bluuebunny/crossref_metadata_2025 huggingface dataset:
ANKLE1 cleaves mitochondrial DNA and contributes to cancer risk by promoting apoptosis resistance and metabolic dysregulation
Authors: Przanowski Piotr , Przanowska Róża K. , Guertin Michael J.
Published: November 2021

Alleles within the chr19p13.1 locus are associated with increased risk of both ovarian and breast cancer and increased expression of theANKLE1gene. ANKLE1 is molecularly characterized as an endonuclease that efficiently cuts branched DNA and shuttles between the nucleus and cytoplasm. However, the role of ANKLE1 in mammalian development and homeostasis remains unknown. In normal development ANKLE1 expression is limited to the erythroblast lineage and we found that ANKLE1’s role is to cleave the mitochondrial genome during erythropoiesis. We show that ectopic expression of ANKLE1 in breast epithelial-derived cells leads to genome instability and mitochondrial DNA (mtDNA) cleavage. mtDNA degradation then leads to mitophagy and causes a shift from oxidative phosphorylation to glycolysis (Warburg effect). Moreover, mtDNA degradation activates STAT1 and expression of epithelial-mesenchymal transition (EMT) genes. Reduction in mitochondrial content contributes to apoptosis resistance, which may allow precancerous cells to avoid apoptotic checkpoints and proliferate. These findings provide evidence that ANKLE1 is the causal cancer susceptibility gene in the chr19p13.1 locus and describe mechanisms by which higher ANKLE1 expression promotes cancer risk.
Causes, characteristics, and patterns of prolonged unplanned school closures prior to the COVID-19 pandemic – United States, 2011 – 2019
Authors: Jahan Ferdous A. , Zviedrite Nicole , Gao Hongjiang , Ahmed Faruque , Uzicanin Amra
Published: November 2021

Introduction

Outside of pandemics, there is little information about occurrence of prolonged unplanned K-12 school closures (PUSC). We describe here the reasons, characteristics, and patterns of PUSC in the United States during 8 consecutive inter-pandemic academic years, 2011-2019.

Methods

From August 1, 2011 through June 30, 2019, daily systematic online searches were conducted to collect data on publicly announced unplanned school closures lasting ≥1 school days in the United States. Closures were categorized as prolonged when schools were closed for ≥5 unplanned days (approximating one full workweek), excluding weekends and scheduled days off per school calendars.

Results

During the eight academic years, a total of 22,112 PUSCs were identified, affecting over 800,000 teachers and 13 million students that resulted in 91.5 million student-days lost. A median of 62.9% of students in PUSC-affected schools were eligible for subsidized school meals. Most affected schools were in cities (35%) and suburban areas (33%). Natural disasters (47%), adverse weather conditions (35%), and budget/teacher strikes (15%) were the most frequently cited reasons for PUSC; illness accounted for 1%, and building/facility issues, environmental issues and violence together accounted for the remaining 2%. The highest number of PUSCs occurred in Health and Human Services Regions 2, 3, 4, and 6 encompassing areas that are frequently in the path of hurricanes and tropical storms. The majority of PUSCs in these regions were attributed to a handful of hurricanes during the fall season, including hurricanes Sandy, Irma, Harvey, Florence, and Matthew.

Conclusions

PUSCs occur annually in the United States due to a variety of causes and are associated with a substantive loss of student-days for in-school learning. Both these prior experiences with PUSCs and those during the current COVID-19 pandemic illustrate a need for creating sustainable solutions for high-quality distance learning and innovative supplemental feeding programs nationwide, especially in disaster-prone areas.
Stable Cell Clones Harboring Self-Replicating SARS-CoV-2 RNAs for Drug Screen
Authors: Liu Shufeng , Chou Chao-Kai , Wu Wells W. , Luan Binquan , Wang Tony T.
Published: November 2021

The development of antivirals against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been hampered by the lack of efficient cell-based replication systems that are amenable to high-throughput screens in biosafety level 2 laboratories. Here we report that stable cell clones harboring autonomously replicating SARS-CoV-2 RNAs without S, M, E genes can be efficiently derived from the baby hamster kidney (BHK-21) cell line when a pair of mutations were introduced into the non-structural protein 1 (Nsp1) of SARS-CoV-2 to ameliorate cellular toxicity associated with virus replication. In a proof-of-concept experiment we screened a 273-compound library using replicon cells and identified three compounds as novel inhibitors of SARS-CoV-2 replication. Altogether, this work establishes a robust, cell-based system for genetic and functional analyses of SARS-CoV-2 replication and for the development of antiviral drugs.

IMPORTANCE

SARS-CoV-2 replicon systems that have been reported up to date were unsuccessful in deriving stable cell lines harboring non-cytopathic replicons. The transient expression of viral sgmRNA or a reporter gene makes it impractical for industry-scale screening of large compound libraries using these systems. Here, for the first time, we derived stable cell clones harboring the SARS-CoV-2 replicon. These clones may now be conveniently cultured in a standard BSL-2 laboratory for high throughput screen of compound libraries. This achievement represents a ground-breaking discovery that will greatly accelerate the pace of developing treatments for COVID-19.
The impact of heating, ventilation and air conditioning (HVAC) design features on the transmission of viruses, including the 2019 novel coronavirus (COVID-19): a systematic review of humidity
Authors: Thornton Gail M. , Fleck Brian A , Dandnayak Dhyey , Kroeker Emily , Zhong Lexuan , Hartling Lisa
Published: November 2021

The aerosol route has been a pathway for transmission of many viruses. Similarly, recent evidence has determined aerosol transmission for SARS-CoV-2 to be significant. Consequently, public health officials and professionals have sought data regarding the role of Heating, Ventilation, and Air Conditioning (HVAC) features as a means to mitigate transmission of viruses, particularly coronaviruses. Using international standards, a systematic review was conducted to comprehensively identify and synthesize research examining the effect of humidity on transmission of coronaviruses and influenza. The results from 24 relevant studies showed that: increasing from mid (40-60%) to high (>60%) relative humidity (RH) for SARS-CoV-2 was associated with decreased virus survival; although SARS-CoV-2 results appear consistent, coronaviruses do not all behave the same; increasing from low (<40%) to mid RH for influenza was associated with decreased persistence, infectivity, viability, and survival, however effects of increased humidity from mid to high for influenza were not consistent; and medium, temperature, and exposure time were associated with inconsistency in results for both coronaviruses and influenza. Adapting HVAC humidity to mitigate virus transmission is a complex approach due to difficulties of humidity control; humidity is a feature to be considered in conjunction with other HVAC features.

Practical Implications

While increasing relative humidity from mid (40-60%RH) to high (>60%RH) was associated with decreased SARS-CoV-2 survival, coronaviruses did not all behave the same way. As a result, blanket prescriptive humidity levels for coronavirus mitigation are difficult to ascertain. While influenza survival varied from mid to high RH, increased humidity from low (<40%RH) to mid (40-60%RH) RH was associated with decreased virus survival with maximum survival at low RH. When controlling humidity as an HVAC feature, practitioners should take into account virus type and temperature. Future research should also consider the impact of exposure time, temperature, and medium when designing experiments, while also working towards more standardized testing procedures.
Three-dimensional spike localization and improved motion correction for Neuropixels recordings
Authors: Boussard Julien , Varol Erdem , Lee Hyun Dong , Dethe Nishchal , Paninski Liam
Published: November 2021

Neuropixels (NP) probes are dense linear multi-electrode arrays that have rapidly become essential tools for studying the electrophysiology of large neural populations. Unfortunately, a number of challenges remain in analyzing the large datasets output by these probes. Here we introduce several new methods for extracting useful spiking information from NP probes. First, we use a simple point neuron model, together with a neural-network denoiser, to efficiently map single spikes detected on the probe into three-dimensional localizations. Previous methods localized individual spikes in two dimensions only; we show that the new localization approach is significantly more robust and provides an improved feature set for clustering spikes according to neural identity (“spike sorting”). Next, we denoise the resulting three-dimensional point-cloud representation of the data, and show that the resulting 3D images can be accurately registered over time, leading to improved tracking of time-varying neural activity over the probe, and in turn, crisper estimates of neural clusters over time. Open source code is available athttps://github.com/int-brain-lab/spikes_localization_registration.git.
NMDA receptor-targeted enrichment of CaMKIIα improves fear memory
Authors: Chifor Anthony , Choi Jeongyoon , Park Joongkyu
Published: November 2021

Calcium/calmodulin-dependent protein kinase II alpha (CaMKIIα) is an essential player in long-term potentiation and memory formation. However, the establishment of effective molecular interventions with CaMKIIα to improve memory remains a long-standing challenge. Here we report a novel intrabody targeting GluN1, a subunit of N-methyl-D-aspartate receptors (NMDARs). We identify this anti-GluN1 intrabody (termed VHH Anti-GluN1; VHHAN1) by a synthetic phage display library selection and yeast-two-hybrid screenings. We validate specific targeting of VHHAN1 to GluN1 in heterologous cells and the mouse hippocampus. We further show that adeno-associated virus (AAV)-mediated expression of CaMKIIα fused with VHHAN1 is locally enriched at excitatory postsynaptic regions of the mouse hippocampus. We also find that the AAV- and VHHAN1-mediated postsynaptic enrichment of CaMKIIα in the hippocampus improves contextual fear memory in mice. This novel approach opens a new avenue to enhance memory ability in health and diseases.
Maternal effects on early-life gut microbiome maturation in a wild nonhuman primate
Authors: Baniel Alice , Petrullo Lauren , Mercer Arianne , Reitsema Laurie , Sams Sierra , Beehner Jacinta C. , Bergman Thore J. , Snyder-Mackler Noah , Lu Amy
Published: November 2021

Early-life gut microbial colonization is an important process shaping host physiology, immunity and long-term health outcomes in humans and other animals. However, our understanding of this dynamic process remains poorly investigated in wild animals, where developmental mechanisms can be better understood within ecological and evolutionary relevant contexts. Using 16s rRNA amplicon sequencing on 525 fecal samples from a large cohort of infant and juvenile geladas (Theropithecus gelada), we characterized gut microbiome maturation during the first three years of life and assessed the role of maternal effects in shaping offspring microbiome assembly. Microbial diversity increased rapidly in the first months of life, followed by more gradual changes until weaning. As expected, changes in gut microbiome composition and function with increasing age reflected progressive dietary transitions: in early infancy when infants rely heavily on their mother’s milk, microbes that facilitate milk glycans and lactose utilization dominated, while later in development as graminoids are progressively introduced into the diet, microbes that metabolize plant complex polysaccharides became dominant. Furthermore, the microbial community of nursing infants born to first-time (primiparous) mothers was more “milk-oriented” compared to similarly-aged infants born to experienced (multiparous) mothers. Comparisons of matched mother-offspring fecal samples to random dyads did not support vertical transmission as a conduit for these maternal effects, which instead could be explained by slower phenotypic development (and associated slower gut microbiome maturation) in infants born to first-time mothers. Together, our findings highlight the dynamic nature of gut colonization in early life and the role of maternal effects in modulating this trajectory in a wild primate.
Neural correlates of masked and unmasked tones: psychoacoustics and late auditory evoked potentials (LAEPs)
Authors: Kim Hyojin , Epp Bastian
Published: November 2021

Hearing thresholds are commonly used to quantify a listener’s ability to detect sound. In the presence of masking sounds, hearing thresholds can vary depending on the signal properties of the target and the masker, commonly referred to as auditory cues. Target detection can be facilitated with comodulated masking noise and interaural phase disparity (IPD). This can be quantified with a decrease in detection thresholds or masking release: comodulation masking release (CMR, for comodulation) and binaural masking level difference (BMLD, for IPD). As these measures only reflect the low limit of levels for target detection, the relevance of masking release at supra-threshold levels is still unclear. Here, we used psychoacoustic and electrophysiological measures to investigate the effect of masking release for a masked tone at supra-threshold levels. Behaviorally, we investigated how the amount of masking release affects the salience at supra-threshold levels. We used intensity just-noticeable difference (JND) to quantify level-dependent changes in the salience of the tonal signal. As a physiological correlate, we investigated late auditory evoked potentials (LAEPs) with electroencephalography (EEG). The results showed that the intensity JNDs were equal at the same physical target tone level, regardless of the presence or absence of masking release. Estimated salience was correlated with the amount of masking release. However, salience measures across conditions converged with the target tone level above 70 dB SPL. For the LAEPs, the P2 amplitudes were more closely linked to behavioral measures than the N1 amplitudes. Both behavioral and electrophysiological measures suggest that the salience of a masked tone at supra-threshold levels is correlated with the amount of masking release.
Mushroom body input connections form independently of sensory activity in Drosophila melanogaster
Authors: Hayashi Tatsuya , MacKenzie Alexander John , Ganguly Ishani , Smihula Hayley Marie , Jacob Miles Solomon , Litwin-Kumar Ashok , Caron Sophie Jeanne Cécile
Published: November 2021

Associative brain centers, such as the insect mushroom body, need to represent sensory information in an efficient manner. In Drosophila melanogaster, the Kenyon cells of the mushroom body integrate inputs from a random set of olfactory projection neurons, but some projection neurons — namely those activated by a few ethologically meaningful odors — connect to Kenyon cells more frequently than others. This biased and random connectivity pattern is conceivably advantageous, as it enables the mushroom body to represent a large number of odors as unique activity patterns while prioritizing the representation of a few specific odors. How this connectivity pattern is established remains largely unknown. Here, we test whether the mechanisms patterning the connections between Kenyon cells and projection neurons depend on sensory activity or whether they are hardwired. We mapped a large number of mushroom body input connections in anosmic flies — flies lacking the obligate odorant co-receptor Orco — and in wildtype flies. Statistical analyses of these datasets reveal that the random and biased connectivity pattern observed between Kenyon cells and projection neurons forms normally in the absence of most olfactory sensory activity. This finding supports the idea that even comparatively subtle, population-level patterns of neuronal connectivity can be encoded by fixed genetic programs and are likely to be the result of evolved prioritization of ecologically and ethologically salient stimuli.
Beyond Fixation: detailed characterization of neural selectivity in free-viewing primates
Authors: Yates Jacob L. , Coop Shanna H. , Sarch Gabriel H. , Wu Ruei-Jr , Butts Daniel A. , Rucci Michele , Mitchell Jude F.
Published: November 2021

Virtually all vision studies use a fixation point to stabilize gaze, rendering stimuli on video screens fixed to retinal coordinates. This approach requires trained subjects, is limited by the accuracy of fixational eye movements, and ignores the role of eye movements in shaping visual input. To overcome these limitations, we developed a suite of hardware and software tools to study vision during natural behavior in untrained subjects. We show this approach recovers receptive fields and tuning properties of visual neurons from multiple cortical areas of marmoset monkeys. Combined with high-precision eye-tracking, it achieves sufficient resolution to recover the receptive fields of foveal V1 neurons. These findings demonstrate the power of free viewing to characterize neural response while simultaneously studying the dynamics of natural behavior.

Highlights

We introduce a free-viewing paradigm for studying neural mechanisms of visual processing during active vision

Receptive fields (RFs) and neural selectivity in primary visual cortex (V1) and area MT can be extracted during free-viewing in minimally-trained subjects

Novel high-resolution eye tracking in this context supports detailed measurements of receptive fields in foveal V1
Predictions of arrhythmic, heart failure and mortality outcomes in pericarditis using automatic electrocardiogram analysis
Authors: Lakhani Ishan , Zhou Jiandong , Wong Michelle Vangi , Lee Sharen , Lau Jovy Ka Yiu , Shi Silverdew , Wong Wing Tak , Liu Tong , Zhang Qingpeng , Tse Gary
Published: November 2021

Background

Pericarditis is a relatively rare disease with a global burden. Despite its strong association with adverse cardiovascular outcomes, identification of patients at risk of future heart failure or arrhythmic events is difficult. In the following study, automated electrocardiogram (ECG) were used to predict new onset ventricular tachycardia/fibrillation (VT/VF), atrial fibrillation (AF) and heart failure with reduced ejection fraction (HF) in an Asian cohort of pericarditis patients.

Methods

Consecutive patients admitted to a single tertiary center in Hong Kong, China, for a diagnosis of pericarditis between 1st January 2005 and 31st December 2019 with baseline ECG measurements were included. Patients with existing AF or HF were excluded. The follow-up period was until the 31st December 2020, or death. Cox regression was applied to identify significant predictors of the primary outcomes (incident VT/VF, AF or HF).

Results

A total of 874 patients were included. The cohort was 57% male and had a median age of 59 (IQR: 50-70) years old. During follow-up, 57 patients (6.5%), 156 (17.8%) and 168 (19.2%) suffered from VT/VF, AF and HF, respectively. Cox regression identified baseline VT/VF, terminal angle of the QRS vector in the transverse plane, mean QRS duration and mean QTc intervals as significant predictors of incident VT/VF events, with only the former most maintaining significance in multivariate analysis. In contrast, baseline age, prior diagnoses of hypertension, initial angle and magnitude of the QRS vector in the transverse plane, P-wave and QRS axis in the frontal plane, ST segment axis in the frontal and horizontal planes, mean PT interval, mean PR segment duration and QTc intervals were all univariate predictors of incident AF, albeit only baseline age and initial angel of the QRS vector in the transverse plane retained significance after multivariate adjustment. As it pertains to new-onset HF, several clinical and electrocardiographic parameters demonstrated an association with HF in univariate analysis, with prior diagnosis of HT or DM, initial QRS angle in transverse plane, I 40 in horizontal axis, ST-segment axis in the horizontal plane, T-wave frontal axis and atrial rate, of which, except for prior diagnosis of DM, I40 in horizontal axis and T-wave frontal axis, all variables showcased significant relationships in multivariate analysis

Interpretation

AF and HF are relatively common complications VT/VF occurs less frequently in the context of pericarditis. Different clinical and ECG predictors of these outcomes were identified. Future studies are still needed to evaluate their use for risk stratification in the clinical setting.
Proposed Mechanism for Monomethylarsonate Reductase Activity of Human Omega-class Glutathione Transferase GSTO1
Authors: Oakley Aaron J
Published: November 2021

Contamination of drinking water with toxic inorganic arsenic is a major public health issue. The mechanisms of enzymes and transporters in arsenic elimination are therefore of interest. The human omega-class glutathione transferases have been previously shown to possess monomethylarsonate (V) reductase activity. To further understanding of this activity, molecular dynamics of human GSTO1-1 bound to glutathione with a monomethylarsonate isostere were simulated to reveal putative monomethylarsonate binding sites on the enzyme. The major binding site is in the active site, adjacent to the glutathione binding site. Based on this and previously reported biochemical data, a reaction mechanism for this enzyme is proposed. Further insights were gained from comparison of the human omega-class GSTs to homologs from a range of animals.
Active DNA demethylation of developmental cis-regulatory regions predates vertebrate origins
Authors: Skvortsova Ksenia , Bertrand Stephanie , Voronov Danila , Duckett Paul Edward , Ross Samuel E , Magri Marta Silvia , Maeso Ignacio , Weatheritt Robert James , Gomez-Skarmeta Jose Luis , Arnone Maria Ina , Escriva Hector , Bogdanovic Ozren
Published: November 2021

DNA methylation (5-methylcytosine; 5mC) is a repressive gene-regulatory mark required for vertebrate embryogenesis. Genomic 5mC is tightly regulated through the coordinated action of DNA methyltransferases, which deposit 5mC, and TET enzymes, which participate in its active removal through the formation of 5-hydroxymethylcytosine (5hmC). TET enzymes are essential for mammalian gastrulation and activation of vertebrate developmental enhancers, however, to date, a clear picture of 5hmC function, abundance, and genomic distribution in non-vertebrate lineages is lacking. By employing base-resolution 5mC and 5hmC quantification during sea urchin and lancelet embryogenesis, we shed light on the roles of non-vertebrate 5hmC and TET enzymes. We find that these invertebrate deuterostomes employ TET enzymes for targeted demethylation of regulatory regions associated with developmental genes and show that the complement of identified 5hmC-regulated genes is conserved to vertebrates. This work thus demonstrates that active 5mC removal from regulatory regions is a common feature of deuterostome embryogenesis suggestive of unexpected deep conservation of a major gene-regulatory module.
The Recombination Landscape of the Khoe-San - the Upper Limits of Recombination Divergence in Humans
Authors: van Eeden Gerald , Uren Caitlin , Pless Evlyn , Mastoras Mira , van der Spuy Gian D. , Tromp Gerard , Henn Brenna M. , Möller Marlo
Published: November 2021

Recombination maps are important resources for epidemiological and evolutionary analyses, however, there are currently no recombination maps representing any African population outside of those with West African ancestry. We inferred the demographic history for the Nama, an indigenous Khoe-San population of southern Africa, and derived a novel, population-specific recombination map from the whole genome sequencing of 54 Nama individuals. We hypothesized that there are no publicly available recombination maps representative of the Nama, considering the deep population divergence and subsequent isolation of the Khoe-San from other African groups. We showed that the recombination landscape of the Nama does not cluster with any continental groups with publicly available representative recombination maps. Finally, we used selection scans as an example of how fine-scale differences between the Nama recombination map and the combined Phase II HapMap recombination map can impact the outcome of selection scans.
Mesowestern Blot: Simultaneous Analysis of Hundreds of Sub-Microliter Lysates
Authors: Zadeh Cameron O. , Huggins Jonah R. , Westbury Baylee C. , Interiano William R. , Phillips S. Ashley , Erdem Cemal , Sarmah Deepraj , Dodd William B. , Meredith Wesley O. , Birtwistle Marc R.
Published: November 2021

Western blotting is a widely-used technique for molecular-weight-resolved analysis of proteins and their post-translational modifications, but has been refractory to affordable scale-up. Here, we report the Mesowestern blot, which uses a 3D-printable gel-casting mold to enable affordable, high-throughput Western blotting with standard sample preparation and small (<1 uL) sample sizes. The casted polyacrylamide gel contains 336, 0.5 uL micropipette-loadable sample wells arranged within a standard microplate footprint. Polyacrylamide % can be altered to change molecular weight resolution range. Proof-of-concept experiments using both infrared-fluorescent molecular weight protein ladder as well as cell lysate (RIPA buffer) demonstrate protein loaded in Mesowestern gels is amenable to the standard Western blotting steps. The main difference between Mesowestern and traditional Western is that semi-dry horizontal instead of immersed vertical gel electrophoresis is used. The linear range of detection is approximately 2 orders of magnitude, with a limit of detection (for β-actin) of around 30 ng of total protein from mammalian cell lysates (~30-3000 cells). Because the gel mold is 3D-printable, users have significant design freedom for custom layouts, and there are few barriers to adoption by the typical cell and molecular biology laboratory already performing Western blots.
Intrinsically disordered regions of Tristetraprolin and DCP2 directly interact to mediate decay of ARE-mRNA
Authors: Maciej Vincent D. , Mateva Nevena , Dittmers Theresa , Chakrabarti Sutapa
Published: November 2021

The RNA binding protein Tristetraprolin (TTP) is a potent activator of mRNA decay, specifically for transcripts bearing AU-rich elements (AREs) in their 3′-untranslated regions. TTP functions as a mediator for mRNA decay by interacting with the decay machinery and recruiting it to the target ARE-mRNA. In this study, we report a weak, but direct interaction between TTP and the human decapping enzyme DCP2, which impacts the stability of ARE-transcripts. The TTP-DCP2 interaction is unusual as it involves intrinsically disordered regions (IDRs) of both binding partners. We show that the IDR of DCP2 has a propensity for oligomerization and liquid-liquid phase separation (LLPS)in vitro. Binding of TTP to DCP2 leads to its partitioning into phase-separated droplets formed by DCP2, suggesting that molecular crowding might facilitate the weak interaction between the two proteins and enable assembly of a decapping-competent mRNA-protein complex on TTP-bound transcripts in cells. Our studies underline the role of weak interactions in the cellular interaction network and their contribution towards cellular functionality.
Dopamine neuron morphology and output are differentially controlled by mTORC1 and mTORC2
Authors: Kosillo Polina , Ahmed Kamran M. , Roberts Bradley M. , Cragg Stephanie J. , Bateup Helen S.
Published: November 2021

The mTOR pathway is an essential regulator of cell growth and metabolism. Midbrain dopamine neurons are particularly sensitive to mTOR signaling status as activation or inhibition of mTOR alters their morphology and physiology. mTOR exists in two distinct multiprotein complexes termed mTORC1 and mTORC2. How each of these complexes affect dopamine neuron properties and whether they act together or independently is unknown. Here we investigated this in mice with dopamine neuron-specific deletion of Rptor or Rictor, which encode obligatory components of mTORC1 or mTORC2, respectively. We find that inhibition of mTORC1 strongly and broadly impacts dopamine neuron structure and function causing somatodendritic and axonal hypotrophy, increased intrinsic excitability, decreased dopamine production, and impaired dopamine release. In contrast, inhibition of mTORC2 has more subtle effects, with selective alterations to the output of ventral tegmental area dopamine neurons. As mTOR is involved in several brain disorders caused by dopaminergic dysregulation including Parkinson’s disease and addiction, our results have implications for understanding the pathophysiology and potential therapeutic strategies for these diseases.
Neuronal origins of biases in economic choices under sequential offers
Authors: Shi Weikang , Ballesta Sébastien , Padoa-Schioppa Camillo
Published: November 2021

Economic choices are characterized by a variety of biases. Understanding their origins is a long-term goal for neuroeconomics, but progress on this front has been limited. Here we examined choice biases observed when two goods are offered sequentially. In the experiments, rhesus monkeys chose between different juices offered simultaneously or in sequence. Choices under sequential offers were less accurate (higher variability). They were also biased in favor of the second offer (order bias) and in favor of the preferred juice (preference bias). Analysis of neuronal activity recorded in orbitofrontal cortex revealed that these phenomena emerged at different computational stages. The lower choice accuracy reflected weaker offer value signals (valuation stage), the order bias emerged during value comparison (decision stage), and the preference bias emerged late in the trial (post-comparison). Our approach, leveraging recent notions on the neural mechanisms of economic decisions, may shed light on other aspects of choice behavior.
Defining the determinants of under-vaccination in migrant populations in Europe to improve routine and COVID-19 vaccine uptake: a systematic review
Authors: Crawshaw Alison F , Farah Yasmin , Deal Anna , Rustage Kieran , Hayward Sally E , Carter Jessica , Knights Felicity , Goldsmith Lucy P , Campos-Matos Ines , Wurie Fatima , Majeed Azeem , Bedford Helen , Forster Alice S , Hargreaves Sally
Published: November 2021

Diverse migrant populations in Europe are at risk of under-immunisation and have recently shown lower levels of COVID-19 vaccination intent and uptake. Understanding the determinants of vaccine uptake in migrants is critical to address immediate COVID-19 vaccination inequities, and longer-term will help improve coverage for routine vaccinations, aligning with the goals of the new Immunisation Agenda 2030. We did a systematic review following PRISMA guidelines and using a PICOS framework (PROSPERO CRD42020219214; MEDLINE, CINAHL, PsycINFO databases, 1 January 2000 – 14 September 2021) exploring barriers and facilitators to vaccine uptake and determinants of under-vaccination in migrants in the EU/EEA, UK, and Switzerland. We categorised barriers/facilitators using the ‘5As’ Determinants of Vaccine Uptake Taxonomy. 5259 data sources were screened, with 67 studies included from 16 countries, representing 366,529 migrants. Access barriers were most commonly reported (language, literacy and communication barriers; practical and legal barriers to accessing/delivering vaccination services; service barriers, including lack of specific guidelines and knowledge of healthcare professionals) for key vaccines including MMR, DTP, HPV, influenza, polio, COVID-19 vaccines. Acceptance barriers were mostly reported in Eastern European and Muslim communities for HPV, measles, and influenza vaccines. We identified 23 determinants of under-vaccination in migrants, including geographical origin (where 25/26 (96%) studies showed significance) – particularly African/Eastern European origin; recent migration; being a refugee/asylum seeker; higher income; parental education level; no healthcare contact in the past year; and lower language skills. Facilitators of migrants’ vaccine uptake included tailored vaccination messaging, community outreach and ‘nudging’ interventions. Migrants’ barriers to accessing healthcare are already well documented, and this review confirms their role in limiting vaccine uptake. These data hold immediate relevance to strengthening vaccination programmes in high-income countries, including for COVID-19. Our findings suggested that targeted, evidence-informed strategies are needed to address access and acceptance barriers to vaccination in migrants, including the development of migrant-sensitive and adaptable vaccination services and systems, unambiguous public health messaging, and coproduction of tailored interventions.
From group to individual - Genotyping by pool sequencing eusocial colonies
Authors: Eynard Sonia E , Vignal Alain , Basso Benjamin , Le Conte Yves , Decourtye Axel , Genestout Lucie , Labarthe Emmanuelle , Mondet Fanny , Tabet Kamila , Servin Bertrand
Published: November 2021

Background

Eusocial insects play a central role in many ecosystems, and particularly the important pollinator honeybee (Apis mellifera). One approach to facilitate their study in molecular genetics, is to consider whole colonies as single individuals by combining DNA of multiple individuals in a single pool sequencing experiment. Such a technique comes with the drawback of producing data requiring dedicated analytical methods to be fully exploited. Despite this limitation, pool sequencing data has been shown to be informative and cost-effective when working on random mating populations. Here, we present new statistical methods for exploiting pool sequencing data of eusocial colonies in order to reconstruct the genotype of the colony founder, the queen. This leverages the possibility to monitor genetic diversity, perform genomic-based studies or implement selective breeding.

Results

Using simulations and honeybee real data, we show that the methods allow for a fast and accurate estimation of the genetic ancestry, with correlations of 0.9 with that obtained from individual genotyping, and for an accurate reconstruction of the queen genotype, with 2% genotyping error. We further validate the inference using experimental data on colonies with both pool sequencing and individual genotyping of drones.

Conclusion

In this study we present statistical models to accurately estimate the genetic ancestry and reconstruct the genotype of the queen from pool sequencing data from workers of an eusocial colony. Such information allows to exploit pool sequencing for traditional population genetics, association studies and selective breeding. While validated in Apis mellifera, these methods are applicable to other eusocial hymenoptera species.
Generation of a mitochondrial protein compendium in Dictyostelium discoideum
Authors: Freitas Anna V , Herb Jake T , Pan Miao , Cheng Yong , Gucek Marjan , Jin Tian , Xu Hong
Published: November 2021

The social amoeba Dictyostelium discoideum is a well-established model to study numerous cellular processes including cell motility, chemotaxis, and differentiation. As energy metabolism is involved in these processes, mitochondrial genetics and bioenergetics are of interest, though many features of Dictyostelium mitochondria differ from metazoans. A comprehensive inventory of mitochondrial proteins is critical to understanding mitochondrial processes and their involvement in various cellular pathways. Here, we utilized high-throughput multiplexed protein quantitation and homology analyses to generate a high-confidence mitochondrial protein compendium. Our proteomic approach, which utilizes quantitative mass spectrometry in combination with mathematical modeling, was validated through mitochondrial targeting sequence prediction and live-cell imaging. Our final compendium consists of 1082 proteins. Within our D. discoideum mitochondrial proteome, we identify many proteins that are not present in humans, yeasts, or the ancestral alpha-proteobacteria, which can serve as a foundation for future investigations into the unique mitochondria of Dictyostelium. Additionally, we leverage our compendium to highlight the complexity of metabolic reprogramming during starvation-induced development. Our compendium lays a foundation to investigate mitochondrial processes that are unique in protists, as well as for future studies to understand the functions of conserved mitochondrial proteins in health and diseases using D. discoideum as the model.
Modelling novelty detection in the thalamocortical loop
Authors: Han Chao , English Gwendolyn , Saal Hannes P. , Indiveri Giacomo , Gilra Aditya , von der Behrens Wolfger , Vasilaki Eleni
Published: November 2021

In complex natural environments, sensory systems are constantly exposed to a large stream of inputs. Novel or rare stimuli, which are often associated with behaviorally important events, are typically processed differently than the steady sensory background, which has less relevance. Neural signatures of such differential processing, commonly referred to as novelty detection, have been identified on the level of EEG recordings as mismatch negativity and the level of single neurons as stimulus-specific adaptation. Here, we propose a multi-scale recurrent network with synaptic depression to explain how novelty detection can arise in the whisker-related part of the somatosensory thalamocortical loop. The architecture and dynamics of the model presume that neurons in cortical layer 6 adapt, via synaptic depression, specifically to a frequently presented stimulus, resulting in reduced population activity in the corresponding cortical column when compared with the population activity evoked by a rare stimulus. This difference in population activity is then projected from the cortex to the thalamus and amplified through the interaction between neurons of the primary and reticular nuclei of the thalamus, resulting in spindle-like, rhythmic oscillations. These differentially activated thalamic oscillations are forwarded to cortical layer 4 as a late secondary response that is specific to rare stimuli that violate a particular stimulus pattern. Model results show a strong analogy between this late single neuron activity and EEG-based mismatch negativity in terms of their common sensitivity to presentation context and timescales of response latency, as observed experimentally. Our results indicate that adaptation in L6 can establish the thalamocortical dynamics that produce signatures of SSA and MMN and suggest a mechanistic model of novelty detection that could generalize to other sensory modalities.

Author summary

Cortical sensory neurons have been shown to be capable of novelty detection, that is they respond more vigorously when a novel, unexpected stimulus is presented, and less so when the stimulus is part of a predictable sequence. However, the neural mechanism underlying this capability is not yet fully understood. Here, we developed a thalamocortical network model that accounts for novelty detection and reproduces physiologically observed neural response patterns in the somatosensory cortex. Specifically, our results demonstrate that the novelty signal arises from the complex recurrent interplay between thalamic neurons and cortical neurons in layers 4 and 6. This work therefore provides a concrete mechanism that can serve as a starting point for further investigating the neural circuit mechanisms underlying novelty detection.
Light contamination in stable isotope-labelled internal peptide standards is frequent and a potential source of false discovery and quantitation error in proteomics
Authors: Salek Mogjiborahman , Förster Jonas D. , Lehmann Wolf-Dieter , Riemer Angelika B.
Published: November 2021

In mass spectrometry-based proteomics, heavy internal standards are used to validate target peptide detections and to calibrate peptide quantification. Here we report light contamination present in heavy labelled synthetic peptides of high isotopic enrichment. Application of such peptides as assay-internal standards potentially compromises the detection and quantification especially of low abundant cellular peptides. Therefore, it is important to adopt guidelines to prevent false-positive identifications of endogenous light peptides as well as errors in their quantification from biological samples.
Nucleobase clustering contributes to the formation and hollowing of repeat-expansion RNA condensate
Authors: Ma Ying-Xue , Li Hao-Zheng , Gong Zhou , Yang Shuai , Wang Ping , Tang Chun
Published: November 2021

RNA molecules with repeat expansion sequences can phase separate into gel-like condensate, and this process may lead to neurodegenerative diseases. Here we report that in the presence of Mg2+ion, RNA molecules containing 20×CAG repeats coacervate into filled droplets or hollowed condensate. Using hyperspectral stimulated Raman spectroscopy, we show that RNA coacervation is accompanied by the stacking and clustering of nucleobases, while forfeiting the canonical base-paired structure. At an increasing RNA/Mg2+ratio, the RNA droplets first expand in sizes, and then shrink and adopt hollow vesicle-like structures. Significantly, for both large and vesicle-like droplets, the nucleobase-clustered structure is more prominent at the rim than at the center, accounting for the rigidification of RNA droplets. Thus, our finding has broad implications for the general aging processes of RNA-containing membrane-less organelles.
TRIM24 controls induction of latent HIV-1 by stimulating transcriptional elongation
Authors: Horvath Riley M. , Dahabieh Matthew , Malcolm Tom , Sadowski Ivan
Published: November 2021

The conserved HIV-1 LTR cis elements RBE1/3 bind the factor RBF2, consisting of USF1/2 and TFII-I, and are essential for reactivation of HIV-1 by T cell signaling. We determined that TFII-I recruits the tripartite motif protein TRIM24 to the LTR, and this interaction is required for efficient reactivation of HIV-1 expression in response to T cell signaling, similar to the effect of TFII-I depletion. Knockout of TRIM24 did not affect recruitment of RNA Pol II to the LTR promoter, but inhibited transcriptional elongation, an effect that was associated with decreased RNA Pol II CTD S2 phosphorylation and impaired recruitment of CDK9 to the LTR. These results demonstrate that TFII-I promotes transcriptional elongation in response to T cell activation through recruitment of the co-factor TRIM24, which is necessary for efficient recruitment of the elongation factor P-TEFb.
Dosage of duplicated and antifunctionalized homeobox proteins influences spikelet development in barley
Authors: Thirulogachandar Venkatasubbu , Govind Geetha , Hensel Götz , Kale Sandip M. , Kuhlmann Markus , Eschen-Lippold Lennart , Rutten Twan , Koppolu Ravi , Rajaraman Jeyaraman , Palakolanu Sudhakar Reddy , Seiler Christiane , Sakuma Shun , Jayakodi Murukarthick , Lee Justin , Kumlehn Jochen , Komatsuda Takao , Schnurbusch Thorsten , Sreenivasulu Nese
Published: November 2021

Illuminating the mechanisms of inflorescence architecture of grain crops that feed our world may strengthen the goal towards sustainable agriculture. Lateral spikelet development of barley (Hordeum vulgare L.) is such an example of a floral architectural trait regulated by VRS1 (Vulgare Row-type Spike 1 or Six-rowed Spike 1, syn. HvHOX1). Its lateral spikelet-specific expression and the quantitative nature of suppressing spikelet development were previously shown in barley. However, the mechanistic function of this gene and its paralog HvHOX2 on spikelet development is still fragmentary.Here, we show that these duplicated transcription factors (TFs) have contrasting nucleotide diversity in various barley genotypes and several Hordeum species. Despite this difference, both proteins retain their basic properties of the homeodomain leucine zipper class I family of TFs. During spikelet development, these genes exhibit similar spatiotemporal expression patterns yet with anticyclic expression levels. A gene co-expression network analysis suggested that both have an ancestral relationship but their functions appear antagonistic to each other, i.e., HvHOX1 suppresses whereas HvHOX2 rather promotes spikelet development. Our transgenic promoter-swap analysis showed that HvHOX2 can restore suppressed lateral spikelets when expression levels are increased; however, at its low endogenous expression level, HvHOX2 appears dispensable for spikelet development. Collectively, this study proposes that the dosage of the two antagonistic TFs, HvHOX1 and HvHOX2, influence spikelet development in barley.
Automated BIM schedule generation approach for solving time–cost trade-off problems
Authors: ElMenshawy Mohamed , Marzouk Mohamed
Published: November 2021

Purpose

Nowadays, building information modeling (BIM) represents an evolution in the architecture, engineering and construction (AEC) industries with its various applications. BIM is capable to store huge amounts of information related to buildings which can be leveraged in several areas such as quantity takeoff, scheduling, sustainability and facility management. The main objective of this research is to establish a model for automated schedule generation using BIM and to solve the time–cost trade-off problem (TCTP) resulting from the various scenarios offered to the user.

Design/methodology/approach

A model is developed to use the quantities exported from a BIM platform, then generate construction activities, calculate the duration of each activity and finally the logic/sequence is applied in order to link the activities together. Then, multiobjective optimization is performed using nondominated sorting genetic algorithm (NSGA-II) in order to provide the most feasible solutions considering project duration and cost. The researchers opted NSGA-II because it is one of the well-known and credible algorithms that have been used in many applications, and its performances were tested in several comparative studies.

Findings

The proposed model is capable to select the near-optimum scenario for the project and export it to Primavera software. A case study is worked to demonstrate the use of the proposed model and illustrate its main features.

Originality/value

The proposed model can provide a simple and user-friendly model for automated schedule generation of construction projects. In addition, opportunities related to the interface between an automated schedule generation model and Primavera software are enabled as Primavera is one of the most popular and common schedule software solutions in the construction industry. Furthermore, it allows importing data from MS Excel, which is used to store activities data in the different scenarios. In addition, there are numerous solutions, each one corresponds to a certain duration and cost according to the performance factor which often reflects the number of crews assigned to the activity and/or construction method.