bluuebunny/crossref_metadata_2025 huggingface dataset:
String/Cdc25 phosphatase is a suppressor of Tau-associated neurodegeneration
Authors: Oliveira Andreia C. , Santos Madalena , Pinho Mafalda , Lopes Carla S.
Published: June 2022

Tau pathology is defined by the intracellular accumulation of abnormally phosphorylated Tau and is prevalent in several neurodegenerative disorders. The identification of modulators of Tau abnormal phosphorylation and aggregation is key to understand disease progression and develop targeted therapeutic approaches. In this study we identify String/Cdc25 phosphatase as a suppressor of Tau abnormal phosphorylation and associated toxicity. Using aDrosophilamodel of tauopathy we show that Tau dephosphorylation by Stg/Cdc25 correlates with reduced Tau oligomerization, brain vacuolization and locomotor deficits in flies. Moreover, using a disease mimetic model, we provide evidence that Stg/Cdc25 reduces Tau phosphorylation levels independently of Tau aggregation status and delays neurodegeneration progression in the fly. These findings uncover a role for Stg/Cdc25 phosphatases as regulators of Tau biology, that extends beyond their well-characterized function as cell-cycle regulators during cell proliferation, and point-out Stg/Cdc25 based approaches as promising entry points to target abnormal Tau phosphorylation.
Adult Camk2a gene reinstatement restores the learning and plasticity deficits of Camk2a knockout mice
Authors: Rigter Pomme M.F. , Wallaard Ilse , Jolfaei Mehrnoush Aghadavoud , Kingma Jenina , Post Laura , Elgersma Minetta , Elgersma Ype , van Woerden Geeske M.
Published: June 2022

With the recent findings that mutations in the gene encoding the α-subunit of calcium/calmodulin-dependent protein kinase II (CAMK2A) causes neurodevelopmental disorder (NDD), it is of great therapeutic relevance to know if there a critical developmental time window in which CAMK2A needs to be expressed for normal brain development, or whether expression of the protein at later stages is still beneficial to restore normal functioning. To answer this question, we generated an inducible Camk2a mouse model, which allows us to express CAMK2A at any desired time. Here, we show that adult expression of CAMK2A rescues the behavioural and electrophysiological phenotypes seen in the Camk2a knock-out mice, including spatial and conditional learning and synaptic plasticity. These results suggest that CAMK2A does not play a critical irreversible role in neurodevelopment, which is of importance for future therapies to treat CAMK2A-dependent disorders.
Nemacol is a Small Molecule Inhibitor of C. elegans Vesicular Acetylcholine Transporter with Anthelmintic Potential
Authors: Harrington Sean , Pyche Jacob , Burns Andrew R. , Spalholz Tina , Baker Rachel J. , Ching Justin , Lautens Mark , Kulke Daniel , Deuther-Conrad Winnie , Brust Peter , Roy Peter J.
Published: June 2022

Nematode parasites of humans and livestock pose a significant burden to human health, economic development, and food security. Anthelmintic drug resistance is widespread among parasites of livestock and many nematode parasites of humans lack effective treatments. Here, we present a nitrophenyl-piperazine scaffold that induces motor defects rapidly in the model nematode Caenorhabditis elegans. We call this scaffold Nemacol and show that it inhibits the vesicular acetylcholine transporter (VAChT), a target recognized by commercial animal and crop health groups as a viable anthelmintic target. We demonstrate that it is possible to create Nemacol analogs that maintain potent in vivo activity whilst lowering their affinity to the mammalian VAChT 10-fold. We also show that Nemacol synergizes with the anthelmintic ivermectin to kill C. elegans. Hence, Nemacol represents a promising new anthelmintic scaffold that acts through an identified viable anthelmintic target.

One sentence summary

A small molecule screen identifies a vesicular acetylcholine transporter inhibitor scaffold that incapacitates parasitic nematodes
The development of intracytoplasmic membranes in alphaproteobacteria involves the conserved mitochondrial crista-developing protein Mic60
Authors: Muñoz-Gómez Sergio A. , Cadena Lawrence Rudy , Gardiner Alastair T. , Leger Michelle M. , Sheikh Shaghayegh , Connell Louise , Bilý Tomáš , Kopejtka Karel , Beatty J. Thomas , Koblížek Michal , Roger Andrew J. , Slamovits Claudio H. , Lukeš Julius , Hashimi Hassan
Published: June 2022

Mitochondrial cristae expand the surface area of respiratory membranes and ultimately allow for the evolutionary scaling of respiration with cell volume across eukaryotes. The discovery of Mic60 homologs among alphaproteobacteria, the closest extant relatives of mitochondria, suggested that cristae might have evolved from bacterial intracytoplasmic membranes (ICMs). Here, we investigated the predicted structure and function of alphaproteobacterial Mic60, and a protein encoded by an adjacent gene Orf52, in two distantly related purple alphaproteobacteria,Rhodobacter sphaeroidesandRhodopseudomonas palustris. In addition, we assessed the potential physical interactors of Mic60 and Orf52 inR. sphaeroides. We show that the three α-helices of mitochondrial Mic60’s mitofilin domain, as well as its adjacent membrane-binding amphipathic helix, are present in alphaproteobacterial Mic60. The disruption of Mic60 and Orf52 caused photoheterotrophic growth defects, which are most severe under low light conditions, and both their disruption and overexpression led to enlarged ICMs in both studied alphaproteobacteria. We also found that alphaproteobacterial Mic60 physically interacts with BamA, the homolog of Sam50, one of the main physical interactors of eukaryotic Mic60. This interaction, responsible for making contact sites at mitochondrial envelopes, has been conserved in modern alphaproteobacteria despite more than a billion years of evolutionary divergence. Our results suggest a role for Mic60 in photosynthetic ICM development and contact site formation at alphaproteobacterial envelopes. Overall, we provide support for the hypothesis that mitochondrial cristae evolved from alphaproteobacterial ICMs, and therefore have improved our understanding of the nature of the mitochondrial ancestor.
Identifying cortical areas that underlie the transformation from retinal to world motion signals
Authors: Wen Puti , Landy Michael S. , Rokers Bas
Published: June 2022

Accurate motion perception requires that the visual system integrate the retinal motion signals received by the two eyes into a single representation of 3D (i.e., world) motion. However, most experimental paradigms limit the motion stimuli to the fronto-parallel plane (i.e., 2D motion) and are thus unable to dissociate retinal and world motion signals. Here, we used stereoscopic displays to present separate motion signals to the two eyes and examined their representation in visual cortex using fMRI. Specifically, we presented random-dot motion stimuli that produced percepts of various 3D motion trajectories. We also presented control stimuli that contained the same retinal motion energy in the two eyes but were inconsistent with any 3D motion trajectory. We decoded the stimuli from BOLD activity using a probabilistic decoding algorithm. We found that 3D motion direction can be reliably decoded in three major clusters in the human visual system. In early visual cortex (V1-V3), we found no significant difference in decoding performance between the 3D motion and control stimuli, suggesting that these areas represent retinal motion rather than world motion signals. In voxels in and surrounding hMT and IPS0 however, decoding performance was consistently superior for 3D motion compared to control stimuli. Our results reveal the parts of the visual processing hierarchy that are critical for the transformation of retinal into world motion signals and suggest a role for IPS0 in the representation of 3D motion signals, in addition to its sensitivity to 3D object structure and static depth.
Conservation at the uterine-placental interface
Authors: Scott Regan L. , Vu Ha T. H. , Jain Ashish , Iqbal Khursheed , Tuteja Geetu , Soares Michael J.
Published: June 2022

The hemochorial placentation site is characterized by a dynamic interplay between trophoblast cells and maternal cells. These cells cooperate to establish an interface required for nutrient delivery to promote fetal growth. In the human, trophoblast cells penetrate deep into the uterus. This is not a consistent feature of hemochorial placentation and has hindered the establishment of suitable animal models. The rat represents an intriguing model for investigating hemochorial placentation with deep trophoblast cell invasion. In this study, we used single cell RNA sequencing to characterize the transcriptome of the invasive trophoblast cell lineage, as well as other cell populations within the rat uterine-placental interface during early (gestation day, gd, 15.5) and late (gd 19.5) stages of intrauterine trophoblast cell invasion. We identified a robust set of transcripts that define invasive trophoblast cells, as well as transcripts that distinguished endothelial, smooth muscle, natural killer, and macrophage cells. Invasive trophoblast, immune, and endothelial cell populations exhibited distinct spatial relationships within the uterine-placental interface. Furthermore, the maturation stage of invasive trophoblast cell development could be determined by assessing gestation-stage dependent changes in transcript expression. Finally, and most importantly, expression of a prominent subset of rat invasive trophoblast cell transcripts is conserved in the invasive extravillous trophoblast cell lineage of the human placenta. These findings provide foundational data to identify and interrogate key conserved regulatory mechanisms essential for development and function of an important compartment within the hemochorial placentation site that is essential for a healthy pregnancy.

SIGNIFICANCE

Trophoblast cell-guided restructuring of the uterus is an essential event in the establishment of the hemochorial placenta. Establishment of a suitable animal model for investigating regulatory mechanisms in this critical developmental process is a key to better understanding the etiology of diseases of placentation, such as early pregnancy loss, preeclampsia, intrauterine growth restriction, and preterm birth. The rat exhibits deep trophoblast cell invasion, as seen in human hemochorial placentation. Similarities are identified in the transcriptomes of rat and human invasive trophoblast cells, leading to the discovery of conserved candidate regulators of the invasive trophoblast cell lineage. This creates opportunities to test hypotheses underlying the pathophysiologic basis of trophoblast cell-guided uterine transformation and new insights into the etiology of diseases of placentation.
Protein Function Prediction from Three-Dimensional Feature Representations Using Space-Filling Curves
Authors: Rappoport Dmitrij , Jinich Adrian
Published: June 2022

Compact and interpretable structural feature representations are required for accurately predicting properties and the function of proteins. In this work, we construct and evaluate three-dimensional feature representations of protein structures based on space-filling curves. We focus on the problem of enzyme substrate prediction, using two ubiquitous enzyme families as case studies: the short-chain dehydrogenase/reductases (SDRs) and the S-adenosylmethionine dependent methyltransferases (SAM-MTases). Space-filling curves such as Hilbert curve and the Morton curve generate a reversible mapping from discretized three-dimensional to one-dimensional representations and thus help to encode three-dimensional molecular structures in a system-independent way and with a minimal number of parameters. Using three-dimensional structures of SDRs and SAM-MTases generated using AlphaFold2, we assess the performance of the SFC-based feature representations in predictions on a new benchmark database of enzyme classification tasks including their cofactor and substrate selectivity. Gradient-boosted tree classifiers yield binary prediction accuracy of 0.766–0.906 and AUC (area under curve) parameters of 0.828–0.922 for the classification tasks. We investigate the effects of amino acid encoding, spatial orientation, and (the few) parameters of SFC-based encodings on the accuracy of the predictions. Our results suggest that geometry-based approaches such as SFCs are promising for generating protein structural representations and are complementary to the highly parametric methods, for example, convolutional neural networks (CNNs).
Phytochemical and antibacterial analyses of Onychium japonicum (Thunb.) Kunze
Authors: Shah Syed AHsan , Shah Ghulam Mujtaba , Hassan Mohamed M. , Alsanie Walaa F. , Nawazish Shamyla , Ali Waqar , Basit Abdul , Shafqath DR. Nosheen , Jabeen Nadia , Shah Syed Abdul Majid , Shah Zarbad , Ishtiaq Muhammad , Gul DR. Alia , alam jan , Islam Muhammad , Faheem Asma ,   Experts from Microbiology and Biichemistry as well participated in the current work
Published: June 2022

In clinical practice bacterial resistance against antibiotics has become a serious health problem, thus using alternative approaches such as natural products as the supplementary drug could solve it. Therefore, the current study was conducted to thoroughly investigate the enrichment of phytochemicals and antibacterial potential of O. japonicum. The fronds samples of O. japonicum prepared in different solvents were used against MDR bacterial strains and phytochemical analyses.

The analyses of data revealed that O. japonicum was enriched with flavonoids, alkaloids, saponins, tannins, glycosides, carotenoids, terpenoids, phlobatanins, phenols, and coumarins while quantitatively this plant has a significantly higher content of phenols(1100.91µM/g) followed by sugar contents (748.67µM/ml), ascorbic acid (426.12mM/g), flavonoids (160.65mg/g), anthocyanin (101.06µM/g) and proline (80.58µM/g). On the other hand, the organic extracts of O. japonicum were highly active against all bacterial strains while hydric extract was inactive against selected bacteria. Specifically, O. japonicum was highly active against S. aureus in all organic extracts (chloroform=16.66±0.33, ethyl acetate=15±0.57, methyl alcohol= 14±0.57, N-hexane=20.33±0.33) followed by K. pneumonia (chloroform=14.33±0.33, ethyl acetate=4.33±4.33, methyl alcohol=3.66±3.66, N-hexane=16.66±0.33) and P. aeruginosa (chloroform= 8.33±4.17, ethyl acetate=8.33±4.17, methyl alcohol=6±3.00, N-hexane=9.33±4.66), while E. coli (chloroform=0±0.00, ethyl acetate=7±3.51, methyl alcohol=3.33±3.33, N-hexane=4±4.00).

Based on current findings it is concluded that O. japonicum is enriched in many useful phytochemicals that could be use as a supplement with other traditionally used antibiotics.
SOX10 Expression Levels may be a Critical Mediator of White Matter Dysfunction in Schizophrenia
Authors: McPhie Donna L , Ren Boyu , Garcıa-Leon Juan Antonio , Verfaillie Catherine M , Cohen Bruce M
Published: June 2022

Abnormalities of brain connectivity are consistently observed in individuals with schizophrenias (SZ). Underlying these anomalies, convergent in vivo, post-mortem, and genomic evidence suggest abnormal oligodendrocyte (OL) development and function, including lower in vivo myelination in SZ. Using patient derived induced pluripotent stem cells (IPSCs), we previously observed a significant and substantial reduction in the number of OLs produced in cells from the SZ group compared to the healthy control (HC) group. We a lso observed a correlation between white matter (WM) estimated in brain in vivo and the number of OLs produced in vitro.

We have now characterized potential mediators that may contribute to the SZ-associated deficit in OL production. We ran qRT-PCRs to detect group-specific differences in key myelin pathway proteins. Significant reductions of PAX6 and SOX10 expression were seen in the SZ group. We focused on SOX10 since one of its functions is the commitment of precursor cells to an oligodendrocyte fate. Using an inducible lentiviral system, we expressed SOX10 in patterned neural stem cells (NSCs) and quantified the number of OLs produced. Expression of SOX10 rescued the SZ-associated deficit in OL production, indicating that reduced SOX10 may be a critical mediator of OL dysfunction in SZ. We then ran qRT-PCRs to screen mRNAs for three proteins (SOX9, QK1 and FEZ1) whose expression was directly influenced by SOX10 or directly influenced the expression of SOX10. We saw significant reductions of SOX9 expression and a reduction in QK1 expression in the SZ group. RNAseq analysis confirmed these gene expression changes.
Dietary polyphenols drive alterations in behavior, transcriptional regulation, and commensal microbiota in models of opioid use
Authors: Osman Aya , Hofford Rebecca S. , Meckel Katherine R. , Dave Yesha A. , Zeldin Sharon M. , Shipman Ava L. , Lucerne Kelsey E. , Trageser Kyle J , Oguchi Tatsunori , Pasinetti Giulio M. , Kiraly Drew D.
Published: June 2022

Opioid Use Disorder (OUD) is a neuropsychiatric condition associated with tremendous medical and social consequences. Despite this burden, current pharmacotherapies for OUD are ineffective or intolerable for many patients. As such, interventions aimed at promoting overall health and resilience against OUD are of immense clinical and societal interest. Recently, treatment with a Bioactive Dietary Polyphenol Preparation (BDPP) was shown to promote behavioral resilience and adaptive neuroplasticity in multiple models of neuropsychiatric disease. Here, we assessed effects of BDPP treatment on behavioral and molecular responses to repeated morphine treatment. We find that BDPP pre-treatment alters responses across the dose range for both locomotor sensitization and conditioned place preference. Most notably, polyphenol treatment consistently reduced formation of preference at low dose (5mg/kg) morphine but enhanced it at high dose (15mg/kg). In parallel, we performed transcriptomic profiling of the nucleus accumbens, which again showed a dose x polyphenol interaction. At high dose morphine, BDPP pre-treatment potentiated gene expression changes induced by morphine particularly for genes related to synaptic function. We also profiled microbiome composition and function, as polyphenols are metabolized by the microbiome and can act as prebiotics. The profile revealed polyphenol treatment markedly altered microbiome composition and function, particularly in the low dose morphine group. Finally, we investigated involvement of the SIRT1 histone deacetylase, and the role of specific polyphenol metabolites in these behavioral phenotypes. Taken together, these results demonstrate that polyphenols have robust dose-dependent effects on behavioral and physiological responses to morphine and lay the foundation for future translational work.
Draft genome of the lowland anoa (Bubalus depressicornis) and comparison with buffalo genome assemblies (Bovidae, Bubalina)
Authors: Porrelli Stefano , Gerbault-Seureau Michèle , Rozzi Roberto , Chikhi Rayan , Curaudeau Manon , Ropiquet Anne , Hassanin Alexandre
Published: June 2022

Genomic data for wild species of the genus Bubalus (Asian buffaloes) are still lacking while several whole genomes are currently available for domestic water buffaloes. To address this, we sequenced the genome of a wild endangered dwarf buffalo, the lowland anoa (Bubalus depressicornis), produced a draft genome assembly, and made comparison to published buffalo genomes.

The lowland anoa genome assembly was 2.56 Gbp long and contained 103,135 contigs, the longest contig being 337.39 kbp long. N50 and L50 values were 38.73 kbp and 19.83 kbp, respectively, mean coverage was 44x and GC content was 41.74%. Two strategies were adopted to evaluate genome completeness: (i) determination of genomic features with de novo and homology-based predictions using annotations of chromosome-level genome assembly of the river buffalo, and (ii) employment of benchmarking against universal single-copy orthologs (BUSCO). Homology-based predictions identified 94.51% complete and 3.65% partial genomic features. De novo gene predictions identified 32,393 genes, representing 97.14% of the reference’s annotated genes, whilst BUSCO search against the mammalian orthologues database identified 71.1% complete, 11.7% fragmented and 17.2% missing orthologues, indicating a good level of completeness for downstream analyses. Repeat analyses indicated that the lowland anoa genome contains 42.12% of repetitive regions. The genome assembly of the lowland anoa is expected to contribute to comparative genome analyses among bovid species.
Void volume fraction of granular scaffolds
Authors: Riley Lindsay , Wei Grace , Bao Yijun , Cheng Peter , Wilson Katrina L. , Liu Yining , Gong Yiyang , Segura Tatiana
Published: June 2022

Void volume fraction (VVF) of granular biomaterials is a global measurement frequently used to characterize void space. There is currently no gold standard for measuring the VVF of granular scaffolds made in lab. To help the biomaterials field, we provide a library of different simulated scaffolds with known VVF for easy look-up. We use our simulated data to explore the relationship between microscope magnification and VVF, and we study the accuracy of approximating VVF using 2-D z-slice images, which is the most common approach for computing VVF of real scaffolds. Lastly, we test four different approaches for computing VVF using microscope images of real granular scaffolds and reveal that VVF may be an unreliable descriptor.
The transition zone in Hirschsprung’s bowel contains abnormal hybrid ganglia with characteristics of extrinsic nerves
Authors: Smith Megan , Chhabra Sumita , Shukla Rajeev , Kenny Simon , Almond Sarah , Edgar David , Wilm Bettina
Published: June 2022

The aganglionic bowel in short segment Hirschsprung’s disease is characterised both by the absence of enteric ganglia and the presence of extrinsic thickened nerve bundles (TNBs). The relationship between the TNBs and the loss of enteric ganglia is unknown. Previous studies have described decreasing numbers of ganglia with increasing density of TNBs within the transition zone (TZ) between ganglionic and aganglionic gut, and there is some evidence of spatial contact between them in this region. To determine the cellular interactions involved, we have analysed the expression of perineurial markers of TNBs and enteric ganglionic markers for both neural cells and their ensheathing telocytes across four cranio-caudal segments consisting of most proximal ganglionic to most distal aganglionic from pull-through resected colon. We show that in the TZ, enteric ganglia are abnormal, being surrounded by perineurium cells characteristic of TNBs. Furthermore, short processes of ganglionic neurons extend caudally towards the aganglionic region, where telocytes in the TNB are located between the perineurium and nerve fibres into which they project telopodes. Thus, enteric ganglia within the TZ have abnormal structural characteristics, the cellular relationships of which are shared by the TNBs. These findings will help towards elucidation of the cellular mechanisms involved in the aetiology of Hirschsprung’s disease.
Prevalence and severity of symptoms 3 months after infection with SARS-CoV-2 compared to test-negative and population controls in the Netherlands
Authors: van der Maaden Tessa , Mutubuki Elizabeth N. , de Bruijn Siméon , Leung Ka Yin , Knoop Hans , Slootweg Jaap , Tulen Anna D. , Wong Albert , van Hoek Albert Jan , Franz Eelco , Van den Wijngaard Cees C.
Published: June 2022

Background

More information is needed on prevalence of long-term symptoms after SARS-CoV-2-infection. This prospective study assesses symptoms three months after SARS-CoV-2-infection compared to test-negative and population controls, and the effect of vaccination prior to infection.

Methods

Participants enrolled after a positive (cases) or negative (test-negative controls) SARS-CoV-2-test, or after invitation from the general population (population controls). After three months, participants indicated presence of 41 symptoms, and severity of four symptoms. Permutation tests were used to select symptoms significantly elevated in cases compared to controls and to compare symptoms between cases that were vaccinated or unvaccinated prior to infection.

Findings

Between May 19th and December 13th 2021 9166 cases, 1698 symptomatic but test-negative controls, and 3708 population controls enrolled. At three months, 13 symptoms, and severity of fatigue, cognitive impairment and dyspnoea, were significantly elevated between cases and controls. Of cases, 48.5% reported ≥1 significantly elevated symptom, compared to 29.8% of test-negative controls and 26.0% of population controls. Effect of vaccination could only be determined for cases <65yrs, and was found to be significantly protective for loss of smell and taste but not for other symptoms.

Interpretation

Three months after SARS-CoV-2 infection, almost half of the cases still report symptoms, which is higher than the background prevalence and prevalence in test-negative controls. Vaccination prior to infection was protective against loss of smell and taste as assessed in cases aged <65.
Daily administration of low-dose daunorubicin or doxorubicin inhibits hypoxia-inducible factor 1 and tumor vascularization
Authors: Yang Yongkang , Qian David Z. , Rey Sergio , Liu Jun O. , Semenza Gregg L.
Published: June 2022

Using a hypoxia-inducible factor 1 (HIF-1)-dependent luciferase reporter in Hep3B human hepatocellular carcinoma cells, we screened over 3,000 drugs that have been used in clinical trials and identified multiple anthracyclines as inhibitors of HIF-1 activity. Anthracyclines interfered with the ability of HIF-1 to bind to DNA. Daily injection of tumor-bearing mice with anthracyclines at low dose inhibited expression of the luciferase reporter and HIF-1 target genes that encode vascular endothelial growth factor A (VEGFA; ligand of VEGFR2), stromal-derived factor 1 (SDF-1; ligand of CXCR4), and stem cell factor (SCF; ligand of CD117) in tumor tissue. Increased numbers of circulating CXCR4+/Sca1+, VEGFR2+/CD34+, and VEGFR2+/CD117+ cells were demonstrated in immunodeficient mice bearing prostate cancer xenografts but not in tumor-bearing mice treated with anthracyclines, which also significantly inhibited angiogenesis in tumor tissue. Our findings indicate that HIF-1 inhibition underlies the anti-angiogenic effect associated with daunorubicin or doxorubicin metronomic therapy and suggest that these drugs may be particularly effective in patients with high levels of HIF-1α in their diagnostic tumor biopsy.
Vibrissae-evoked activity in the somatosensory thalamus of rat pups: an intracellular study
Authors: Sheroziya Maxim , Khazipov Roustem
Published: June 2022

Spontaneous and sensory-evoked neuronal activity plays a decisive role in network formation during postnatal development. The thalamus is a major gateway for sensory outputs to the cortex, so that thalamic neuronal activity in newborn animals might be crucial for maturation of the thalamocortical network. The sensory-evoked intracellular thalamic activity and signal propagation in newborn animals remain largely unknown. Here we performed local field potential (LFP), juxtacellular, and patch clamp recordings in the somatosensory thalamus of urethane anesthetized rats at postnatal days 6-7 (P6-7, both sexes) with one whisker stimulation. To reach the thalamus with the electrodes the majority of the overlying cortex and hippocampus were removed. Deflection of only one (the principal) whisker induced spikes in a particular thalamic cell. Sensory stimulation evoked excitatory and inhibitory postsynaptic events in thalamocortical cells. Up to 5-10 sensory-evoked large-amplitude excitatory events followed with 100-200 ms inter-event intervals, while multiple inhibitory events tended to form 20-40 ms inter-event intervals. Large-amplitude excitatory events produced spike bursts with an intraburst frequency of 50-100 Hz and/or short plateau potentials in thalamocortical cells. Inhibitory events could down-modulate evoked spiking or prevented a depolarization block. Juxtacellular recordings confirmed the partial inactivation of spikes during short plateau potentials. Excitatory events evoked low-threshold spikes (LTS) in thalamocortical cells, but, in agreement with previously reported results, hyperpolarizing current pulses generated weak LTS without spike bursts. We conclude that thalamic neuronal activity in rat pups is determined by relatively weak and slow intrinsic membrane currents and relatively strong synapses that might underlay immature forms of thalamocortical synchrony and signal propagation.
Auto-regressive Rank Order Similarity (aros) test
Authors: Clausner Tommy , Gentili Stefano
Published: June 2022

In the present paper we propose a non-parametric statistical test procedure for interval scaled, paired samples data that circumvents the multiple comparison problem (MCP) by relating the data to the rank order of its group averages. Using an auto-regressive procedure, a single test statistic for multiple groups is obtained that allows for qualitative statements about whether multiple group averages are in fact different and how they can be sorted. The presented procedure outperforms classical tests, such as pairwise conducted t-tests and ANOVA, in some circumstances. Furthermore, the test is robust against noise and does not require the data to follow any particular distribution. If A is a data matrix containing N observations for k groups, then the test statistic η can be computed by , where s is a vector of length k containing the average for each group, transformed into unique rank values. This statistic is compared to the distribution D, obtained by Monte Carlo sampling from the permutation distribution. It will be demonstrated that D can be described by a normal distribution for a variety of input data distributions and choices for f, as long as a set of criteria is met. Comparing η to the permutation distribution controls the false alarm (FA) rate sufficiently, since the exact p-value can be estimated [1]. Multiple examples of possible choices for f will be discussed, as well as detailed descriptions of the underlying test assumptions, possible interpretations and use cases. All mathematical derivations are supported with a set of simulations, written in Python that can be downloaded from https://gitlab.com/TommyClausner/aros-test together with an implementation of the test itself.
Endothelial TET2 Regulates Cardiac Remodeling by Modifying Endothelial-to-Mesenchymal Transition
Authors: Kou Wenxin , Shi Yefei , Li Bo , Zeng Yanxi , Zhai Ming , You Shuangjie , Yu Qing , Gong Shiyu , Zhuang Jianhui , Zhao Yifan , Jian Weixia , Xu Yawei , Peng Wenhui
Published: June 2022

DNA methylation modification has been proved to play an important role in heart diseases. In this study, the role of Ten-Eleven Translocation-2 (TET2), which is a key demethylation enzyme, is investigated in cardiac remodeling. TET2 is abundant in endothelial cells but decreased in hypertrophic hearts. TET2 knockdown in endothelial cells triggers endothelial-to-mesenchymal transition (EndMT), while overexpression of TET2 inhibits the EndMT. In vivo, Cdh5-CreERT2/TET2flox/flox; Rosa26-mTmG+/- mice are developed and undergo transverse aortic constriction (TAC) subsequently to induce pathological cardiac hypertrophy model. Hearts of Cdh5-CreERT2/TET2flox/flox mice show more severe hypertrophy and fibrosis than controls in the TAC model. Furthermore, EGLN3 is identified to participate in EndMT as the downstream target of TET2 by using RNA sequencing and whole-genome bisulfite sequencing (WGBS). Finally, vitamin C, which can mimic TET2 restoration, is found to partially improve cardiac function and inhibit myocardial fibrosis. These insights into how TET2 alleviates cardiac fibrosis may open new avenues for treating cardiac remodeling in the future.
PTK7 is a positive allosteric modulator of GPR133 (ADGRD1) signaling in GBM
Authors: Frenster Joshua D. , Erdjument-Bromage Hediye , Liu Wenke , Stephan Gabriele , Ravn-Boess Niklas , Bready Devin , Wilcox Jordan , Kieslich Björn , Jankovic Manuel , Wilde Caroline , Horn Susanne , Sträter Norbert , Liebscher Ines , Schöneberg Torsten , Fenyo David , Neubert Thomas A. , Placantonakis Dimitris G.
Published: June 2022

GPR133 (ADGRD1), an adhesion G protein-coupled receptor, supports growth of glioblastoma, a brain malignancy. We demonstrated that GPR133 is intramolecularly cleaved, and that dissociation of its N-terminal and C-terminal fragments (NTF and CTF) at the plasma membrane correlates with increased receptor signaling. However, how the extracellular interactome of GPR133 in glioblastoma modulates signaling remains unknown. Here, we use affinity purification and mass spectrometry to identify extracellular binding partners of GPR133 in patient-derived glioblastoma cells. We show that the transmembrane protein PTK7 binds the GPR133 NTF and its expression in trans increases GPR133 signaling. This effect requires the intramolecular cleavage of GPR133 and PTK7’s anchoring in the plasma membrane. The GPR133-PTK7 interaction facilitates orthosteric activation of GPR133 by soluble peptide mimicking the endogenous tethered Stachel agonist, suggesting PTK7 binding allosterically enhances accessibility of GPR133’s orthosteric Stachel binding pocket. GPR133 and PTK7 are expressed in adjacent cells in glioblastoma, where their knockdown phenocopies each other. We propose that this novel ligand-receptor interaction is relevant to the pathogenesis of glioblastoma, as well as physiological processes in several tissues.
Neural responses to instructed positive couple interaction: An fMRI study on compliment sharing
Authors: Eckstein Monika , Stößel Gabriela , Gerchen Martin Fungisai , Bilek Edda , Kirsch Peter , Ditzen Beate
Published: June 2022

Love is probably the most fascinating feeling that a person ever experiences. However, little is known about what is happening in the brains of a romantic couple –the central and most salient relationship during adult age– while they are particularly tender and exchanging loving words with one another.

To gain insight into nearly natural couple interaction, we collected data from N=84 individuals (including N=43 heterosexual couples) simultaneously in two functional magnetic resonance imaging scanners, while they sent and received compliments, i.e. short messages about what they liked about each other and their relationship. Activation patterns during compliment sharing in the individuals revealed a broad pattern of activated brain areas known to be involved in empathy and reward processing. Notably, the ventral striatum, including parts of the putamen, was activated particularly when selecting messages for the partner. This provides initial evidence that giving a verbal treat to a romantic partner seems to involve neural reward circuitry in the basal ganglia.

These results can have important implications for the neurobiological mechanisms protecting and stabilizing romantic relationships, which build a highly relevant aspect of human life and health.
Myeloid-derived suppressor cell dynamics control outcomes in the metastatic niche
Authors: Kreger Jesse , Roussos Torres Evanthia T. , MacLean Adam L.
Published: June 2022

Myeloid-derived suppressor cells (MDSCs) play a prominent and rising role in the tumor microenvironment. An understanding of the tumor-MDSC interactions that influence disease progression is critical, and currently lacking. To address this, we developed a mathematical model of metastatic growth and progression in immune-rich tumor microenvironments. We model the tumor-immune dynamics with stochastic delay differential equations, and study the impact of delays in MDSC activation/recruitment on tumor growth outcomes. We find when the circulating level of MDSCs is low, the MDSC delay has a pronounced impact on the probability of new metastatic establishment: blocking MDSC recruitment can reduce the probability of metastasis by as much as 50%. We also quantify the extent to which decreasing the immuno-suppressive capability of the MDSCs impacts the probability that a new metastasis will persist or grow. In order to quantify patient-specific MDSC dynamics under different conditions we fit individual tumors treated with immune checkpoint inhibitors to the tumor-MDSC model via Bayesian parameter inference. We reveal that control of the inhibition rate of natural killer cells by MDSCs has a larger influence on tumor outcomes than controlling the tumor growth rate directly. Posterior classification of tumor outcomes demonstrates that incorporating knowledge of the MDSC responses improves predictive accuracy from 63% to 82%. Our results illustrate the importance of MDSC dynamics in the tumor microenvironment and predict interventions that may shift environments towards a less immune-suppressed state. We argue that there is a pressing need to more often consider MDSCs in analyses of tumor microenvironments.
Coupling gene expression dynamics to cell size dynamics and cell cycle events: exact and approximate solutions of the extended telegraph model
Authors: Jia Chen , Grima Ramon
Published: June 2022

The standard model describing the fluctuations of mRNA numbers in single cells is the telegraph model which includes synthesis and degradation of mRNA, and switching of the gene between active and inactive states. While commonly used, this model does not describe how fluctuations are influenced by the cell cycle phase, cellular growth and division, and other crucial aspects of cellular biology. Here we derive the analytical time-dependent solution of an extended telegraph model that explicitly considers the doubling of gene copy numbers upon DNA replication, dependence of the mRNA synthesis rate on cellular volume, gene dosage compensation, partitioning of molecules during cell division, cell-cycle duration variability, and cell-size control strategies. Based on the time-dependent solution, we obtain the analytical distributions of transcript numbers for lineage and population measurements in steady-state growth and also find a linear relation between the Fano factor of mRNA fluctuations and cell volume fluctuations. We show that generally the lineage and population distributions in steady-state growth cannot be accurately approximated by the steady-state solution of extrinsic noise models, i.e. a telegraph model with parameters drawn from probability distributions. This is because the mRNA lifetime is often not small enough compared to the cell cycle duration to erase the memory of division and replication. Accurate approximations are possible when this memory is weak, e.g. for genes with bursty expression and for which there is sufficient gene dosage compensation when replication occurs.
Beta oscillations and waves in motor cortex can be accounted for by the interplay of spatially-structured connectivity and fluctuating inputs
Authors: Kang Ling , Ranft Jonas , Hakim Vincent
Published: June 2022

The beta rhythm (13-30 Hz) is a prominent brain rhythm. Recordings in primates during instructed-delay reaching tasks have shown that different types of traveling waves of oscillatory activity are associated with episodes of beta oscillations in motor cortex during movement preparation. We propose here a simple model of motor cortex based on local excitatory-inhibitory neuronal populations coupled by longer range excitation, where additionally inputs to the motor cortex from other neural structures are represented by stochastic inputs on the different model populations. We show that the model accurately reproduces the statistics of recording data when these external inputs are correlated on a short time scale (25 ms) and have two different components, one that targets the motor cortex locally and another one that targets it in a global and synchronized way. The model reproduces the distribution of beta burst durations, the proportion of the different observed wave types, and wave speeds, which we show not to be linked to axonal propagation speed. When the long-range connectivity is anisotropic, traveling waves are found to preferentially propagate along the axis where connectivity decays the fastest. Different from previously proposed mechanistic explanations, the model suggests that traveling waves in motor cortex are the reflection of the dephasing by external inputs, putatively of thalamic origin, of an oscillatory activity that would otherwise be spatially synchronized by recurrent connectivity.
Dermal nerve growth factor is increased in prurigo nodularis compared to atopic dermatitis
Authors: Deng Junwen , Parthasarathy Varsha , Bordeaux Zachary , Marani Melika , Lee Kevin , Trinh Chi , Sutaria Nishadh , Cornman Hannah L. , Kambala Anusha , Pritchard Thomas , Chen Shihua , Oladipo Olusola O. , Kwatra Madan M. , Alphonse Martin P. , Kwatra Shawn G.
Published: June 2022

Background

Prurigo nodularis (PN) is a chronic, pruritic, inflammatory skin disease characterized by hyperkeratotic nodules on the trunk and extremities. While there is growing research on the immunological basis of PN, the neuropathic and structural components of PN lesions are unknown.

Objective

To determine the inflammatory, neuropathic, and structural pathways in PN compared to atopic dermatitis (AD).

Methods

Lesional and non-lesional skin biopsies were collected from 13 PN and 6 AD patients. mRNA and protein expression in biopsies was determined using RNA-Sequencing and immunohistochemistry (IHC), respectively. Differentially expressed genes (DEGs) were identified using the DESeq2 R package and pathway level enrichment was determined using Gene Set Enrichment Analysis. IHC expression was quantified with QuPath followed by statistical comparison with the Student’s t-test and Mann-Whitney U.

Results

Compared to lesional AD, lesional PN had greater mRNA expression of MMPs, OSM, NGF, IL1β, CXCL2, CXCL5, CXCL8, and insulin-like growth factors, and lower expression of CCL13, CCL26, EPHB1, and collagens. Compared to non-lesional AD, non-lesional PN showed upregulation of keratin-family genes. GSEA revealed that lesional PN had greater keratinization, cornified envelope, myelin sheath, TGF-beta signaling, extracellular matrix disassembly, metalloendopeptidase activity, and neutrotrophin-TRK receptor signaling, while non-lesional PN had higher keratin filament, extracellular structure organization, extracellular matrix disassembly, and angiogenesis. IHC showed increased dermal nerve growth factor (NGF) expression in lesional PN compared to lesional AD (p=0.038), and greater epidermal NGF compared to dermal NGF in non-lesional PN (p=0.014).

Limitations

Single, tertiary care center.

Conclusions

PN demonstrated increased neurotrophic and extracellular matrix (ECM) remodeling signatures compared to AD, possibly explaining the morphological differences in their lesions. These signatures may therefore be important components of the PN pathogenesis and may serve as therapeutic targets.
Differentiating Bayesian model updating and model revision based on their prediction error dynamics
Authors: Rutar Danaja , Colizoli Olympia , Selen Luc , Spieß Lukas , Kwisthout Johan , Hunnius Sabine
Published: June 2022

Within predictive processing learning is construed as Bayesian model updating with the degree of certainty for different existing hypotheses changing in light of new evidence. Bayesian model updating, however, cannot explain how new hypotheses are added to a model. Model revision, unlike model updating, makes structural changes to a generative model by altering its causal connections or adding or removing hypotheses. Whilst model updating and model revision have recently been formally differentiated, they have not been empirically distinguished. The aim of this research was to empirically differentiate between model updating and revision on the basis of how they affect prediction errors and predictions over time. To study this, participants took part in a within-subject computer-based learning experiment with two phases: updating and revision. In the updating phase, participants had to predict the relationship between cues and target stimuli and in the revision phase, they had to correctly predict a change in the said relationship. Based on previous research, phasic pupil dilation was taken as a proxy for prediction error. During model updating, we expected that the prediction errors over trials would be gradually decreasing as a reflection of the continuous integration of new evidence. During model revision, in contrast, prediction errors over trials were expected to show an abrupt decrease following the successful integration of a new hypothesis within the existing model. The opposite results were expected for predictions. Our results show that the learning dynamics as reflected in pupil and accuracy data are indeed qualitatively different between the revision and the updating phase, however in the opposite direction as expected. Participants were learning more gradually in the revision phase compared to the updating phase. This could imply that participants first built multiple models from scratch in the updating phase and updated them in the revision phase.
Spatiotemporal dynamics of memory encoding and memory retrieval states
Authors: Hong Yuju , Moore Isabelle L. , Smith Devyn E. , Long Nicole M.
Published: June 2022

Memory encoding and memory retrieval are neurally distinct brain states that can be differentiated on the basis of cortical network activity. However, it is unclear whether sustained engagement of one network or fluctuations between multiple networks give rise to these memory states. The spatiotemporal dynamics of memory states may have important implications for memory behavior and cognition; however, measuring temporally resolved signals of cortical networks poses a challenge. Here we recorded scalp electroencephalography from subjects performing a mnemonic state task in which they were biased toward memory encoding or retrieval. We performed a microstate analysis in order to measure the temporal dynamics of cortical networks throughout this mnemonic state task. We find that microstate E, a putative analog of the default mode network, shows temporally sustained dissociations between memory encoding and retrieval, with greater engagement during retrieve compared to encode trials. We further show that decreased engagement of microstate E is a general property of encoding, rather than a reflection of retrieval suppression. Together, these findings show that memory states are supported by sustained engagement of a particular cortical network. Memory success, as well as cognition more broadly, may be influenced by the ability to engage or disengage microstate E in a goal-dependent manner.