bluuebunny/crossref_metadata_2025 huggingface dataset:
Choroid plexus tissue perfusion and secretory function in rats measured by non-invasive MRI reveal significant effects of anesthesia
Authors: Lee Hedok , Ozturk Burhan , Stringer Michael S. , MacIntosh Bradley J. , Rothman Douglas , Benveniste Helene
Published: March 2022

The choroid plexus (ChP) of the cerebral ventricles is a source of cerebrospinal fluid (CSF) production and also plays a key role in immune surveillance at the level of blood-to-CSF-barrier (BCSFB). In this study, we quantify ChP blood perfusion and BCSFB mediated water exchange from arterial blood into ventricular CSF using non-invasive continuous arterial spin labelling magnetic resonance imaging (CASL-MRI). Systemic administration of anti-diuretic hormone (vasopressin) was used to validate BCSFB mediated water exchange as a metric of choroidal CSF secretory function. To further investigate the coupling between ChP perfusion and CSF secretory function, we characterized the effects of two anesthetic regimens known to have large-scale differential effects on cerebral blood flow. For quantification of ChP blood perfusion a multi-compartment perfusion model was employed, and we discovered that partial volume correction improved measurement accuracy. Vasopressin significantly reduced both ChP blood perfusion and CSF secretory function. ChP perfusion was significantly higher with pure isoflurane anesthesia (2-2.5%) when compared to a balanced anesthesia with dexmedetomidine and low-dose isoflurane (1.0 %), however there was no significant difference in BCSFB water secretory function. In summary, here we introduce a non-invasive, robust, and spatially resolved in vivo imaging platform to quantify ChP perfusion as well as BCSFB water secretory function which can be applied to study coupling of these two key parameters in future clinical translational studies.
Does a postpartum “Green Star” family planning decision aid for adolescent mothers reduce decisional conflict? : A quasi-experimental study
Authors: Mushy Stella E. , Shishido Eri , Horiuchi Shigeko
Published: March 2022

Aim

To our knowledge, there are still no studies in Tanzania regarding decision aids on long-acting reversible contraception. We evaluated the effects of our postpartum “Green Star” family planning decision aid on decisional conflict, knowledge, satisfaction, and uptake of long-acting reversible contraception among pregnant adolescents in Tanzania.

Methods

We used a facility-based quasi-experimental design with control. The participants were purposively recruited and randomly assigned (intervention, n = 33; control, n = 33). The intervention received the routine family planning counseling and decision aid. The control received only the routine family planning counseling. The primary outcome was change in decisional conflict measured using the validated Decisional Conflict Scale (DCS). The secondary outcomes were knowledge, satisfaction, and contraception uptake. We hypothesized that pregnant adolescents who use the decision aid will have a lower DCS score.

Results

We recruited 66 pregnant adolescents; 62 completed the study. Participants in the intervention had a lower mean difference score in the DCS than participants in the control (intervention: -24.7 [SD 7.99] vs. control: -11.6 [SD 10.9], t = -5.53, p < 0.001). The mean difference score in knowledge was significantly higher in the intervention than in the control (intervention: 4.53 [SD 2.54] vs. control: 2.0 [SD 1.45], t = 4.88, p < 0.001). The mean score of satisfaction was significantly higher in the intervention than in the control (intervention: 100 [SD 0.0] vs. control: 55.8 [SD 30.7], t = 8.112, p < 0.001). Choice of contraception was significantly higher in the intervention [29 (45.3%)] than in the control [13 (20.3%)] (x2 = 17.73, p < 0.001).

Conclusion

The postpartum “Green Star” family planning decision aid was useful as it lowered decisional conflict, improved knowledge and satisfaction with decision making, and enhanced contraception uptake. The decision aid demonstrated positive applicability and affordability for pregnant adolescents in Tanzania.
Deep learning in human neurons predicts mechanistic subtypes of Parkinson’s
Authors: D’Sa Karishma , Evans James R. , Virdi Gurvir S. , Vecchi Giulia , Adam Alex , Bertolli Ottavia , Fleming James , Chang Hojong , Athauda Dilan , Choi Minee L. , Gandhi Sonia
Published: March 2022

Parkinson’s disease (PD) is a common, devastating, and incurable neurodegenerative disorder. Several molecular mechanisms have been proposed to drive PD, with genetic and pathological evidence pointing towards aberrant protein homeostasis and mitochondrial dysfunction. PD is clinically highly heterogeneous, it is likely that different mechanisms underlie the pathology in different individuals, each requiring a specific targeted treatment. Recent advances in stem cell technology and fluorescent live-cell imaging have enabled the generation of patient-derived neurons with different mechanistic subtypes of PD. Here, we performed multi-dimensional fluorescent labelling of organelles in iPSC-derived neurons, in healthy control cells, and in four different disease subclasses. We generated a machine learning-based model that can simultaneously predict the presence of disease, and its primary mechanistic subtype. We independently trained a series of classifiers using both quantitative single-cell fluorescence variables and images to build deep neural networks. Quantitative cellular profile-based classifiers achieve an accuracy of 82%, whilst image based deep neural networks predict control, and four distinct disease subtypes with an accuracy of 95%. The classifiers achieve their accuracy across all subtypes primarily utilizing the organellar features of the mitochondria, with additional contribution of the lysosomes, confirming their biological importance in PD. Taken together, we show that machine learning approaches applied to patient-derived cells are able to predict disease subtypes, demonstrating that this approach may be used to guide personalized treatment approaches in the future.
Genome-wide analysis of the non-coding RNA synthetic genetic network reveals extensive plasticity and unique phenotypes in yeast
Authors: Fraczek Marcin G , Timouma Soukaina , Balarezo-Cisneros Laura Natalia , Parker Steven , Duangrattanalert Kobchai , Feng Matthew Wenjie , Griffiths-Jones Sam , O’Keefe Raymond T , Delneri Daniela
Published: March 2022

Recent studies identified non-coding RNAs (ncRNAs) with unknown function that are responsible for major fitness changes in yeast. To understand ncRNA interplay and aid their functional assignment, the synthetic genetic array (SGA) methodology was employed to create >15,000 double mutants and to score their epistasis in different environments. Unlike the protein network, ncRNAs mostly displayed positive epistasis in rich medium. Interestingly, the negative interactions significantly increased under stressors, showing environmental-dependent functions for ncRNAs. No correlation was found between the network of ncRNAs and that of their neighbouring genes, suggesting functional independence. The U3 paralogs, SNR17A and SNR17B, share the majority of genetic interactions in rich medium as expected. For example, SUT480 interacted with both paralogs and its function was linked to 18S rRNA processing. However, under stressors, a large number of unique epistatic interactions were observed, supporting the notion that SNR17A and SNR17B have diverged and sub-functionalised after genome duplication.
RF4Del: A Random Forest approach for accurate deletion detection
Authors: Xavier Roberto , Fiston-Lavier Anna-Sophie , Alves Ronnie C.O. , Cherif Emira
Published: March 2022

Efficiently detecting genomic structural variants (SVs) is a key step to grasp the “missing heritability” underlying complex traits involved in major evolutionary processes such as speciation, phenotypic plasticity, and adaptive responses. Yet, the SV-based genotype/trait association studies are still largely overlooked mainly due to the lack of reliable detection methods. Here, we present a random forest (RF) method for accurate deletion identification: RF4Del. By relying on the analysis of the mapping profiles, data already available in most sequencing projects, RF4Del can easily and quickly call deletions.

Several classic and ensemble learning strategies were carefully evaluated using proper benchmark data. RF4Del was trained and tested on simulated data from the model species Drosophila melanogaster to detect deletions. The model consists of 13 features extracted from a mapping file. We show that RF4Del outperforms established SV callers (DELLY, Pindel) with higher overall performance (F1-score > 0.75; 6x-12x sequence coverage) and is less affected by low sequencing coverage and deletion size variations. RF4Del could learn from a compilation of sequence patterns linked to a given SV. Such models can then be combined to form a learning system able to detect all types of SVs in a given genome, beyond the one used in our study. https://github.com/alvesrcoo/eletric-scheep
High nutrient loads hinder successful restoration of natural habitats in freshwater wetlands
Authors: Moeslund Jesper Erenskjold , Andersen Dagmar Kappel , Brunbjerg Ane Kirstine , Fløjgaard Camilla , Nygaard Bettina , Ejrnæs Rasmus
Published: March 2022

Restoration of natural processes in ecosystems is key to halt the biodiversity crisis. Here, we evaluate 20 different stream-valley wetland restoration projects – mainly rewetting – in a large region in Denmark in terms of successful restoration of natural wetland habitats. We used quadratic discriminant analysis and generalized linear models to compare the projects’ 80 vegetation plots with >50.000 natural wetland-habitat reference plots and modelled the influence of time, grazing, rewetting and nutrient availability on the study plots’ probabilities of belonging to such natural habitats and their richness of high-quality habitat indicator species. In our study, the probability of a restored wetland being a natural wetland habitat – almost always an alkaline fen – was generally below 10 %. Also, we only found half as many indicator species in restored wetlands than in reference wetlands and we demonstrated that the number of characteristic alkaline fen species did not deviate from what could be expected under the prevailing nutrient conditions. We found a negative effect of nutrient availability on the number of high-quality habitat indicator species and the lowest probability of plots being natural wetlands in the most nutrient rich plots. The effect of grazing was only positive in the first years after restoration and only in the most nutrient rich plots, while the effect of rewetting sites to their historical hydrological conditions was generally negative. Our findings reveal that unnaturally high nutrient availability is probably the core limiting factor for successful restoration of natural wetlands and their associated plant diversity.

Implications for practice

- To successfully restore natural and characteristic freshwater wetland habitats focus on recreating natural processes and conditions is needed

- Restoring natural hydrology and grazing is not enough, the soil and water must be naturally nutrient poor for successful restoration of these habitats

- Restoration of stream-valley wetlands such as alkaline springs and fens is more likely to be successful in spring-dominated landscapes where clean groundwater diffusely exfiltrates the soil
A genomic analysis of parasite-mediated population differentiation in a metapopulation
Authors: Halter Meret , Du Pasquier Louis , Ebert Dieter , Fields Peter D.
Published: March 2022

Understanding the genetics of host adaptation is a powerful approach to study host – parasite interactions. Hosts are often assumed to have a simple genetic architecture underlying resistance. However, in natural populations the genetics are rarely known and the link between host adaptation and evolutionary models cannot be easily established. To shed light on the genetic basis of host evolution in the presence and absence of parasites we studied a highly dynamic rockpool metapopulation of the planktonic crustacean Daphnia magna and its microsporidian parasite Hamiltosporidium tvaerminnensis. We examined genome-wide allele frequencies estimated from pooled Illumina sequencing (Pool-seq) of 12 subpopulations of a metapopulation. Subpopulations that had evolved for several years with the parasite were contrasted to uninfected subpopulations, with the aim to find genomic sites of diversifying selection. Consistent with earlier attempts to find resistance genes in this system, we observe many minor-effect outliers, suggesting that the response of the host to this parasite is based on a quantitative-trait architecture. We found 34 outliers across 11 genomic regions that indicate increased differentiation between population groups as well as signs of positive selection. Some of these regions contain immune-related genes, of which four are likely involved in immune downregulation. Our findings show that in the presence of the microsporidium parasite, hosts evolve in a complex polygenic way, driving population differentiation in the metapopulation under study. Such evolutionary differentiation is a powerful mechanism to maintain genetic diversity in spatially structured populations.
ILnc: Prioritizing Long Non-coding RNAs for Pan-cancer Analysis of Immune Cell Infiltration
Authors: Li Xinhui , Yang Changbo , Bai Jing , Xie Yunjin , Xu Mengjia , Liu Hui , Shao Tingting , Xu Juan , Li Xia
Published: March 2022

The distribution and extent of immune cell infiltration into solid tumors play pivotal roles in cancer immunology and therapy. Here we introduced an immune long non-coding RNA (lncRNA) signature-based method (ILnc), for estimating the abundance of 14 immune cell types from lncRNA transcriptome data. Performance evaluation through pure immune cell data shows that our lncRNA signature sets can be more accurate than protein-coding gene signatures. We found that lncRNA signatures are significantly enriched to immune functions and pathways, such as immune response and T cell activation. In addition, the expression of these lncRNAs is significantly correlated with expression of marker genes in corresponding immune cells. Application of ILnc in 33 cancer types provides a global view of immune infiltration across cancers and we found that the abundance of most immune cells is significantly associated with patient clinical signatures. Finally, we identified six immune subtypes spanning cancer tissue types which were characterized by differences in immune cell infiltration, homologous recombination deficiency (HRD), expression of immune checkpoint genes, and prognosis. Altogether, these results demonstrate that ILnc is a powerful and exhibits broad utility for cancer researchers to estimate tumor immune infiltration, which will be a valuable tool for precise classification and clinical prediction.
Age- and sex-dependent effects of DNA glycosylase Neil3 on amyloid pathology, adult neurogenesis, and memory in a mouse model of Alzheimer’s disease
Authors: Egiazarian Milena A. , Strømstad Silje , Sakshaug Teri , Nunez-Nescolarde Ana B. , Bethge Nicole , Bjørås Magnar , Scheffler Katja
Published: March 2022

Oxidative stress generating DNA damage has been shown to be a key characteristic in Alzheimer’s disease (AD). However, how it affects the pathogenesis of AD is not yet fully understood. Neil3 is a DNA glycosylase initiating repair of oxidative DNA base lesions and with a distinct expression pattern in proliferating cells. In brain, its function has been linked to hippocampal-dependent memory and to induction of neurogenesis after stroke and in prion disease. Here, we generated a novel AD mouse model deficient for Neil3 to study the impact of impaired oxidative base lesion repair on the pathogenesis of AD. Our results demonstrate an age-dependent decrease in amyloid-β (Aβ) plaque deposition in female Neil3-deficient AD mice, whereas no significant difference was observed in male mice. Furthermore, male but not female Neil3-deficient AD mice show reduced neural stem cell proliferation in the adult hippocampus and impaired working memory compared to controls. These effects seem to be independent of DNA repair as both sexes show increased level of oxidative base lesions in the hippocampus upon loss of Neil3. Thus, our findings suggest an age- and sex-dependent role of Neil3 in the progression of AD by altering cerebral Aβ accumulation and promoting adult hippocampal neurogenesis to maintain cognitive function.
Reference genome choice and filtering thresholds jointly influence phylogenomic analyses
Authors: Rick Jessica A. , Brock Chad D. , Lewanski Alexander L. , Golcher-Benavides Jimena , Wagner Catherine E.
Published: March 2022

Abstract

Molecular phylogenies are a cornerstone of modern comparative biology and are commonly employed to investigate a range of biological phenomena, such as diversification rates, patterns in trait evolution, biogeography, and community assembly. Recent work has demonstrated that significant biases may be introduced into downstream phylogenetic analyses from processing genomic data; however, it remains unclear whether there are interactions among bioinformatic parameters or biases introduced through the choice of reference genome for sequence alignment and variant-calling. We address these knowledge gaps by employing a combination of simulated and empirical data sets to investigate to what extent the choice of reference genome in upstream bioinformatic processing of genomic data influences phylogenetic inference, as well as the way that reference genome choice interacts with bioinformatic filtering choices and phylogenetic inference method. We demonstrate that more stringent minor allele filters bias inferred trees away from the true species tree topology, and that these biased trees tend to be more imbalanced and have a higher center of gravity than the true trees. We find greatest topological accuracy when filtering sites for minor allele count>3–4 in our 51-taxa data sets, while tree center of gravity was closest to the true value when filtering for sites with minor allele count>1–2. In contrast, filtering for missing data increased accuracy in the inferred topologies; however, this effect was small in comparison to the effect of minor allele filters and may be undesirable due to a subsequent mutation spectrum distortion. The bias introduced by these filters differs based on the reference genome used in short read alignment, providing further support that choosing a reference genome for alignment is an important bioinformatic decision with implications for downstream analyses. These results demonstrate that attributes of the study system and dataset (and their interaction) add important nuance for how best to assemble and filter short read genomic data for phylogenetic inference.
STracking: a free and open-source python library for particle tracking and analysis
Authors: Prigent Sylvain , Valades-Cruz Cesar Augusto , Leconte Ludovic , Salamero Jean , Kervrann Charles
Published: March 2022

Analysis of intra and extra cellular dynamic like vesicles transport involves particle tracking algorithms. Designing a particle tracking pipeline is a routine but tedious task. Therefore, particle dynamics analysis is often performed by combining several pieces of software (filtering, detection, tracking…) requiring a lot of manual operations, and therefore leading to poorly reproducible results. A good synergy between particle detector with a tracker is of paramount importance. In addition, a user-friendly interface to control the quality of estimated trajectories is necessary. To address these issues, we developed STracking a python library that allows to combine algorithms into standardized particle tracking pipelines.

Availability and Implementation

STracking is available as a python library using “pip install” and the source code is publicly available on GitHub (https://github.com/sylvainprigent/stracking). A graphical interface is available using two napari plugins: napari-stracking and napari-tracks-reader. These napari plugins can be installed via the napari plugins menu or using “pip install”. The napari plugin source codes are available on GitHub (https://github.com/sylvainprigent/napari-tracks-reader, https://github.com/sylvainprigent/napari-stracking).

Contact

sylvain.prigent@inria.fr, cesar-augusto.valades-cruz@curie.fr
A distinct subset of oligodendrocyte lineage cells interact with the developing dorsal root entry during its genesis
Authors: Green Lauren A. , Gallant Robert , Brandt Jacob P. , Nichols Evan L. , Smith Cody J.
Published: March 2022

Oligodendrocytes are the myelinating cell of the CNS and are critical for the functionality of the nervous system. In the packed CNS, we know distinct profiles of oligodendrocytes are present. Here, we used intravital imaging in zebrafish to identify a distinct oligodendrocyte lineage cell (OLC) that resides on the dorsal root ganglia sensory neurons in the spinal cord. Our profiling of OLC cellular dynamics revealed a distinct cell cluster that interacts with peripheral sensory neurons at the dorsal root entry zone (DREZ). With pharmacological, physical and genetic manipulations, we show that the entry of dorsal root ganglia pioneer axons across the DREZ is important to produce sensory located oligodendrocyte lineage cells. These oligodendrocyte lineage cells on peripherally derived sensory neurons display distinct processes that are stable and do not express mbp. Upon their removal, sensory behavior related to the DRG neurons is abolished. Together, these data support the hypothesis that peripheral neurons at the DREZ can also impact oligodendrocyte development.
CATHe: Detection of remote homologues for CATH superfamilies using embeddings from protein language models
Authors: Nallapareddy Vamsi , Bordin Nicola , Sillitoe Ian , Heinzinger Michael , Littmann Maria , Waman Vaishali , Sen Neeladri , Rost Burkhard , Orengo Christine
Published: March 2022

1.

CATH is a protein domain classification resource that combines an automated workflow of structure and sequence comparison alongside expert manual curation to construct a hierarchical classification of evolutionary and structural relationships. The aim of this study was to develop algorithms for detecting remote homologues that might be missed by state-of-the-art HMM-based approaches. The proposed algorithm for this task (CATHe) combines a neural network with sequence representations obtained from protein language models. The employed dataset consisted of remote homologues that had less than 20% sequence identity. The CATHe models trained on 1773 largest, and 50 largest CATH superfamilies had an accuracy of 85.6+−0.4, and 98.15+−0.30 respectively. To examine whether CATHe was able to detect more remote homologues than HMM-based approaches, we employed a dataset consisting of protein regions that had annotations in Pfam, but not in CATH. For this experiment, we used highly reliable CATHe predictions (expected error rate <0.5%), which provided CATH annotations for 4.62 million Pfam domains. For a subset of these domains from homo sapiens, we structurally validated 90.86% of the predictions by comparing their corresponding AlphaFold structures with experimental structures from the CATHe predicted superfamilies.
Quantitative Analysis of Transcriptome Dynamics Provides Novel Insights into Developmental State Transitions
Authors: Johnson Kristin , Freedman Simon , Braun Rosemary , LaBonne Carole
Published: March 2022

During embryogenesis, the developmental potential of initially pluripotent cells becomes progressively restricted as they transit to lineage restricted states. The pluripotent cells of Xenopus blastula-stage embryos are an ideal system in which to study cell state transitions during developmental decision-making, as gene expression dynamics can be followed at high temporal resolution. Here we use transcriptomics to interrogate the process by which pluripotent cells transit to four different lineage-restricted states: neural progenitors, epidermis, endoderm and ventral mesoderm, providing quantitative insights into the dynamics of Waddington’s landscape. Our findings shed light on why the neural progenitor state is the default lineage state for pluripotent cells, and uncover novel components of lineage-specific gene regulation. These data reveal an unexpected overlap in the transcriptional responses to BMP4/7 and activin signaling, and provide mechanistic insight into how the timing of signaling inputs such as BMP are temporally controlled to ensure correct lineage decisions. Together these analyses provide quantitative insights into the logic and dynamics of developmental decision making in early embryos.
Continuing decline of the eastern quoll in Tasmania
Authors: Cunningham Calum X , Aandahl Zach , Jones Menna E , Hamer Rowena , Johnson Christopher N
Published: March 2022

Like many other Australian mammals, the eastern quoll (Dasyurus viverrinus)was widespread on the Australian mainland but went extinct there during the 20th century. The species remained abundant in Tasmania until a rapid decline occurred from 2001 to 2003, coinciding with a period of unsuitable weather. We provide an updated analysis of eastern quoll population trends in Tasmania by analysing a Tasmania-wide time series of annual spotlight counts (1985-2019). Eastern quolls were widespread and abundant in Tasmania until the early 2000s. A distinct change occurred in the early 2000s in the east and northeast, which led to severe population reductions. However, we present new evidence of an earlier decline in the north (mid-1990s) and a more recent decline around 2009 in the south. Range-wide declines have continued unabated during the last decade, resulting in a ∼67% decline (since the late 1990s) in the area with high quoll abundance. Although the timing of the major decline in the early 2000s coincided with unfavourable weather, the continuing decline and more recent change points suggest other causes are also involved. We can no longer assume that the existence of eastern quolls in Tasmania ensures the species’ long-term survival, highlighting the urgent need to increase efforts to conserve the remaining populations in Tasmania.
Influenza A Virus Exacerbates Group A Streptococcus Infection and Thwarts Anti-bacterial Inflammatory Responses in Murine Macrophages
Authors: Aleith Johann , Brendel Maria , Weipert Erik , Müller Michael , Schultz Daniel ,   Ko-Infekt Study Group, Müller-Hilke Brigitte
Published: March 2022

Seasonal influenza epidemics pose a considerable hazard for global health. In the past decades, accumulating evidence revealed that influenza A virus (IAV) renders the host vulnerable to bacterial superinfections which in turn are a major cause for morbidity and mortality. However, whether the impact of influenza on anti-bacterial innate immunity is restricted to the vicinity of the lung or systemically extends to remote sites is underexplored. We therefore sought to investigate intranasal infection of adult C57BL/6J mice with IAV H1N1 in combination with bacteremia elicited by intravenous application of Group A Streptococcus (GAS). Co-infectionin vivowas supplementedin vitroby challenging murine bone marrow derived macrophages and exploring gene expression and cytokine secretion. Our results show that viral infection of mice caused mild disease and induced the depletion of CCL2 in the periphery. Influenza preceding GAS infection promoted the occurrence of paw edemas and was accompanied by exacerbated disease scores.In vitroco-infection of macrophages led to significantly elevated expression of TLR2 and CD80 compared to bacterial mono-infection, whereas CD163 and CD206 were downregulated. The GAS-inducible upregulation of inflammatory genes, such asNos2, as well as the secretion of TNFα and IL-1β were notably reduced or even abrogated following co-infection. Our results indicate that IAV primes an innate immune layout that is inadequately equipped for bacterial clearance.
Repetitive Transcranial Magnetic Stimulation for Tobacco Treatment in Cancer Patients: A Preliminary Report of a One-Week Treatment
Authors: Li Xingbao , Toll Benjamin A. , Carpenter Matthew J. , Nietert Paul J , Dancy Morgan , George Mark S.
Published: March 2022

Background

Smoking cessation represents a significant opportunity to improve cancer survival rates, reduce the risk of cancer treatment complications, and improve quality of life. However, about half of cancer patients who smoke continue to smoke despite the availability of several treatments. Previous studies demonstrate that repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) decreases cue craving, reduces cigarette consumption, and increases the quit rate in tobacco use disorder. We investigated whether 5 sessions of rTMS can be safely and efficaciously used for smoking cessation in cancer patients.

Methods

We enrolled 11 treatment-seeking smokers with cancer (> 5 cigarettes per day) in a randomized, double-blind, sham-controlled proof-of-concept study. Participants received 5 daily sessions of active 10Hz rTMS of the left DLPFC (3000 pulses per session) or sham rTMS, and were followed up for 1 month via phone assessments. Main outcomes included reductions in the number of smoked-cigarettes per day (primary) and craving (secondary). Adverse effects were reported daily by participants.

Results

Seven of 11 participants completed 5 sessions of rTMS over one week. Compared to sham treatment (n = 4), the active rTMS (n = 3) exhibited modest effects overtime on smoking (Cohen’s f2 effect size of 0.16) and large effects on cue craving (Cohen’s f2 = 0.40). No serious side effects related to rTMS were reported in the treatment.

Conclusions

Five sessions of daily rTMS over the left DLPFC might benefit cancer patients who smoke cigarettes. However, further evidence is needed to determine with more certainty its therapeutic effect and adverse effects for cancer patients who smoke cigarettes.
PTPRG activates m6A methyltransferase VIRMA to block mitochondrial autophagy mediated neuronal death in Alzheimer’s disease
Authors: Luo Jiefeng , Huang Xiaohua , Li Rongjie , Xie Jieqiong , Chen Liechun , Zou Chun , Pei Zifei , Mao Yingwei , Zou Donghua
Published: March 2022

In Alzheimer’s disease (AD), neuronal death is one of the key pathology. However, the initiation of neuronal death in AD is far from clear, and new targets are urgently needed to develop effective therapeutic methods. This study analyzed sequencing data from single-cell RNAseq and spatialomics, and revealed the impact of global single-cell mapping and cell spatial distribution relationships in early stage of AD. We found that microglia subpopulation Mic_PTPRG can anchor neurons based on ligand-receptor interaction pairs and cause ectopic expression of PTPRG in neurons during AD progression. PTPRG in neurons can bind and upregulate VIRMA expression, which in turn increases the level of m6A methylation, enhances PRKN transcript degradation and represses translation. Repressed PRKN expression blocks the clearance of damaged mitochondria in neurons, which in turn reprograms neuronal energy and nutrient metabolic pathways and leads to neuronal death during AD progression. This study elucidates novel mechanisms, by which the PTPRG-dependent microglia-synaptic modification may play a role in AD, providing a new scientific basis for potential therapeutic targets for AD.
SEROLOGICAL TESTING OF BLOOD DONORS TO CHARACTERISE THE IMPACT OF COVID-19 IN MELBOURNE, AUSTRALIA, 2020
Authors: Machalek Dorothy A , Vette Kaitlyn M , Downes Marnie , Carlin John B , Nicholson Suellen , Hirani Rena , Irving David O , Gosbell Iain B , Gidding Heather F , Shilling Hannah , Aung Eithandee , Macartney Kristine , Kaldor John M
Published: March 2022

Rapidly identifying and isolating people with acute SARS-CoV-2 infection has been a core strategy to contain COVID-19 in Australia, but a proportion of infections go undetected. We estimated SARS-CoV-2 specific antibody prevalence (seroprevalence) among blood donors in metropolitan Melbourne following a COVID-19 outbreak in the city between June and September 2020. The aim was to determine the extent of infection spread and whether seroprevalence varied demographically in proportion to reported cases of infection. The design involved stratified sampling of residual specimens from blood donors (aged 20–69 years) in three postcode groups defined by low (<3 cases/1,000 population), medium (3-7 cases/1,000 population) and high (>7 cases/1,000 population) COVID-19 incidence based on case notification data. All specimens were tested using the Wantai SARS-CoV-2 total antibody assay. Seroprevalence was estimated with adjustment for test sensitivity and specificity for the Melbourne metropolitan blood donor and residential populations, using multilevel regression and poststratification. Overall, 4,799 specimens were collected between 23 November and 17 December 2020. Seroprevalence for blood donors was 0.87% (90% credible interval: 0.25–1.49%). The highest estimates, of 1.13% (0.25–2.15%) and 1.11% (0.28–1.95%), respectively, were observed among donors living in the lowest socioeconomic areas (Quintiles 1 and 2) and lowest at 0.69% (0.14–1.39%) among donors living in the highest socioeconomic areas (Quintile 5). When extrapolated to the Melbourne residential population, overall seroprevalence was 0.90% (0.26–1.51%), with estimates by demography groups similar to those for the blood donors. The results suggest a lack of extensive community transmission and good COVID-19 case ascertainment based on routine testing during Victoria’s second epidemic wave. Residual blood donor samples provide a practical epidemiological tool for estimating seroprevalence and information on population patterns of infection, against which the effectiveness of ongoing responses to the pandemic can be assessed.
Multi-omics comparison of malignant and normal uveal melanocytes reveals novel molecular features of uveal melanoma
Authors: Gentien David , Saberi-Ansari Elnaz , Servant Nicolas , Jolly Ariane , de la Grange Pierre , Némati Fariba , Liot Géraldine , Saule Simon , Teissandier Aurélie , Bourchis Deborah , Girard Elodie , Wong Jennifer , Planchon Julien Masliah , Rodrigues Manuel , Gaudé Laure Villoing , Reyes Cécile , Bazire Matéo , Chenegros Thomas , Bohec Mylene , Baulande Sylvain , M’kacher Radhia , Jeandidier Eric , Nicolas André , Decaudin Didier , Cassoux Nathalie , Piperno-Neumann Sophie , Stern Marc-Henri , Gibcus Johan Harmen , Dekker Job , Heard Edith , Roman-Roman Sergio , Waterfall Joshua J.
Published: March 2022

Uveal Melanoma (UM) is a rare cancer resulting from transformation of melanocytes residing in the uveal tract. Integrative analysis has identified four molecular and clinical subsets in UM. To improve our molecular understanding of UM we performed extensive multi-omics characterization comparing two aggressive UM patient-derived xenograft models with normal choroidal melanocytes, including DNA optical mapping, specific histone modifications, and DNA topology analysis by Hi-C. Our gene expression and cytogenetic analyses suggest that genomic instability is a hallmark of UM. We also identified a recurrent deletion in the BAP1 promoter resulting in loss of expression and associated with high risk of metastases in UM patients. Hi-C revealed chromatin topology changes associated with up-regulation of PRAME, an independent prognostic biomarker in UM and potential therapeutic target. Our findings illustrate how multi-omics approaches can improve the understanding of tumorigenesis and reveals two novel mechanisms of gene expression dysregulation in UM.
Accelerating PERx Reaction Enables Covalent Nanobodies for Potent Neutralization of SARS-Cov-2 and Variants
Authors: Yu Bingchen , Li Shanshan , Tabata Takako , Wang Nanxi , Kumar G. Renuka , Liu Jun , Ott Melanie M. , Wang Lei
Published: March 2022

The long-lasting COVID-19 pandemic and increasing SARS-CoV-2 variants demand effective drugs for prophylactics and treatment. Protein-based biologics offer high specificity yet their noncovalent interactions often lead to drug dissociation and incomplete inhibition. Here we developed covalent nanobodies capable of binding with SARS-CoV-2 spike protein irreversibly via proximity-enabled reactive therapeutic (PERx) mechanism. A novel latent bioreactive amino acid FFY was designed and genetically encoded into nanobodies to accelerate PERx reaction rate. After covalent engineering, nanobodies binding with the Spike in the down state, but not in the up state, were discovered to possess striking enhancement in inhibiting viral infection. In comparison with the noncovalent wildtype nanobody, the FFY-incorporated covalent nanobody neutralized both authentic SARS-CoV-2 and its Alpha and Delta variants with potency drastically increased over tens of folds. This PERx-enabled covalent nanobody strategy and uncovered insights on potency increase can be valuable to developing effective therapeutics for various viral infections.
Proinflammatory innate cytokines and metabolomic signatures shape the T cell response in active COVID-19
Authors: Binayke Akshay , Zaheer Aymaan , Dandotiya Jyotsna , Gupta Sonu K , Mani Shailendra , Tripathi Manas , Madan Upasna , Shrivastava Tripti , Kumar Yashwant , Pandey Anil K , Rathore Deepak K , Awasthi Amit
Published: March 2022

The underlying factors contributing to the evolution of SARS-CoV-2-specific T cell responses during COVID-19 infection remain unidentified. To address this, we characterized innate and adaptive immune responses with metabolomic profiling longitudinally at three different time points (0-3, 7-9, and 14-16 days post-COVID-19 positivity) from young mildly symptomatic active COVID-19 patients infected during the first wave in mid-2020. We observed that anti-RBD IgG and viral neutralization are significantly reduced against the Delta variant compared to the ancestral strain. In contrast, compared to the ancestral strain, T cell responses remain preserved against the delta and omicron variants. We determined innate immune responses during the early stage of active infection in response to TLR 3/7/8 mediated activation in PBMCs and serum metabolomic profiling. Correlation analysis indicated PBMCs-derived proinflammatory cytokines, IL-18, IL-1β, and IL-23, and the abundance of plasma metabolites involved in arginine biosynthesis were predictive of a robust SARS-CoV-2-specific Th1 response at a later stage (two weeks after PCR positivity). These observations may contribute to designing effective vaccines and adjuvants that promote innate immune responses and metabolites to induce long-lasting anti-SARS-CoV-2 specific T cells response.
Syntaxin-1A modulates vesicle fusion in mammalian neurons via juxtamembrane domain dependent palmitoylation of its transmembrane domain
Authors: Vardar Gülçin , Salazar-Lázaro Andrea , Zobel Sina , Trimbuch Thorsten , Rosenmund Christian
Published: March 2022

SNAREs are undoubtedly one of the core elements of synaptic transmission. On the contrary to the well characterized function of their SNARE domains bringing the plasma and vesicular membranes together, the level of contribution of their juxtamembrane domain (JMD) and the transmembrane domain (TMD) to the vesicle fusion is still under debate. To elucidate this issue, we analyzed three groups of STX1A mutations: 1) elongation of STX1A’s JMD by three amino acid insertions in the junction of SNARE-JMD or JMD-TMD; 2) charge reversal mutations in STX1A’s JMD; and 3) palmitoylation deficiency mutations in STX1A’s TMD. We found that both JMD elongations and charge reversal mutations have position dependent differential effects on Ca2+-evoked and spontaneous neurotransmitter release in cultured murine hippocampal neurons. Importantly, we show that STX1A’s JMD regulates the palmitoylation of STX1A’s TMD and loss of STX1A palmitoylation either through charge reversal mutation K260E or by loss of TMD cysteines particularly inhibits spontaneous vesicle fusion. Interestingly, the retinal ribbon specific STX3B has a glutamate in the position corresponding to the K260E mutation in STX1A and mutating it with E259K acts as a molecular on-switch. Furthermore, palmitoylation of post-synaptic STX3A can be induced by the exchange of its JMD with STX1A’s JMD together with the incorporation of two cysteines into its TMD. Forced palmitoylation of STX3A dramatically enhances spontaneous vesicle fusion suggesting that STX1A regulates spontaneous release through two distinct mechanisms: one through the C-terminal half of its SNARE domain and the other through the palmitoylation of its TMD.
Neurons in inferior temporal cortex are sensitive to motion trajectory during degraded object recognition
Authors: Burk Diana C. , Sheinberg David L.
Published: March 2022

Our brains continuously acquire sensory information and make judgments even when visual information is limited. In some circumstances, an ambiguous object can be recognized from how it moves, such as an animal hopping or a plane flying overhead. Yet it remains unclear how movement is processed by brain areas involved in visual object recognition. Here we investigate whether inferior temporal cortex, an area traditionally known for shape processing, has access to motion information during degraded shape recognition. We developed a matching task that required monkeys to recognize moving shapes with variable levels of shape degradation. Neural recordings in area IT showed that, surprisingly, some IT neurons preferred blurry shapes over clear ones. Further, many of the neurons exhibited motion sensitivity at different times during the presentation of the blurry target. Population decoding analyses showed that motion pattern could be decoded from IT neuron pseudo-populations. Contrary to previous findings, these results suggest that neurons in IT can integrate visual motion and shape information, particularly when shape information is degraded, in a way that has been previously overlooked. Our results highlight the importance of using challenging multi-feature recognition tasks to understand the role of area IT in naturalistic visual object recognition. (Word count: 199)
Comparative analysis of total alpha-synuclein (αSYN) immunoassays reveals that they do not capture the diversity of modified αSYN proteoforms
Authors: Petricca Lara , Chiki Nour , Hanna-El-Daher Layane , Aeschbach Lorène , Burai Ritwik , Stoops Erik , Fares Mohamed-Bilal , Lashuel Hilal A.
Published: March 2022

Background

The development of therapeutics for Parkinson’s disease (PD) requires the establishment of biomarker assays to enable stratifying patients, monitoring disease progression and assessing target engagement. Attempts to develop diagnostic assays based on detecting levels of the α-synuclein (αSYN) protein, a central player in the pathogenesis of PD, have yielded inconsistent results.

Objective

To determine whether the three commercial kits that have been extensively used for total αSYN quantification in human biological fluids (from Euroimmun, MSD, and Biolegend) are capable of capturing the diversity and complexity of relevant αSYN proteoforms.

Methods

We investigated and compared the ability of the different assays to detect the diversity of αSYN proteoform using a library of αSYN proteins that compromise the majority of disease-relevant αSYN variants and post-translational modification.

Results

Our findings showed that none of the three tested immunoassays accurately capture the totality of relevant αSYN species and are unable to recognize most disease-associated C-terminally truncated variants of αSYN. Moreover, several N-terminal truncations and phosphorylation/nitration differentially modify the level of αSYN detection and recovery by different immunoassays, and a CSF matrix effect was observed for most of the αSYN proteoforms analyzed by the three immunoassays.

Conclusions

Our results showed that these immunoassays do not capture the totality of the relevant αSYN species and therefore may not be appropriate tools to provide an accurate measure of total αSYN levels in samples containing modified forms of the protein. This highlights the need for next-generation αSYN immunoassays that capture the diversity of αSYN proteoforms.
Cortical interneuron loss and seizure generation as novel clinically relevant disease phenotypes in Cln2R207X mice
Authors: Takahashi Keigo , Eultgen Elizabeth M. , Wang Sophie H. , Rensing Nicholas R. , Nelvagal Hemanth R. , Dearborn Joshua T. , Sands Mark S. , Wong Michael , Cooper Jonathan D.
Published: March 2022

Aims

CLN2 disease is a fatal inherited childhood neurodegenerative disorder. Although a disease-modifying therapy now exists, a fundamental lack of understanding of disease pathogenesis has hampered development of more effective therapies. To better understand the cellular pathophysiology of CLN2 disease, we investigated the nature and progression of neuropathological and neurological changes in the recently generated Cln2R207X mouse.

Methods

We have detailed microglial activation, astrogliosis, cytokine and chemokine expression, and neuron loss across the forebrain and spinal cords of Cln2R207X mice, along with quantitative gait analysis. We also performed long-term electroencephalography (EEG) recordings to characterize seizure activity, a clinically-relevant phenotype yet to be defined in any CLN2 disease model.

Results

Histology revealed early localized microglial activation months before neuron loss in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. These pathological changes were more pronounced and occurred in the cortex before the thalamus or spinal cord. There were early-onset and progressive changes in the expression of specific chemokines and cytokines including IL-33, IP-10, and MIP-1α. Gait analysis revealed impaired performance only at disease end stage. EEG recordings revealed robust and progressive epileptiform activity from disease mid-stage including spontaneous seizures, which were accompanied by a profound loss of cortical GABAergic interneurons.

Conclusions

Our data reveal novel phenotypes in Cln2R207X mice that differ markedly in their timing and progression through the CNS from other NCL mouse models. Our findings provide new insights on CLN2 disease pathogenesis and clinically-relevant readouts for future therapeutic studies.
Functional convergence in slow-growing microbial communities arises from thermodynamic constraints
Authors: George Ashish B. , Wang Tong , Maslov Sergei
Published: March 2022

The dynamics of microbial communities is complex, determined by competition for metabolic substrates and cross-feeding of byproducts. Species in the community grow by harvesting energy from chemical reactions that transform substrates to products. In many anoxic environments, these reactions are close to thermodynamic equilibrium and growth is slow. To understand the community structure in these energy-limited environments, we developed a microbial community consumer-resource model incorporating energetic and thermodynamic constraints on an intercon-nected metabolic network. The central element of the model is product inhibition, meaning that microbial growth may be limited not only by depletion of metabolic substrates but also by accu-mulation of products. We demonstrate that these additional constraints on microbial growth cause a convergence in the structure and function of the community metabolic network—independent of species composition and biochemical details—providing a possible explanation for convergence of community function despite taxonomic variation observed in many natural and industrial en-vironments. Furthermore, we discovered that the structure of community metabolic network is governed by the thermodynamic principle of maximum free energy dissipation. Our results predict the decrease of functional convergence in faster growing communities, which we validate by ana-lyzing experimental data from anaerobic digesters. Overall, the work demonstrates how universal thermodynamic principles may constrain community metabolism and explain observed functional convergence in microbial communities.