bluuebunny/crossref_metadata_2025 huggingface dataset:
Phylloxera and aphids show distinct features of genome evolution despite similar reproductive modes
Authors: Li Zheng , Xue Allen Z. , Maeda Gerald P. , Li Yiyuan , Nabity Paul D. , Moran Nancy A.
Published: August 2023

Genomes of aphids (family Aphididae) show several unusual evolutionary patterns. In particular, within the XO sex determination system of aphids, the X chromosome exhibits a lower rate of interchromosomal rearrangements, fewer highly expressed genes, and faster evolution at nonsynonymous sites compared to the autosomes. In contrast, other hemipteran lineages have similar rates of interchromosomal rearrangement for autosomes and X chromosomes. One possible explanation for these differences is the aphid’s life cycle of cyclical parthenogenesis, where multiple asexual generations alternate with one sexual generation. If true, we should see similar features in the genomes of Phylloxeridae, an outgroup of aphids which also undergoes cyclical parthenogenesis. To investigate this, we generated a chromosome-level assembly for the grape phylloxera, an agriculturally important species of Phylloxeridae, and identified its single X chromosome. We then performed synteny analysis using the phylloxerid genome and 30 high-quality genomes of aphids and other hemipteran species. Unexpectedly, we found that the phylloxera does not share aphids’ patterns of chromosome evolution. By estimating interchromosomal rearrangement rates on an absolute time scale, we found that rates are elevated for aphid autosomes compared to their X chromosomes, but this pattern does not extend to the phylloxera branch. Potentially, the conservation of X chromosome gene content is due to selection on XO males that appear in the sexual generation. We also examined gene duplication patterns across Hemiptera and uncovered horizontal gene transfer events contributing to phylloxera evolution.
Comparing tonic and phasic calcium in the dendrites of vulnerable midbrain neurons
Authors: Chen Rita Yu-Tzu , Evans Rebekah C.
Published: August 2023

Several midbrain nuclei degenerate in Parkinson’s Disease (PD). Many of these nuclei share the common characteristics that are thought to contribute to their selective vulnerability, including pacemaking activity and high levels of calcium influx. In addition to the well-characterized dopaminergic neurons of the substantia nigra pars compacta (SNc), the cholinergic neurons of the pedunculopontine nucleus (PPN) also degenerate in PD. It is well established that the low-threshold L-type calcium current is a main contributor to tonic calcium in SNc dopaminergic neurons and is hypothesized to contribute to their selective vulnerability. However, it is not yet clear whether the vulnerable PPN cholinergic neurons share this property. Therefore, we used two-photon dendritic calcium imaging and whole-cell electrophysiology to evaluate the role of L-type calcium channels in the tonic and phasic activity of PPN neurons and the corresponding dendritic calcium signal and directly compare these characteristics to SNc neurons. We found that blocking L-type channels reduces tonic firing rate and dendritic calcium levels in SNc neurons. By contrast, the calcium load in PPN neurons during pacemaking did not depend on L-type channels. However, we find that blocking L-type channels reduces phasic calcium influx in PPN dendrites. Together, these findings show that L-type calcium channels play different roles in the activity of SNc and PPN neurons, and suggest that low-threshold L-type channels are not responsible for tonic calcium levels in PPN cholinergic neurons and are therefore not likely to be a source of selective vulnerability in these cells.
Sex Differences in Discrimination Behavior and Orbitofrontal Engagement During Context-Gated Reward Prediction
Authors: Peterson Sophie , Maheras Amanda , Chavira Jose , Wu Brenda , Keiflin Ronald
Published: August 2023

Animals, including humans, rely on contextual information to interpret ambiguous stimuli. Impaired context processing is a hallmark of several neuropsychiatric disorders, including schizophrenia, autism spectrum disorders, post-traumatic stress disorder, and addiction. While sex differences in the prevalence and manifestations of these disorders are well established, potential sex differences in context processing remain uncertain. Here we examined sex differences in the contextual control over cue-evoked reward seeking and its neural correlates, in rats. Male and female rats were trained in a bidirectional occasion-setting preparation in which the validity of two auditory reward-predictive cues was informed by the presence, or absence, of a visual contextual feature (LIGHT: X+ / DARK: X− / LIGHT: Y− / DARK: Y+). Females were significantly slower to acquire contextual control over cue-evoked reward seeking. However, once established, the contextual control over behavior was more robust in female rats; it showed less within-session variability (less influence of prior reward) and greater resistance to acute stress. This superior contextual control achieved by females was accompanied by an increased activation of the orbitofrontal cortex compared to males. Critically, these behavioral and neural sex differences were specific to the contextual modulation process and not observed in simple, context-independent, reward prediction tasks. These results indicate a sex-biased trade-off between the speed of acquisition and the robustness of performance in the contextual modulation of cued reward seeking. The different distribution of sexes along the fast learning ↔ steady performance continuum might reflect different levels of engagement of the orbitofrontal cortex, and might have implications for our understanding of sex differences in psychiatric disorders.
Cortico-hippocampal representational similarity contributes to learning of multiple motor sequences
Authors: Yoon Seojin , Kim Sungshin
Published: August 2023

Cortico-hippocampal interaction is integral to memory consolidation during sleep or wakeful rest. However, the extent of its engagement in non-declarative motor memory during skill learning remains largely undefined. Specifically, it remains unclear how neural representations in cortical and hippocampal regions are related to learning multiple motor sequences. Here, we conducted an fMRI experiment in which participants learned four distinct motor sequences in a pseudo-random order with interleaved rest periods. We found pattern separation in the sensorimotor regions was significant, particularly in the anterior motor cortex, related to early learning performance. However, there was no pattern separation in the hippocampus during the rest periods. Intriguingly, the representational similarity between the motor cortex during task periods and the hippocampus during rest periods was highly correlated with overall learning performance. These findings suggest a new role of hippocampal replay in motor sequence learning, that is, learning a more abstract relational structure of sequences instead of representing sequences per se.
ASTA-P: a pipeline for the detection, quantification and statistical analysis of complex alternative splicing events
Authors: Tiwari Kanupriya , Nielsen Lars Keld
Published: August 2023

Alternative splicing dramatically increases the repertoire of the human transcriptome and plays a critical role in cellular differentiation. Long read sequencing has dramatically improved our ability to explore isoform diversity directly. However, short read sequencing still provides advantages in terms of sequencing depth at low cost, which is important in comparative quantitative studies. Here, we present a pipeline called ASTA-P for profiling, quantification, and differential splicing analysis of tissue-specific, arbitrarily complex alternative splicing patterns. We discover novel events by supplementing existing annotation with reconstructed transcripts and use spliced RNA-seq reads to quantify splicing changes accurately based on their unique assignments. We used simulated RNA-seq data to demonstrate that ASTA-P provides a good trade-off between discovery and accuracy compared with several popular methods. Further, we applied ASTA-P to analyse AS patterns in real data from hiPSC derived cranial neural crest cells capturing the transition from primary neural cells into migratory cranial neural crest cells, differentiated by their expression of the transcription factor, SOX10. Our analysis revealed a significant splicing complexity, i.e., numerous AS events that cannot be described using the conventionally analysed 2D splicing event patterns. Such events are misclassified when analysed using current differential splicing analysis methods. Thus, ASTA-P provides a new approach for studying both conventional and complex splicing across different cellular conditions and the dynamic regulation of AS. The pipeline is available athttps://github.com/uqktiwar/ASTAP/tree/main
The Atad5 RFC-like complex is the major unloader of proliferating cell nuclear antigen inXenopusegg extracts
Authors: Kawasoe Yoshitaka , Shimokawa Sakiko , Gillespie Peter J. , Blow J. Julian , Tsurimoto Toshiki , Takahashi Tatsuro S.
Published: August 2023

Proliferating cell nuclear antigen (PCNA) is a homo-trimeric clamp complex that serves as the molecular hub for various DNA transactions, including DNA synthesis and post-replicative mismatch repair. Its timely loading and unloading are critical for genome stability. PCNA loading is catalyzed by Replication factor C (RFC) and the Ctf18 RFC-like complex (Ctf18-RLC), and its unloading is catalyzed by Atad5/Elg1-RLC. However, RFC, Ctf18-RLC, and even some subcomplexes of their shared subunits are capable of unloading PCNAin vitro, leaving an ambiguity in the division of labor in eukaryotic clamp dynamics. By using a system that specifically detects PCNA unloading, we show here that Atad5-RLC, which accounts for only approximately 3% of RFC/RLCs, nevertheless provides the major PCNA unloading activity inXenopusegg extracts. RFC and Ctf18-RLC each account for approximately 40% of RFC/RLCs, while immunodepletion of neither Rfc1 nor Ctf18 detectably affects the rate of PCNA unloading in our system. PCNA unloading is dependent on the ATP-binding motif of Atad5, independent of nicks on DNA and chromatin assembly, and inhibited effectively by PCNA-interacting peptides. These results support a model in which Atad5-RLC preferentially unloads DNA-bound PCNA molecules that are free from their interactors.
Effectiveness of mass dengue vaccination in the state of Paraná, Brazil: integrating case-cohort and case-control designs
Authors: Diaz-Quijano Fredi Alexander , de Carvalho Denise Siqueira , Raboni Sonia Mara , Shimakura Silvia Emiko , de Mello Angela Maron , da Costa-Ribeiro Magda Clara Vieira , Silva Lineu , da Cruz Magalhães Buffon Marilene , Maluf Eliane Mara Cesario Pereira , Graeff Gabriel , Almeida Gustavo , Preto Clara , Luhm Karin Regina
Published: August 2023

We aimed to estimate the effectiveness of CYD-TDV in preventing symptomatic dengue cases during a campaign targeting individuals aged 15-27 years in selected municipalities in Paraná, Brazil. Additionally, we examined whether a history of dengue, as recorded by the surveillance system, modified the vaccine’s effectiveness.

Methods

We conducted a case-cohort analysis comparing the frequency of vaccination, with at least one dose of CYD-TDV, in individuals confirmed to have dengue by RT-PCR, identified by the surveillance system during 2019 and 2020, with the vaccination coverage in the target population. Moreover, with a case-control design using weighted controls, we assessed the history of dengue as a modifier of the vaccine’s effectiveness. The analyses were performed using a logistic random-effects regression model, with data clustered in municipalities and incorporating covariates such as the incidence of dengue before the campaign, age, and sex.

Results

During the study period, 1,869 cases of dengue were identified. The vaccination frequency among these cases was significantly lower than the overall vaccination coverage of the participating municipalities (50.4% vs. 57.2%, respectively; adjusted odds ratio: 0.79; 95% confidence interval: 0.72–0.87). In individuals with a history of dengue, vaccination was more than 70% effective in reducing the incidence of dengue. However, vaccination was not associated with significantly reducing the overall dengue case risk in individuals without a history of dengue.

Conclusion

Vaccination significantly decreased dengue cases in the target population. The case-control design suggested that this reduction was primarily driven by the benefits seen in individuals with a history of dengue. Previous dengue diagnosis recorded by epidemiological surveillance could serve as a criterion for the recommendation of CYD-TDV, especially in endemic regions with limited serological testing facilities.
Outpatient treatment with concomitant vaccine-boosted convalescent plasma for patients with immunosuppression and COVID-19
Authors: Ripoll Juan G. , Tulledge-Scheitel Sidna M. , Stephenson Anthony A. , Ford Shane , Pike Marsha L. , Gorman Ellen K. , Hanson Sara N. , Juskewitch Justin E. , Miller Alex J. , Zaremba Solomiia , Ovrom Erik A. , Razonable Raymund R. , Ganesh Ravindra , Hurt Ryan T. , Fischer Erin N. , Derr Amber N. , Eberle Michele R. , Larsen Jennifer J. , Carney Christina M. , Theel Elitza S. , Parikh Sameer A. , Kay Neil E. , Joyner Michael J. , Senefeld Jonathon W.
Published: August 2023

Although severe coronavirus disease 2019 (COVID-19) and hospitalization associated with COVID-19 are generally preventable among healthy vaccine recipients, patients with immunosuppression have poor immunogenic responses to COVID-19 vaccines and remain at high risk of infection with SARS-CoV-2 and hospitalization. Additionally, monoclonal antibody therapy is limited by the emergence of novel SARS-CoV-2 variants that have serially escaped neutralization. In this context, there is interest in understanding the clinical benefit associated with COVID-19 convalescent plasma collected from persons who have been both naturally infected with SARS-CoV-2 and vaccinated against SARS-CoV-2 (“vax-plasma”). Thus, we report the clinical outcome of 386 immunocompromised outpatients who were diagnosed with COVID-19 and who received contemporary COVID-19 specific therapeutics (standard of care group) and a subgroup who also received concomitant treatment with very high titer COVID-19 convalescent plasma (vax-plasma group) with a specific focus on hospitalization rates. The overall hospitalization rate was 2.2% (5 of 225 patients) in the vax-plasma group and 6.2% (10 of 161 patients) in the standard of care group, which corresponded to a relative risk reduction of 65% (P=0.046). Evidence of efficacy in nonvaccinated patients cannot be inferred from these data because 94% (361 of 386 patients) of patients were vaccinated. In vaccinated patients with immunosuppression and COVID-19, the addition of vax-plasma or very high titer COVID-19 convalescent plasma to COVID-19 specific therapies reduced the risk of disease progression leading to hospitalization.

IMPORTANCE

As SARS-CoV-2 evolves, new variants of concern (VOCs) have emerged which evade available anti-spike monoclonal antibodies, particularly among immunosuppressed patients. However, high-titer COVID-19 convalescent plasma continues to be effective against VOCs because of its broad-spectrum immunomodulatory properties. Thus, we report clinical outcomes of 386 immunocompromised outpatients who were treated with COVID-19 specific therapeutics and a subgroup also treated with vaccine-boosted convalescent plasma. We found that administration of vaccine-boosted convalescent plasma was associated with a significantly decreased incidence of hospitalization among immunocompromised COVID-19 outpatients. Our data add to the contemporary data providing evidence to support the clinical utility of high-titer convalescent plasma as antibody replacement therapy in immunocompromised patients.
A Systematic Review on the Effect of Diabetes Mellitus on the Pharmacokinetics of Tuberculosis Drugs
Authors: Cevik Muge , Sturdy Ann , Maraolo Alberto Enrico , Dekkers Bart G.J. , Akkerman Onno W. , Gillespie Stephen H. , Alffenaar Jan-Willem C.
Published: August 2023

Objectives

The coexistence of TB and DM (TB-DM) has been associated with an increased risk of treatment failure, death, delayed culture conversion and drug resistance. As plasma concentrations may influence clinical outcomes, we evaluated the evidence on the PK of TB drugs in DM individuals to guide management.

Methods

We performed a systematic review and meta-analysis through searches of major databases from 1946 to 6 July 2023. PROSPERO (CRD42022323566).

Results

Out of 4173 potentially relevant articles, we identified 16 studies assessing rifampicin PK, 9 on isoniazid, 8 on pyrazinamide and 3 on ethambutol. Two studies reported on second line anti-TB drugs. According to our analysis, RIF Tmax was significantly prolonged in patients with DM compared to non-DM patients. We found no significant differences for RIF Cmax, AUC0-24or C2hr, INH C2hr, PZA C2hr, PZA Tmaxand ETB Tmax. While RIF C2hr was slightly reduced in TB-DM patients, this finding was not statistically significant.

Conclusions

This review comprehensively examines the impact of DM on the PK of TB drugs. We observed significant heterogeneity among studies. Given the association between lower plasma concentrations and poor clinical outcomes among DM patients, we recommend a higher dose limit to correct for larger bodyweight of patients with DM.
Changes in respiratory infection trends during the COVID-19 pandemic in the haematologic malignancy patients
Authors: RYOO Jiwon , Kim Seok Chan , Lee Jongmin
Published: August 2023

Background

The coronavirus disease 2019 (COVID-19) pandemic globally changed respiratory infection patterns. However, its impact on community-acquired pneumonia (CAP) in high risk patients with haematological malignancies (HM) is uncertain. We aimed to examine CAP aetiology changes in patients with HM pre- and post-COVID-19 pandemic.

Methods

This retrospective study included 524 HM patients hospitalised with CAP between March 2018 and February 2022. Those who underwent bronchoscopy within 24 hours after admission to identify CAP aetiology were included. Data on patient characteristics, laboratory findings, and results of bronchioalveolar lavage fluid cultures and PCR tests were analysed to compare etiological changes and identify in-hospital mortality risk factors.

Results

Patients were divided into pre-COVID-19 (44.5%) and post-COVID-19 (55.5%) groups. This study found a significant decrease in viral CAP in the post-COVID-19 era, particularly for influenza A, parainfluenza, adenovirus, and rhinovirus (3.0% vs. 0.3%, respectively, P = 0.036; 6.5% vs. 0.7%, respectively, P = 0.001; 5.6% vs. 1.4%, respectively, P = 0.015; 9.5% vs. 1.7%, respectively, P < 0.001). Bacterial, fungal, and unknown CAP aetiologies remain unchanged. Higher Sequential Organ Failure Assessment scores and lower platelet count correlated with in-hospital mortality after adjusting for potential confounding factors.

Conclusion

The incidence of CAP in HM patients did not decrease after COVID-19. Additionally, CAP aetiology among patients with HM changed following the COVID-19 pandemic, with a significant reduction in viral pneumonia while bacterial and fungal pneumonia persisted. Further studies are required to evaluate the impact of COVID-19 on the prognosis of patients with HM and CAP.
Atypical memory B cells form a pre-plasmacellular reservoir for steady-state IgD responses to common nasopharyngeal antigens
Authors: Tachó-Piñot Roser , Bashour Habib , Filipska Martyna , Tejedor-Vaquero Sonia , de Campos-Mata Leire , Sáez-Gordón Alba , Perera-Bel Júlia , Guzman Mauricio , Marcos-Fa Xavi , Canales-Herrerias Pablo , Domínguez-Barragán Jorge , Arcós-Ribas Berta , Slabodkin Andrei , Chernigovskaya Maria , de la Concepción María Luisa Rodríguez , Gutierrez-Marcos José , García-García Ana , Nascimento-Osorio Andrés , Pascal Mariona , Alsina Laia , Aróstegui Juan I. , Mehandru Saurabh , Cunningham-Rundles Charlotte , Carrillo Jorge , Magri Giuliana , Greiff Victor , Cerutti Andrea
Published: August 2023

The human nasopharyngeal mucosa includes organized lymphoepithelial structures continually engaged in frontline immune responses to aerodigestive antigens. Advancing our understanding of these responses might lead to the development of new strategies for the prevention and treatment of common immune disorders such as allergies. Here we identified a hitherto elusive tonsillar subset of atypical IgD class-switched IgD+IgM-memory (IgD-ME) B cells that were clonally related to IgD+IgM−germinal center (IgD-GC) B cells and IgD-secreting IgD+IgM−plasma cells (IgD-PCs) but not anergic IgD+IgM−B cells. Consistent with their pre-plasmacellular properties, IgD-ME B cells served as preferential precursors of IgD-PCs over IgD-GC B cells. IgD antibodies from IgD+IgM−cells acquired reactivity to multiple oral, airborne and commensal antigens through a mutation-dependent pathway involving both innate and adaptive signals. Thus, IgD-ME B cells may form a ready-to-use pre-plasmacellular reservoir for steady-state IgD responses likely aimed at enhancing nasopharyngeal homeostasis.

One Sentence Summary

Tonsillar atypical memory B cells form a ready-to-use pre-plasmacellular repertoire for IgD responses to common aerodigestive antigens.
Building a realistic, scalable memory model with independent engrams using a homeostatic mechanism
Authors: Kaster Marvin , Czappa Fabian , Butz-Ostendorf Markus , Wolf Felix
Published: August 2023

Memory formation is usually associated with Hebbian learning, using synaptic plasticity to change the synaptic strengths but omitting structural changes. Recent work suggests that structural plasticity can also lead to silent memory engrams, reproducing a conditioned learning paradigm with neuron ensembles. However, this work is limited by its way of synapse formation, enabling the formation of only one memory engram. Overcoming this, our model allows the formation of many engrams simultaneously while retaining high neurophysiological accuracy, e.g., as found in cortical columns. We achieve this by substituting the random synapse formation with the Model of Structural Plasticity (Butz and van Ooyen, 2013). As a homeostatic model, neurons regulate their activity by growing and pruning synaptic elements based on their current activity. Utilizing synapse formation based on the Euclidean distance between the neurons with a scalable algorithm allows us to easily simulate 4 million neurons with 343 memory engrams. These engrams do not interfere with one another by default, yet we can change the simulation parameters to form long-reaching associations. Our model paves the way for simulations addressing further inquiries, ranging from memory chains and hierarchies to complex memory systems comprising areas with different learning mechanisms.
Opportunities for risk-taking during play alters cognitive performance and prefrontal inhibitory signalling in rats of both sexes
Authors: Bijlsma Ate , Birza Evelien E. , Pimentel Tara C. , Maranus Janneke P.M. , van Gaans Marieke J.J.M , Lozeman-van t Klooster José G. , Baars Annemarie J.M. , Achterberg E.J. Marijke , Lesscher Heidi M.B. , Wierenga Corette J. , Vanderschuren Louk J.M.J.
Published: August 2023

Social play behaviour is a rewarding activity that can entail risks, thus allowing young individuals to test the limits of their capacities and to train their cognitive and emotional adaptability to challenges. Here, we tested in rats how opportunities for risk-taking during play affect the development of cognitive and emotional capacities and medial prefrontal cortex (mPFC) function, a brain structure important for risk-based decision-making. Male and female rats were housed socially or social play-deprived (SPD) between postnatal day (P)21 and P42. During this period, half of both groups were daily exposed to a high-risk play environment. Around P85, all rats were tested for cognitive performance and emotional behaviour after which inhibitory currents were recorded in layer 5 pyramidal neurons in mPFC slices. We show that playing in a high-risk environment altered cognitive flexibility in both sexes, and improved behavioural inhibition in males. High-risk play altered anxiety-like behaviour in the elevated plus maze in males and in the open field in females, respectively. SPD affected cognitive flexibility in both sexes and decreased anxiety-like behaviour in the elevated plus maze in females. We found that synaptic inhibitory currents in the mPFC were increased in male, but not female, rats after high-risk play, while SPD lowered PFC synaptic inhibition in both sexes. Together, our data show that exposure to risks during play affects the development of cognition, emotional behaviour and inhibition in the mPFC. Furthermore, our study suggests that the opportunity to take risks during play cannot substitute for social play behaviour.
Treatment with a selective histone deacetylase (HDAC) 1 and 2 inhibitor in aged mice rejuvenates multiple organ systems
Authors: Tammaro Alessandra , Daniels Eileen G. , Hu Iman M. , ‘t Hart Kelly C. , Reid Kim , Juni Rio P. , Butter Loes M. , Vasam Goutham , Kamble Rashmi , Jongejan Aldo , Aviv Richard I. , Roelofs Joris J.T.H. , Aronica Eleonora , Boon Reinier A. , Menzies Keir J. , Houtkooper Riekelt H. , Janssens Georges E.
Published: August 2023

The process of aging increases the risk of developing age-related diseases, which come at great societal healthcare costs and suffering to individuals. Meanwhile, targeting the basic mechanisms of aging can reduce the risk of developing age-related diseases during aging, essentially resulting in a ‘healthy aging’ process. Multiple aging pathways exist, which over past decades have systematically been confirmed through gene knockout or overexpression studies in mammals and the ability to increase healthy lifespan. In this work, we perform transcriptome-based drug screening to identify small molecules that mimic the transcriptional profiles of long-lived genetic interventions in mammals. We identify one small molecule whose transcriptional effects mimic diverse known genetic longevity interventions: compound 60 (Cmpd60), which is a selective inhibitor of histone deacetylase 1 (HDAC1) and 2 (HDAC2). In line with this, in a battery of molecular, phenotypic, and bioinformatic analyses, in multiple disease cell and animal models, we find that Cmpd60 treatment rejuvenates multiple organ systems. These included the kidney, brain, and heart. In renal aging, Cmpd60 reduced partial epithelial-mesenchymal transition (EMT)in vitroand decreased fibrosisin vivo. For the aging brain, Cmpd60 reduced dementia-related gene expressionin vivo, effects that were recapitulated when treating the APPSWE-1349 Alzheimer mouse. In cardiac aging, Cmpd60 treatment activated favorable developmental gene expressionin vivoand in line with this, improved ventricular cardiomyocyte contraction and relaxation in a cell model of cardiac hypertrophy. Our work establishes that a systemic, two-week treatment with an HDAC1/2 inhibitor serves as a multi-tissue, healthy aging intervention in mammals. This holds potential for translation towards therapeutics that promote healthy aging in humans.
Open access-enabled evaluation of epigenetic age acceleration in colorectal cancer and development of a classifier with diagnostic potential
Authors: Widayati Tyas Arum , Schneider Jadesada , Panteleeva Kseniia , Chernysheva Elizabeth , Hrbkova Natalie , Beck Stephan , Voloshin Vitaly , Chervova Olga
Published: August 2023

Aberrant DNA methylation (DNAm) is known to be associated with the aetiology of cancer, including colorectal cancer (CRC). In the past, the availability of open access data has been the main driver of innovative method development and research training. However, this is increasingly being eroded by the move to controlled access, particularly of medical data, including cancer DNAm data. To rejuvenate this valuable tradition, we leveraged DNAm data from 1,845 samples (535 CRC tumours, 522 normal colon tissues adjacent to tumours, 72 colorectal adenomas, and 716 normal colon tissues from healthy individuals) from 14 open access studies deposited in NCBI GEO and ArrayExpress. We calculated each sample’s epigenetic age (EA) using eleven epigenetic clock models and derived the corresponding epigenetic age acceleration (EAA). For EA, we observed that most first- and second-generation epigenetic clocks reflect the chronological age in normal tissues adjacent to tumours and healthy individuals (e.g. Horvath (r= 0.77 and 0.79), Zhang EN (r= 0.70 and 0.73)) unlike the epigenetic mitotic clocks (EpiTOC, HypoClock, MiAge) (r <0.3). For EAA, we used PhenoAge, Wu, and the above mitotic clocks and found them to have distinct distributions in different tissue types, particularly between normal colon tissues adjacent to tumours and cancerous tumours, as well as between normal colon tissues adjacent to tumours and normal colon tissue from healthy individuals. Finally, we harnessed these associations to develop a classifier using elastic net regression (with lasso and ridge regularisations) that predicts CRC diagnosis based on a patient’s sex and EAAs calculated from histologically normal controls (i.e. normal colon tissues adjacent to tumours and normal colon tissue from healthy individuals). The classifier demonstrated good diagnostic potential with ROC-AUC=0.886, which suggests that an EAA-based classifier trained on relevant data could become a tool to support diagnostic/prognostic decisions in CRC for clinical professionals. Our study also reemphasises the importance of open access clinical data for method development and training of young scientists. Obtaining the required approvals for controlled access data would not have been possible in the timeframe of this study.
The A53T mutation in α-synuclein enhances pro-inflammatory activation in human microglia
Authors: Krzisch Marine , Yuan Bingbing , Chen Wenyu , Osaki Tatsuya , Fu Dongdong , Garrett-Engele Carrie , Svoboda Devon , Andrykovich Kristin , Sur Mriganka , Jaenisch Rudolf
Published: August 2023

Parkinson’s disease (PD) is characterized by the aggregation of α-synuclein into Lewy bodies and Lewy neurites in the brain. Microglia-driven neuroinflammation may contribute to neuronal death in PD, however the exact role of microglia remains unclear and has been understudied. The A53T mutation in the gene coding for α-synuclein has been linked to early-onset PD, and exposure to A53T-mutant human α-synuclein increases the potential for inflammation of murine microglia. To date, its effect has not been studied in human microglia. Here, we used 2-dimensional cultures of human iPSC-derived microglia and transplantation of these cells into the mouse brain to assess the effects of the A53T mutation on human microglia. We found that A53T-mutant human microglia had an intrinsically increased propensity towards pro-inflammatory activation upon inflammatory stimulus. Additionally, A53T mutant microglia showed a strong decrease in catalase expression in non-inflammatory conditions, and increased oxidative stress. Our results indicate that A53T mutant human microglia display cell-autonomous phenotypes that may worsen neuronal damage in early-onset PD.
Genome Report: First whole genome sequence and assembly of the Ecuadorian brown-headed spider monkey (Ateles fusciceps fusciceps), a critically endangered species, using Oxford Nanopore Technologies
Authors: Pozo Gabriela , Quintana Martina Albuja , Larreátegui Lizbeth , Gutiérrez Bernardo , Fuentes Nathalia , Alfonso-Cortés Felipe , de Lourdes Torres María
Published: August 2023

The Ecuadorian brown-headed spider monkey (Ateles fusciceps fusciceps) is currently considered one of the most endangered primates in the world and is classified as critically endangered (IUCN). It faces multiple threats, the most significant one being habitat loss due to deforestation in western Ecuador. Genomic tools are key for the management of endangered species, but this requires a reference genome which until now was unavailable forA. f. fusciceps. The present study reports the first whole genome sequence and assembly ofA. f. fuscicepsgenerated using Oxford Nanopore long reads. DNA was extracted from a subadult male and libraries were prepared for sequencing following the Ligation Sequencing Kit SQK-LSK112 workflow. Sequencing was performed using a MinION Mk1C sequencer. The sequencing reads were processed to generate a genome assembly. Two different assemblers were used to obtain draft genomes using raw reads, of which the Flye assembly was found to be superior. The final assembly has a total length of 2.63 Gb and contains 3,861 contigs, with an N50 of 7,560,531 bp. The assembly was analyzed for annotation completeness based on primate ortholog prediction using a high-resolution database, and was found to be 84.3% complete, with a low number of duplicated genes indicating a precise assembly. The annotation of the assembly predicted 31,417 protein-coding genes, comparable to other mammal assemblies. A reference genome for this critically endangered species will allow researchers to gain insight into the genetics of its populations and thus aid conservation and management efforts of this vulnerable species.
Visual looming is a primitive for human emotion
Authors: Thieu Monica K. , Ayzenberg Vladislav , Lourenco Stella F. , Kragel Philip A.
Published: August 2023

Looming objects afford threat of collision across the animal kingdom. Defensive responses to looming and neural computations for looming detection are strikingly conserved across species. In mammals, information about rapidly approaching threats is conveyed from the retina to the midbrain superior colliculus, where variables that indicate the position and velocity of approach are computed to enable defensive behavior. Although neuroscientific theories posit that midbrain representations contribute to emotion through connectivity with distributed brain systems, it remains unknown whether a computational system for looming detection can predict both defensive behavior and phenomenal experience in humans. Here, we show that a shallow convolutional neural network based on theDrosophilavisual system predicts defensive blinking to looming objects in infants and superior colliculus responses to optical expansion in adults. Further, the responses of the convolutional network to a broad array of naturalistic video clips predict self-reported emotion largely on the basis of subjective arousal. Our findings illustrate how motor and experiential components of human emotion relate to species-general systems for survival in unpredictable environments.
Repair of CRISPR-guided RNA breaks enables site-specific RNA editing in human cells
Authors: Nemudraia Anna , Nemudryi Artem , Wiedenheft Blake
Published: August 2023

Genome editing with CRISPR RNA-guided endonucleases generates DNA breaks that are resolved by cellular DNA repair machinery. However, analogous methods to manipulate RNA remain unavailable. Here, we show that site-specific RNA breaks generated with RNA-targeting CRISPR complexes are repaired in human cells, and this repair can be used for programmable deletions in human transcripts that restore gene function. Collectively, this work establishes a technology for precise RNA manipulation with potential therapeutic applications.

One-Sentence Summary

CRISPR-guided RNA breaks are repaired in human cells, and this RNA repair can be used for programmable editing of human transcriptomes.
Logic Gate Activated Lysosome Targeting DNA Nanodevice for Controlled Proteins Degradation
Authors: Shang Yuzhe , Zhu Longyi , Xiao Yang , Du Songyuan , Ji Ruoyang , Li Bin , Chen Jialiang , Deng Shengyuan , Ren Kewei
Published: August 2023

Targeted protein degradation (TPD) is a powerful technique for regulation of protein homeostasis. Current TPD mainly focuses on the therapeutical consequences rather than the operation processes of the molecular tools. Herein, we construct a platform for precisely manipulate the protein degradation by activatable lysosome targeting DNA nanodevices. In the design, a lysosome-targeting CD63 aptamer is locked by the single-stranded DNA with a photocleavable group and a disulfide bond. This locked CD63 aptamer is connected with the aptamer targeting the protein of interest via double-stranded DNA linkages to form the logic-gate activated lysosome targeting DNA nanodevice (LALTD). With the UV light and endogenous GSH as inputs, AND logic-gate is built to efficiently manipulate the protein delivery processes by LALTD. The protein of interest could be degraded via efficient lysosome hydrolysis. Further studies shows that the logic-gate operation could be used for modulating the T cell-mediated antitumor immunity. The modularly designed activatable lysosome targeting DNA nanodevices exhibits good stability, controllability, programmability and universality, providing a new prospect for accurate protein degradation and precise therapy.

Entry for the Table of Contents

Through rational integration of dual molecular switches with bispecific aptamer systems, a logic-gate activated lysosome targeting DNA nanodevice (LALTD) was developed for precisely controlled process of protein hydrolysis in living cells. The designed LALTD system provide a general platform for designing accurate protein degradation.
Vaccination status and re-infection among COVID patients admitted in COVID High Dependency Unit (HDU) of a tertiary hospital in Eastern Nepal: A cross-sectional study
Authors: Kafle Sujan , Chhetri Varsha , Bajracharya Joshan Lal , Pokharel Lenish , Dawadi Suyash , Basnet Ujwal , Dhungana Shreya , Neupane Durga
Published: August 2023

Introduction

The relationship between COVID-19 vaccination and Coronavirus disease severity and outcomes remain topics of significant interest. This cross-sectional study done among COVID-19 patients admitted to the High-dependency unit of a tertiary hospital in Eastern Nepal aimed to assess the association between vaccination status, prior infection, and disease outcomes, and the modification of these associations by the presence or absence of comorbidities.

Methodology

Demographic and clinical data were collected from 102 COVID-19 patients admitted to the High-Dependency Unit of Mechi Zonal Hospital, including information on vaccination status, comorbidities, disease severity, and outcomes. Statistical analysis, including chi-square tests and Fisher’s exact tests, was performed to examine the associations.

Results

Among the study participants, 49% had received at least one dose of COVID-19 vaccine. Vaccinated individuals had a significantly lower rate of severe disease compared to non-vaccinated individuals (χ²=10.05, p=0.002). Recovery and mortality rates did not differ significantly between the two groups (χ²=1.008, p=0.315). However, when stratified by comorbidities, vaccinated individuals with comorbidities had higher recovery rates compared to non-vaccinated individuals (85.29% vaccinated vs. 25.00% non-vaccinated, Fisher’s exact test p=0.024). Vaccinated individuals, both with and without comorbidities, had lower rates of severe disease compared to non-vaccinated individuals. However, the association was found to be significant only in individuals with comorbidities (12.50% vaccinated without comorbidities vs. 47.92% non-vaccinated, p=0.017; 23.53% vaccinated with comorbidities vs. 75.00% non-vaccinated, p=0.065).

Conclusion

Our findings suggest that COVID-19 vaccination is associated with a reduced risk of severe disease among individuals with or without comorbidities and decreased risk of mortality among those with comorbidities. However, larger studies are needed to validate these findings and further explore the impact of vaccination on disease outcomes. These findings support the ongoing efforts to promote COVID-19 vaccination as a crucial public health intervention.
Opto4E-BP, an optogenetic tool for inducible, reversible, and cell type-specific inhibition of translation initiation
Authors: Alapin Jessica M. , Mohamed Muhaned S. , Shrestha Prerana , Khaled Houda G. , Vorabyeva Anna G. , Bowling Heather L. , Oliveira Mauricio M. , Klann Eric
Published: August 2023

The protein kinase mechanistic target of rapamycin complex 1 (mTORC1) is one of the primary triggers for initiating cap-dependent translation. Amongst its functions, mTORC1 phosphorylates eIF4E-binding proteins (4E-BPs), which prevents them from binding to eIF4E and thereby enables translation initiation. mTORC1 signaling is required for multiple forms of protein synthesis-dependent synaptic plasticity and various forms of long-term memory (LTM), including associative threat memory. However, the approaches used thus far to target mTORC1 and its effectors, such as pharmacological inhibitors or genetic knockouts, lack fine spatial and temporal control. The development of a conditional and inducible eIF4E knockdown mouse line partially solved the issue of spatial control, but still lacked optimal temporal control to study memory consolidation. Here, we have designed a novel optogenetic tool (Opto4E-BP) for cell type-specific, light-dependent regulation of eIF4E in the brain. We show that light-activation of Opto4E-BP decreases protein synthesis in HEK cells and primary mouse neurons.In situ, light-activation of Opto4E-BP in excitatory neurons decreased protein synthesis in acute amygdala slices. Finally, light activation of Opto4E-BP in principal excitatory neurons in the lateral amygdala (LA) of mice after training blocked the consolidation of LTM. The development of this novel optogenetic tool to modulate eIF4E-dependent translation with spatiotemporal precision will permit future studies to unravel the complex relationship between protein synthesis and the consolidation of LTM.
Modular control of time and space during vertebrate axis segmentation
Authors: Seleit Ali , Brettell Ian , Fitzgerald Tomas , Vibe Carina , Loosli Felix , Wittbrodt Joachim , Naruse Kiyoshi , Birney Ewan , Aulehla Alexander
Published: August 2023

How temporal and spatial control of developmental processes are linked remains a fundamental question. Do underlying mechanisms form a single functional unit or are these dissociable modules?

We address this question by studying the periodic process of embryonic axis segmentation, using genetic crosses of inbred medaka fish strains representing two species,Oryzias sakaizumiiandlatipes. Our analysis revealed correlated interspecies differences with regard to the timing of segmentation, the size of segments and of the presomitic mesoderm (PSM), from which segments are periodically formed. We then did interspecies crosses and real-time imaging quantifications, which revealed extensive phenotypic variation in ∼600 F2 embryos. Importantly, while the F2 analysis showed correlated changes of PSM and segment size, these spatial measures were not correlated to the timing of segmentation. This shows that the control of time and space of axis segmentation can, in principle, be decoupled. In line with this finding, we identified, usingdevelopmentalquantitative trait loci (devQTL) mapping, distinct chromosomal regions linked to either the control of segmentation timing or PSM size. We were able to validate thedevQTL findings using a CRISPR/Cas9 loss-of-function approach on several candidate genesin vivo.

Combined, this study reveals that a developmental constraint mechanism underlies spatial scaling of axis segmentation, while its spatial and temporal control are dissociable modules. Our findings emphasise the need to reveal the selective constraints linking these modules in the natural environment.
Activity of MukBEF for chromosome management in E. coli and its inhibition by MatP
Authors: Seba Mohammed , Boccard Frédéric , Duigou Stéphane
Published: August 2023

Structural maintenance of chromosomes (SMC) complexes share conserved structures and serve a common role in maintaining chromosome architecture. In the bacteriumEscherichia coli, the SMC complex MukBEF is necessary for rapid growth and the accurate segregation and positioning of the chromosome, although the specific molecular mechanisms involved are still unknown. Here we used a number ofin vivoassays to reveal how MukBEF controls chromosome conformation and how the MatP/matSsystem prevents MukBEF activity. Our results indicate that the loading of MukBEF occurs preferentially on newly replicated DNA, at multiple loci on the chromosome where it can promote long-range contacts inciseven though MukBEF can promote long-range contacts in the absence of replication. Using HiC and ChIP-seq analyses in strains with rearranged chromosomes, the prevention of MukBEF activity increases with the number ofmatSsites and this effect likely results from the unloading of MukBEF by MatP. Altogether, our results reveal how MukBEF operates to control chromosome folding and segregation in E. coli.
Breaking the silence: exploring the challenges of oral participation faced by Chinese undergraduate students in a Sino-US university in China
Authors: Noman Mohammad , Xu Ruman
Published: August 2023

Purpose

This study aimed to explore the underlying reasons for student silence in EMI classrooms and identify the coping strategies employed by students and teachers.

Design/methodology/approach

Employing qualitative case study methods, in-depth semi-structured interviews and focus group discussions were conducted with both teachers and students. Thematic analysis was used for the findings.

Findings

Thematic analysis of the data revealed four primary reasons for student silence, and several effective coping strategies used by students and teachers to mitigate this challenge.

Research limitations/implications

The findings provide a comprehensive understanding of the phenomenon of silence among Chinese undergraduate students in English as a medium of instruction classrooms and offer valuable insights to students and teachers to adapt and succeed in these challenging environments.

Originality/value

The originality of this study lies in the fact that this is among the few studies conducted on students from a foreign branch campus of an American university in China that explores the explores the phenomenon of silence of Chinese students in such universities.