative nitrite-reducing methanotrophs (Ca. Methylomirabilis) were the most abundant methanotrophs above the incubation layer at Station 2 and 3, which suggests that nitrite reduction also plays a role in driving AOM in the study lake. We conclude that AOM is not uniquely coupled to nitrate reduction in sediments of nitrate-rich, oligo-mesotrophic, boreal lakes.
Evaluating Sleep Disturbances in Children with Rare Genetic Neurodevelopmental Syndromes
Authors: Veatch Olivia J. , Malow Beth A. , Lee Hye-Seung , Knight Aryn , Barrish Judy O. , Neul Jeffrey L. , Lane Jane B. , Skinner Steven A. , Kaufmann Walter E. , Miller Jennifer L. , Driscoll Daniel J. , Bird Lynne M. , Butler Merlin G. , Dykens Elisabeth M. , Gold June-Anne , Kimonis Virginia , Bacino Carlos A. , Tan Wen-Hann , Kothare Sanjeev V. , Peters Sarika U. , Percy Alan K. , Glaze Daniel G.
Published: February 2021

Background

Adequate sleep is important for proper neurodevelopment and positive health outcomes. Sleep disturbances are more prevalent in children with genetically determined neurodevelopmental syndromes compared to typically developing counterparts. We characterize sleep behavior in Rett (RTT), Angelman (AS) and Prader-Willi (PWS) syndromes in order to identify effective approaches for treating sleep problems in these populations. We compared sleep-related symptoms across individuals with these different syndromes to each other, and to typically developing controls.

Methods

Children were recruited from the Rare Diseases Clinical Research Network (RDCRN) consortium registries; unaffected siblings were enrolled as related controls. For each participant, a parent completed multiple sleep questionnaires including: Pediatric Sleep Questionnaire (Sleep-Disordered Breathing [SDB]); Children’s Sleep Habits Questionnaire; Pediatric Daytime Sleepiness Scale.

Results

Sleep data were analyzed from 714 participants, ages 2-18 years. Young children with AS had more reported sleep problems than children with RTT or PWS. Older children with RTT had more reported daytime sleepiness than those with AS or PWS. Finally, all individuals with RTT had more evidence of sleep-disordered breathing when compared to individuals with PWS. Notably, typically developing siblings were also reported to have sleep problems, except for sleep-related breathing disturbances which were associated with each of the genetic syndromes.

Conclusions

Individuals with RTT, AS and PWS frequently experience sleep problems, including sleep-disordered breathing. Screening for sleep problems in individuals with these and other neurogenetic disorders should be included in clinical assessment and managements. These data may also be useful in developing treatment strategies and in clinical trials.
Epigenetic changes with age primes mammary luminal epithelia for cancer initiation
Authors: Sayaman Rosalyn W. , Miyano Masaru , Senapati Parijat , Shalabi Sundus , Zirbes Arrianna , Todhunter Michael E. , Seewaldt Victoria , Neuhausen Susan L. , Stampfer Martha R. , Schones Dustin E. , LaBarge Mark A.
Published: February 2021

Aging causes molecular changes that manifest as stereotypical phenotypes yet aging-associated diseases progress only in certain individuals. At lineage-specific resolution, we show how stereotyped and variant responses are integrated in mammary epithelia. Age-dependent directional changes in gene expression and DNA methylation (DNAm) occurred almost exclusively in luminal cells and implicated genome organizersSATB1andCTCF. DNAm changes were robust indicators of aging luminal cells, and were either directly (anti-)correlated with expression changes or served as priming events for subsequent dysregulation, such as demethylation ofESR1-binding regions in DNAm-regulatoryCXXC5in older luminal cells and luminal-subtype cancers. Variance-driven changes in the transcriptome of both luminal and myoepithelial lineages further contributed to age-dependent loss of lineage fidelity. The pathways affected by transcriptomic and DNAm changes during aging are commonly linked with breast cancer, and together with the differential variability found across individuals, influence aging-associated cancer susceptibility in a subtype-specific manner.
Impaired clock gene expression and abnormal diurnal regulation of hippocampal inhibitory transmission and spatial memory in a mouse model of Alzheimer’s disease
Authors: Fusilier Allison R. , Davis Jennifer A. , Paul Jodi R. , Yates Stefani D. , McMeekin Laura J. , Goode Lacy K. , Mokashi Mugdha V. , van Groen Thomas , Cowell Rita M. , McMahon Lori L. , Roberson Erik D. , Gamble Karen L.
Published: February 2021

Patients with Alzheimer’s disease (AD) often have fragmentation of sleep/wake cycles and disrupted 24-h (circadian) activity. Despite this, little work has investigated the potential underlying day/night disruptions in cognition and neuronal physiology in the hippocampus. The molecular clock, an intrinsic transcription-translation feedback loop that regulates circadian behavior, may also regulate hippocampal neurophysiological activity. We hypothesized that disrupted diurnal variation in clock gene expression in the hippocampus corresponds with loss of normal day/night differences in membrane excitability, synaptic physiology, and cognition. We previously reported that the Tg-SwDI mouse model of AD has disrupted circadian locomotor rhythms and neurophysiological output of the suprachiasmatic nucleus (the primary circadian clock). Here, we report that Tg-SwDI mice failed to show day-night differences in a spatial working memory task, unlike wild-type controls that exhibited enhanced spatial working memory at night. Moreover, Tg-SwDI mice had lower levels of Per2, one of the core components of the molecular clock, at both mRNA and protein levels when compared to age-matched controls. Interestingly, we discovered neurophysiological impairments in area CA1 of the Tg-SwDI hippocampus. In controls, spontaneous inhibitory post-synaptic currents (sIPSCs) in pyramidal cells showed greater amplitude and lower inter-event interval during the day than the night. However, the normal day/night differences in sIPSCs were absent (amplitude) or reversed (inter-event interval) in pyramidal cells from Tg-SwDI mice. In control mice, current injection into CA1 pyramidal cells produced more firing during the night than during the day, but no day/night difference in excitability was observed in Tg-SwDI mice. The normal day/night difference in excitability in controls was blocked by GABA receptor inhibition. Together, these results demonstrate that the normal diurnal regulation of inhibitory transmission in the hippocampus is diminished in a mouse model of AD, leading to decreased daytime inhibition onto hippocampal CA1 pyramidal cells. Uncovering disrupted day/night differences in circadian gene regulation, hippocampal physiology, and memory in AD mouse models may provide insight into possible chronotherapeutic strategies to ameliorate Alzheimer’s disease symptoms or delay pathological onset.
The effect of resource depletion on the thermal response of mosquito population fitness
Authors: Huxley Paul J. , Murray Kris A. , Cator Lauren J. , Pawar Samraat
Published: February 2021

The temperature-dependencies of life history traits are increasingly being used to predict how climatic warming will affect vector-borne disease dynamics, partially by affecting the abundance dynamics of the vector population. Such predictions generally arise from mathematical models that incorporate the temperature dependence of traits measured under laboratory conditions. These temperature-trait relationships are typically estimated from juvenile populations reared under optimal resource conditions, even though natural populations experience intermittent resource depletion. Using laboratory experiments on the mosquitoAedes aegypti, combined with a stage-structured population model, we show that resource depletion in the juvenile habitat can significantly depress the vector’s maximal population growth rate (rm) across the entire temperature range, cause it to peak at a lower temperature, and narrow its thermal niche width. Our results provide compelling evidence for future studies to consider resource depletion when predicting the effects of global change on vector-borne disease transmission, disease vectors and other arthropods.
Stress diminishes outcome but enhances response representations during instrumental learning
Authors: Meier Jacqueline Katharina , Staresina Bernhard P. , Schwabe Lars
Published: February 2021

Stress may shift behavioural control from a goal-directed system that encodes action-outcome relationships to a habit system that learns stimulus-response associations. Although this shift to habits is highly relevant for stress-related psychopathologies, limitations of existing behavioural paradigms hindered previous research to answer the fundamental question of whether the stress-induced bias to habits is due to impaired goal-directed or enhanced habitual processing (or both). Here, we leveraged EEG-based multivariate pattern analysis to decode neural outcome representations, crucial for goal-directed control, and response representations, essential for habitual responding, during instrumental learning. We show that stress reduces outcome representations but enhances response representations, both of which were directly associated with a behavioural index of habitual responding. Further, changes in outcome and response representations were uncorrelated, suggesting that these may reflect distinct processes. Our findings indicate that habit behaviour under stress is the result of both enhanced habitual and diminished goal-directed processing.
Impact of an oral amino acid provision on Achilles peritendinous amino acid concentrations in young and older adults
Authors: Carroll Chad C. , Couture Samantha , Farino Dominick O. , Patel Shivam H. , Campbell Nathan W.C. , Stout Julianne , Sabbaghi Arman
Published: February 2021

Recent studies have indicated that consumption of amino acid-rich compounds can increase tendon collagen content and enhance biomechanical function. Still, it is not clear as to what extent oral consumption of amino acids alters peritendinous amino acid concentrations. Whether aging alters the delivery of amino acids to tendon tissue after oral consumption is also not known. Using microdialysis, we determined the impact of a single oral essential amino acid bolus on Achilles peritendinous amino acid concentrations in younger (n=7; 27±1 yr.) and older adults (n=6; 68±2 yrs.) over four hours. The peritendinous concentration of all amino acids in the beverage except methionine (p=0.136) and glycine (p=0.087) increased with time (p<0.05). Additionally, the concentrations of glycine and arginine were greater in older adults (p≤0.05). We also accessed the impact of amino acid consumption on peritendinous concentrations of pro-collagen Iα1, a marker of collagen synthesis. Pro-collagen Iα1 tended to change with time (p=0.071) but was not altered age (p=0.226). We demonstrate that an oral amino acid bolus leads to modest increases in Achilles peritendinous amino acid concentrations in young and older adults. The concentration of some amino acids was also greater in older adults. However, the amino acid bolus did not significantly impact peritendinous pro-collagen concentrations.
Streamlining differential exon and 3’ UTR usage with diffUTR
Authors: Gerber Stefan , Schratt Gerhard , Germain Pierre-Luc
Published: February 2021

Background

Despite the importance of alternative poly-adenylation and 3’ UTR length for a variety of biological phenomena, there are limited means of detecting UTR changes from standard transcriptomic data.

Results

We present thediffUTRBioconductor package which streamlines and improves upon differential exon usage (DEU) analyses, and leverages existing DEU tools and alternative polyadenylation site databases to enable differential 3’ UTR usage analysis. We demonstrate thediffUTRfeatures and show that it is more flexible and more accurate than state-of-the-art alternatives, both in simulations and in real data.

Conclusions

diffUTRenables differential 3’ UTR analysis and more generally facilitates DEU and the exploration of their results.
Cholinergic signalling at the body wall neuromuscular junction couples to distal inhibition of feeding inC. elegans
Authors: Izquierdo Patricia G. , Thisainathan Thibana , Atkins James H. , Lewis Christian J. , Tattersall John E.H. , Green A. Christopher , Holden-Dye Lindy , O’Connor Vincent
Published: February 2021

Complex biological functions within organisms are frequently orchestrated by systemic communication between tissues. In the model organismC. elegans, the pharyngeal and body wall neuromuscular junctions are two discrete structures that control feeding and locomotion, respectively. These distinct tissues are controlled by separate, well-defined neural circuits. Nonetheless, the emergent behaviours, feeding and locomotion, are coordinated to guarantee the efficiency of food intake. We show that pharmacological hyperactivation of cholinergic transmission at the body wall muscle reduces the rate of pumping behaviour. This was evidenced by a systematic screening of the cholinesterase inhibitor aldicarb’s effect on the rate of pharyngeal pumping on food in mutant worms. The screening revealed that the key determinant of the inhibitory effect of aldicarb on pharyngeal pumping is the L-type nicotinic acetylcholine receptor expressed in body wall muscle. This idea was reinforced by the observation that selective hyperstimulation of the body wall muscle L-type receptor by the agonist levamisole inhibited pumping. Overall, our results reveal that body wall cholinergic transmission controls locomotion and simultaneously couples a distal inhibition of feeding.
An exon junction complex-independent function of Barentsz in neuromuscular synapse growth
Authors: Ho Cheuk Hei , Roignant Jean-Yves , Tang Zuojian , Brown Stuart , Treisman Jessica E.
Published: February 2021

The exon junction complex controls the translation, degradation and localization of spliced mRNAs, and three of its four core subunits also play a role in splicing. Here we show that the fourth subunit, Barentsz, has distinct biological functions within and separate from the exon junction complex in neuromuscular development. Barentsz controls the distribution of mitochondria in larval muscles, a function that also depends on other subunits of the exon junction complex and that is not rescued by a transgene in which residues required for binding to the core subunit eIF4AIII are mutated. In contrast, interactions with the exon junction complex are not required for Barentsz to promote the growth of neuromuscular synapses. We found that the Activin ligand Dawdle shows reduced expression inbarentszmutants and acts downstream of Barentsz to control synapse growth. Bothbarentszanddawdleare required in motor neurons, muscles and glia for normal synapse growth, and exogenous Dawdle can rescue synapse growth in the absence ofbarentsz. These results identify a biological function for Barentsz that is independent of the exon junction complex.
Protocell Arrays for Simultaneous Detection of Diverse Analytes
Authors: Zhang Yan , Kojima Taisuke , Kim Ge-Ah , McNerney Monica P. , Takayama Shuichi , Styczynski Mark P.
Published: February 2021

Simultaneous detection of multiple analytes from a single sample (multiplexing), particularly when at the point of need, can guide complex decision-making without increasing the required sample volume or cost per test. Despite recent advances, multiplexing still typically faces the critical limitation of measuring only one type of molecule per assay platform – for example, only small molecules or only nucleic acids. In this work, we address this bottleneck with a customizable platform that integrates cell-free expression (CFE) with a polymer-based aqueous two-phase system (ATPS) to produce membrane-less “protocells” containing transcription and translation machinery used for analyte detection. Multiple protocells are arrayed in microwells where each protocell droplet performs distinct reactions to detect chemically diverse targets including small molecules, minerals, and nucleic acid sequences, all from the same sample. We demonstrate that these protocell arrays can measure analytes in a human biofluid matrix, maintain function after lyophilization and rehydration, and produce visually interpretable readouts, illustrating its potential for application as a minimal-equipment, field-deployable, multi-analyte detection tool.
Overexpression of ELOVL6 has been associated with poor prognosis in patients with head and neck squamous cell carcinoma
Authors: Wang Ruoya
Published: February 2021

Head and neck squamous cell carcinoma (HNSCC) is a high mortality disease. Extension of long-chain fatty acid family member 6 (ELOVL6) is a key enzyme involved in fat formation that catalyzes the elongation of saturated and monounsaturated fatty acids. Overexpression of ELOVL6 has been associated with obesity-related malignancies, including hepatocellular carcinoma, breast, colon, prostate, and pancreatic cancer. The following study investigated the role of ELOVL6 in HNSCC patients. Gene expression and clinicopathological analysis, enrichment analysis, and immune infiltration analysis were based on the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA), with additional bioinformatics analyses. The statistical analysis was conducted in R, and TIMER was used to analyze the immune response of ELOVL6 expression in HNSCC. The expression of ELOVL6 was related to tumor grade. Survival analysis showed that patients with high expression of ELOVL6 had a poor prognosis. Moreover, the results of GSEA enrichment analysis showed that ELOVL6 affects the occurrence of HNSCC through fatty acid metabolism, biosynthesis of unsaturated fatty acids, and other pathways. Finally, ELOVL6 verified by the Human Protein Atlas (HPA) database were consistent with the mRNA levels in HNSCC samples. ELOVL6 is a new biomarker for HNSCC that may be used as a potential predictor of the prognosis of human HNSCC.
Developmental change in prefrontal cortex recruitment supports the emergence of value-guided memory
Authors: Nussenbaum Kate , Hartley Catherine A.
Published: February 2021

Prioritizing memory for valuable information can promote adaptive behavior across the lifespan, but it is unclear how the neurocognitive mechanisms that enable the selective acquisition of useful knowledge develop. Here, using a novel task coupled with functional magnetic resonance imaging, we examined how children, adolescents, and adults (N = 90) learn from experience what information is likely to be rewarding, and modulate encoding and retrieval processes accordingly. We found that the ability to use learned value signals to selectively enhance memory for useful information strengthened throughout childhood and into adolescence. Encoding and retrieval of high- vs. low-value information was associated with increased activation in striatal and prefrontal regions implicated in value processing and cognitive control. Age-related increases in value-based lateral prefrontal cortex modulation mediated the relation between age and memory selectivity. Our findings demonstrate that developmental increases in the strategic engagement of the prefrontal cortex support the emergence of adaptive memory.
p53 pro-apoptotic activity is regulated by the G2/M promoting factor Cdk1 in response to DNA damage
Authors: Ruiz-Losada Mireya , González Raul , Peropadre Ana , Baonza Antonio , Estella Carlos
Published: February 2021

Exposure to genotoxic stress promotes cell-cycle arrest and DNA repair or apoptosis. These “life” or “death” cell fate decisions often rely on the activity of the tumor suppressor genep53. Therefore, howp53activity is precisely regulated is essential to maintain tissue homeostasis and to prevent cancer development. Here we demonstrate thatDrosophila p53pro-apoptotic activity is regulated by the G2/M kinase Cdk1. We find that cell cycle arrested or endocycle-induced cells are refractory to ionizing radiation induced apoptosis. We show that the p53 protein is not able to bind to and to activate the expression of the pro-apoptotic genes in experimentally arrested cells. Our results indicate that p53 genetically and physically interacts with Cdk1 and that p53 pro-apoptotic role is regulated by the cell cycle status of the cell. We propose a model in which cell cycle progression and p53 pro-apoptotic activity are molecularly connected to coordinate the appropriate response after DNA damage.
Attention to speech: Mapping distributed and selective attention systems
Authors: Agmon Galit , Yahav Paz Har-Shai , Ben-Shachar Michal , Golumbic Elana Zion
Published: February 2021

Daily life is full of situations where many people converse at the same time. Under these noisy circumstances, individuals can employ different listening strategies to deal with the abundance of sounds around them. In this fMRI study we investigated how applying two different listening strategies – Selective vs. Distributed attention – affects the pattern of neural activity. Specifically, in a simulated ‘cocktail party’ paradigm, we compared brain activation patterns when listenersattend selectivelyto only one speaker and ignore all others, versus when theydistribute their attentionand attempt to follow two or four speakers at the same time. Results indicate that the two attention types activate a highly overlapping, bilateral fronto-temporal-parietal network of functionally connected regions. This network includes auditory association cortex (bilateral STG/STS) and higher-level regions related to speech processing and attention (bilateral IFG/insula, right MFG, left IPS). Within this network, responses in specific areas were modulated by the type of attention required. Specifically, auditory and speech-processing regions exhibited higher activity during Distributed attention, whereas fronto-parietal regions were activated more strongly during Selective attention. This pattern suggests that a common perceptual-attentional network is engaged when dealing with competing speech-inputs, regardless of the specific task at hand. At the same time, local activity within nodes of this network varies when implementing different listening strategies, reflecting the different cognitive demands they impose. These results nicely demonstrate the system’s flexibility to adapt its internal computations to accommodate different task requirements and listener goals.

Significance Statement

Hearing many people talk simultaneously poses substantial challenges for the human perceptual and cognitive systems. We compared neural activity when listeners applied two different listening strategy to deal with these competing inputs:attending selectivelyto one speaker vs.distributing attentionamong all speakers. A network of functionally connected brain regions, involved in auditory processing, language processing and attentional control was activated when applying both attention types. However, activity within this network was modulated by the type of attention required and the number of competing speakers. These results suggest a common ‘attention to speech’ network, providing the computational infrastructure to deal effectively with multi-speaker input, but with sufficient flexibility to implement different prioritization strategies and to adapt to different listener goals.
A Multiscale Model for Quantitative Prediction of Insulin Aggregation Nucleation Kinetics
Authors: Mishra Rit Pratik , Goel Gaurav
Published: February 2021

We combined kinetic, thermodynamic, and structural information from single molecule (protein folding) and two molecule (protein association) explicit-solvent simulations for determination of kinetic parameters in protein aggregation nucleation with insulin as model protein. A structural bioinformatics approach was developed to account for heterogeneity of aggregation-prone species with the transition complex theory, developed for native protein-receptor interactions, found applicable in modeling association kinetics involving this non-native species. We show that a key simplification arises from presence of only a few relevant modes for non-native association kinetics and that it is necessary to explicitly account for conformational rearrangement of a diffusional intermediate leading to the formation of aggregation pathway dimer and small oligomers. The kinetic parameters thus obtained were used in a population balance model and very accurate predictions for aggregation nucleation time varying over two orders of magnitude with changes in concentration of insulin or an aggregation-inhibitor ligand were obtained while an empirical parameter set was not found to be transferable for prediction of ligand effects. This physically determined kinetic parameter set also provided several insights into the mechanism of aggregation nucleation. Finally we discuss a route for application of our approach in high-throughput computational screening of ligands for inhibiting aggregation.
Synthesis, Physiochemical and Biological evaluation of Inclusion Complex of Benzyl Isothiocyanate encapsulated in cyclodextrins for triple negative breast cancer
Authors: Uppal Shivani , Kumar Rajendra , Kaur Khushwinder , Sareen Shweta , Bhatia Alka , Mehta S.K.
Published: February 2021

Benzyl isothiocyanate (BITC), an organic dietary compound, is allied with a major role in the potential chemopreventive effects. BITC has acknowledged rising attention as a therapeutic compound to be used in medicine because of its high potency and characteristic biopharmaceutical properties, like high permeability with marginal aqueous solubility. The highly volatile and hydrophobic nature brought a need to provide a suitable delivery-matrix to BITC to exploit its pharmacological potential to the fullest. It has been successfully incorporated in β-CD and HP-β-CD using acoustic forces and thoroughly characterized using UV-vis spectroscopy, FTIR, DSC, TEM, and SAXS. The complexation helped in masking the acute odour, achieving a controlled release of BITC, and made its use viable by prolonging the retention time and thereby sustaining the biological effects. Different models like Higuchi, first-order kinetic decay, Korsmeyer-Peppas model were applied, suggesting a diffusion-controlled mechanism of release. Also, the bioaccessibility and stability of BITC in anin vitrodigestion model was evaluated. The main objective of the present work was to systemically study the credibility of BITC-CD complexes in well-established tumor mimicking 2D cell culture models and produce a conclusive report on its chemotherapeutic activity. Thein vitroanti-cancer activity of BITC and the formed sonochemical complexes was confirmed by MTT assay and further evaluated using apoptosis assay and production of ROS like moieties. Cell cycle analysis was done to evaluate the growth inhibitory mechanism of BITC. Strikingly, BITC and its complexes showcased ROS generation and lysosome-mediated cell death. Effect on cell migration was assessed using wound healing assay. The results promptly suggest the functional efficacy of the CDs in releasing BITC and attest the ability of the complexes to provide alternate to otherwise remedially sparse triple-negative breast cancer.