bluuebunny/crossref_metadata_2025 huggingface dataset:
Mixing Loops, Mixing Envelopes, and Scattered Correlations among Trace Elements and Isotope Ratios Produced by Mixing of Melts Derived from a Spatially and Lithologically Heterogenous Mantle
Authors: Liang Yan
Published: September 2022

Mixing has been widely used in the interpretation of radiogenic isotope ratios and highly incompatible trace element variations in basalts produced by melting of a heterogeneous mantle. The binary mixing model is constructed by considering mass balance of endmember components, which is independent of physical state and spatial distribution of the endmembers in the mantle source. Variations of radiogenic isotope ratios and highly incompatible trace elements in basalts also depend on the size and spatial distribution of chemical and lithological heterogeneities in the mantle source. Here we present a new mixing model and a mixing scheme that take into account of the size, spatial location, and melting history of enriched mantle (EM) and depleted mantle (DM) parcels in the melting column. We show how Sr, Nd, and Hf concentrations and isotope ratios in the aggregated or pooled melt collected at the top of the melting column vary as a function of location of the EM parcel in the melting column. With changing location of the EM parcel in the upwelling melting column, compositions of the pooled melt do not follow a single mixing curve expected by the binary mixing model. Instead, they define a mixing loop that has an enriched branch and a depleted branch joined by two extreme points in composition space. The origin of the mixing loop can be traced back to four types of EM distribution or configuration in the melting column. The shape of the mixing loop depends on the relative melting rate of the EM to that of the DM and the number and spacing of EM parcels in the melting column. Probabilities of sampling the enriched and depleted branches in the pooled melt are proportional to volume fractions of the enriched and depleted materials in the mantle source. Mixing of pooled melts from a bundle of melting columns results in mixing envelopes in the isotope ratio correlation diagrams. The mixing envelope is a useful tool for studying chemical variations in mantle-derived melts. As an application, we consider scattered correlations in 87Sr/86Sr vs. 143Nd/144Nd and 143Nd/144Nd vs. 176Hf/177Hf in mid-ocean ridge basalts. We show that such correlations arise naturally from melting of a spatially heterogeneous mantle.
Multiple cyclic nucleotide-gated channels function as ABA-activated Ca2+ channels required for ABA-induced stomatal closure in Arabidopsis
Authors: Tan Yan-Qiu , Yang Yang , Shen Xin , Zhu Meijun , Shen Jianlin , Zhang Wei , Hu Honghong , Wang Yong-Fei
Published: September 2022

Abscisic acid (ABA)-activated inward Ca2+-permeable channels in the plasma membrane (PM) of guard cells are required for the initiation and regulation of ABA-specific cytosolic Ca2+ signaling and stomatal closure in plants. But the identities of the PM Ca2+ channels are still unknown. We hypothesized that the ABA-activated Ca2+ channels consist of multiple CYCLIC NUCLEOTIDE-GATED CHANNEL (CNGC) proteins from the CNGC family, which is known as a Ca2+-permeable channel family in Arabidopsis (Arabidopsis thaliana). In this research, we observed high expression of multiple CNGC genes in Arabidopsis guard cells, namely CNGC5, CNGC6, CNGC9, and CNGC12. The T-DNA insertional loss-of-function quadruple mutant cngc5-1 cngc6-2 cngc9-1 cngc12-1 (hereafter c5/6/9/12) showed a strong ABA-insensitive phenotype of stomatal closure. Further analysis revealed that ABA-activated Ca2+ channel currents were impaired, and ABA-specific cytosolic Ca2+ oscillation patterns were disrupted in c5/6/9/12 guard cells compared with in wild-type guard cells. All ABA-related phenotypes of the c5/6/9/12 mutant were successfully rescued by the expression of a single gene out of the four CNGCs under the respective native promoter. Thus, our findings reveal a type of ABA-activated PM Ca2+ channel comprising multiple CNGCs, which is essential for ABA-specific Ca2+ signaling of guard cells and ABA-induced stomatal closure in Arabidopsis.
Plant-specific HDT family histone deacetylases are nucleoplasmins
Authors: Bobde Ruchir C , Kumar Ashish , Vasudevan Dileep
Published: September 2022

Histone acetyltransferase (HAT)- and histone deacetylase (HDAC)-mediated histone acetylation and deacetylation regulate nucleosome dynamics and gene expression. HDACs are classified into different families, with HD-tuins or HDTs being specific to plants. HDTs show some sequence similarity to nucleoplasmins, the histone chaperones that aid in binding, storing, and loading H2A/H2B dimers to assemble nucleosomes. Here, we solved the crystal structure of the N-terminal domain (NTD) of all four HDTs (HDT1, HDT2, HDT3, and HDT4) from Arabidopsis (Arabidopsis thaliana). The NTDs form a nucleoplasmin fold, exist as pentamers in solution, and are resistant to protease treatment, high temperature, salt, and urea conditions. Structurally, HDTs do not form a decamer, unlike certain classical nucleoplasmins. The HDT-NTD requires an additional A2 acidic tract C-terminal to the nucleoplasmin domain for interaction with histone H3/H4 and H2A/H2B oligomers. We also report the in-solution structures of HDT2 pentamers in complex with histone oligomers. Our study provides a detailed structural and in vitro functional characterization of HDTs, revealing them to be nucleoplasmin family histone chaperones. The experimental confirmation that HDTs are nucleoplasmins may spark new interest in this enigmatic family of proteins.
Preferences for preventive treatments for rheumatoid arthritis: discrete choice survey in the UK, Germany and Romania
Authors: Simons Gwenda , Veldwijk Jorien , DiSantostefano Rachael L , Englbrecht Matthias , Radawski Christine , Bywall Karin Schölin , Valor Méndez Larissa , Hauber Brett , Raza Karim , Falahee Marie
Published: September 2022

Objective

To quantify preferences for preventive therapies for rheumatoid arthritis (RA) across three countries.

Methods

A web-based survey including a discrete choice experiment was administered to adults recruited via survey panels in the UK, Germany and Romania. Participants were asked to assume they were experiencing arthralgia and had a 60% chance of developing RA in the next 2 years and completed 15 choices between no treatment and two hypothetical preventive treatments. Treatments were defined by six attributes (effectiveness, risks and frequency/route of administration) with varying levels. Participants also completed a choice task with fixed profiles reflecting subjective estimates of candidate preventive treatments. Latent class models (LCMs) were conducted and the relative importance of attributes, benefit–risk trade-offs and predicted treatment uptake was subsequently calculated.

Results

Completed surveys from 2959 participants were included in the analysis. Most participants preferred treatment over no treatment and valued treatment effectiveness to reduce risk more than other attributes. A five-class LCM best fitted the data. Country, perceived risk of RA, health literacy and numeracy predicted class membership probability. Overall, the maximum acceptable risk for a 40% reduction in the chance of getting RA (60% to 20%) was 21.7%, 19.1% and 2.2% for mild side effects, serious infection and serious side effects, respectively. Predicted uptake of profiles reflecting candidate prevention therapies differed across classes.

Conclusion

Effective preventive pharmacological treatments for RA were acceptable to most participants. The relative importance of treatment attributes and likely uptake of fixed treatment profiles were predicted by participant characteristics.
Benefits and concerns of seeking and experiencing lucid dreams: benefits are tied to successful induction and dream control
Authors: Mallett Remington , Sowin Laura , Raider Rachel , Konkoly Karen R , Paller Ken A
Published: September 2022

Therapies focused on lucid dreaming could be useful for treating various sleep disorders and other conditions. Still, one major roadblock is the paucity of systematic information on the consequences of attempting these sorts of dreams. The current study sought to quantify positive and negative aspects of seeking lucid dreams, describe their phenomenology in detail, and identify features associated with positive or negative experiences. Observational data from a massive lucid-dream discussion forum were analyzed to capture lucid-dreaming themes. Forum posts were independently rated on multiple dimensions hypothesized to contribute to the valence of lucidity-related phenomena. Our results revealed that lucid dreams can end nightmares and prevent their recurrence, but they can also induce harrowing dysphoric dreams. The realization of dreaming (lucidity) and dreams with high-control were both associated with positive experiences. We translated our results into a process model that describes the progression from lucid dream induction to waking benefit, identifying potential areas of concern. Our results and model suggest that negative outcomes primarily result from failed induction attempts or lucid dreams with low dream control, and that successfully inducing high-control lucid dreams poses low risk for negative outcomes. Lucid dreaming has valuable therapeutic and recreational potential, but a better understanding of the risks is required. Our findings provide new insights into possible negative repercussions and how to avoid them in future applications.
A Novel C2 Screw Corridor Parallel to the Sagittal Plane for Transpedicular Fixation – A 3D-CT Study
Authors: Wu Chao , Deng Jiayan , Zeng Baifang , Wang Qing , Shen Danwei , Qiu Guigang , Liu Xin , Wang Xiangyu , Luo Min
Published: September 2022

Study Design:

A 3D-CT Study.

Objective:

To research the feasibility and advantages of screw corridors parallel to the sagittal plane (SPC) of the C2 for transpedicular fixation.

Summary of Background Data:

A total of 125 patients were enrolled for analysis, and the 3D model of the C2 for the 125 patients were reconstructed and analyzed.

Methods:

The SPC screw and the corridor of the general pedicle (GPC) screw of both sides were inserted into these C2 models. The anatomic parameters of the SPC and GPC, including the inner circle diameter, length of the corridors, medial angle and cephalad angle, were measured and compared. The anatomic location of the entry point for the SPC screw was evaluated.

Results:

The diameter of the SPC averaged 5.5±1.8 mm; 81.2% (203/250) were larger than 4 mm. There was no significant difference between the SPC and GPC in diameter or percentage of diameter greater than 4 mm. There was a significant difference between the length of the SPC (25.3±2.4 mm) and the GPC (27.4±2.2 mm). The cephalad angle was 51.6±6.9° for the SPC and 43.3±4.4° for the GPC, and there was a significant difference between the SPC and GPC. The entry point of the SPC screw was located on the cortical crest at the lower 1/4 of the lamina and located to the lower and inner side of the GPC screw entry point.

Conclusion:

It is feasible for most patients to accommodate an SPC screw with a diameter of 3.5 mm. All SPC screws crossed the pedicle completely. The optimal entry point of the SPC screw was located on the cortical crest of the axial lamina.
Early Surgery (Within 24 Hours) Benefits Patients Suffering from Acute Thoracolumbar Spinal Cord Injury
Authors: Wang Yang , Yi Hanxiao , Wang Jian , Song Yancheng
Published: September 2022

Study Design:

A meta-analysis of early surgery for acute thoracolumbar spinal cord injury.

Objective:

To evaluate whether early surgery increases the American Spinal Injury Association (ASIA) grade of patients confronted with acute thoracolumbar spinal cord injury.

Summary of Background Data:

The idea that early surgery aids the recovery of spinal cord function in patients confronted with acute thoracolumbar spinal cord injury is controversial.

Methods:

All articles were retrieved from the PubMed, Embase, Web of Science and Scopus databases, which were searched from onset until 1 May 2021. All data are presented as odds ratios (ORs) and mean deviations (MDs) with 95% confidential intervals (CIs).

Results:

Ten studies, including 6 prospective studies, 3 retrospective studies, and 1 randomized controlled trial, containing 952 patients, were included in the analysis. The results showed that early surgery significantly reduced the number of patients with ASIA grade A (OR 0.27, 95% CI: 0.13–0.58, P<0.01) and B (OR 0.56, 95% CI: 0.39–0.82, P<0.01) status but greatly increased the number of patients with grade E status (OR 1.44, 95% CI: 1.06–1.96, P<0.01). Generally, the patients receiving early surgery achieved >1 ASIA grade improvement (OR 1.70, 95% CI: 1.31–2.21, P<0.01) or >2 ASIA grade (OR 3.55, 95% CI: 2.20–5.70, P<0.01) improvements. Although early surgery did not reduce the incidence of operative complications (OR 0.72, 95% CI: 0.45–1.16, P<0.01), the duration of hospitalization was greatly shortened (MD−3.48, 95% CI: −0.45 to−2.91, P<0.01).

Conclusions:

The spinal cord function of acute thoracolumbar spinal cord injury patients can benefit from early decompression. This conclusion should be further verified with randomized controlled trials.
Patients with breath test positive are necessary to be identified from irritable bowel syndrome: a clinical trial based on microbiomics and rifaximin sensitivity
Authors: Liu Zuojing , Zhu Shiwei , He Meibo , Li Mo , Wei Hui , Zhang Lu , Sun Qinghua , Jia Qiong , Hu Nan , Fang Yuan , Song Lijin , Zhou Chen , Tao Heqing , Kao John Y , Zhu Huaiqiu , Owyang Chung , Duan Liping
Published: September 2022

Background:

As a non-invasive and effective diagnostic method for small intestinal bacterial overgrowth (SIBO), wild-use of breath test (BT) has demonstrated a high comorbidity rate in patients with diarrhea-predominant irritable bowel syndrome (IBS-D) and SIBO. Patients overlapping with SIBO respond better to rifaximin therapy than those with IBS-D only. Gut microbiota plays a critical role in both of these two diseases. We aimed to determine the microbial difference between IBS-D overlapping with/without SIBO, and to study the underlying mechanism of its sensitivity to rifaximin.

Methods:

Patients with IBS-D were categorized as BT-negative (IBSN) and BT-positive (IBSP). Healthy volunteers (BT-negative) were enrolled as healthy control. The patients were clinically evaluated before and after rifaximin treatment (0.4 g bid, 4 weeks). Blood, intestine, and stool samples were collected for cytokine assessment and gut microbial analyses.

Results:

Clinical complaints and microbial abundance were significantly higher in IBSP than in IBSN. In contrast, severe systemic inflammation and more active bacterial invasion function that were associated with enrichment of opportunistic pathogens were seen in IBSN. The symptoms of IBSP patients were relieved in different degrees after therapy, but the symptoms of IBSN rarely changed. We also found that the presence of IBSN-enriched genera (Enterobacter and Enterococcus) are unaffected by rifaximin therapy.

Conclusions:

IBS-D patients overlapping with SIBO showed noticeably different fecal microbial composition and function compared with IBS-D only. The better response to rifaximin in those comorbid patients might associate with their different gut microbiota, which suggests that BT is necessary before IBS-D diagnosis and use of rifaximin.

Registration:

Chinese Clinical Trial Registry, ChiCTR1800017911.
The Impact of Caregiving Length and Intensity on Labor Force Participation Among Middle-Aged Canadians
Authors: Zhang Wei , Sun Huiying , L'Heureux Jacynthe
Published: September 2022

Objectives: To assess the association between caregiving length/intensity and labor force participation among middle-aged Canadians. Methods: We used baseline data from the Canadian Longitudinal Study on Aging. Labor force participation status included working full-time, part-time, part retirement, complete retirement, and nonparticipation. We defined caregiving length as short-term versus long-term, and intensity as low, medium, and high. Multinomial logistic regressions and instrumental variable method were used. Results: Compared with non-caregivers, long-term and high-intensity caregivers were more likely to be completely retired, partly retired, and nonparticipants. Short-term and high-intensity caregivers were more likely to be completely retired, partly retired, and nonparticipants for women. Conclusions: Our findings emphasize the importance of considering caregiving intensity and length. Prioritizing support for long-term and high-intensity caregivers and promoting partial retirement or part-time working opportunities could help retain caregivers in the labor force.
Hepatitis‐associated Aplastic Anemia
Authors: Gonnot Maxime , Neumann Florent , Huet Frédéric , Maudinas Raphaëlle , Leblanc Thierry , Lacaille Florence
Published: September 2022

Hepatitis‐associated aplastic anemia (HAAA) accounts for 4% of autoimmune hepatitis in children. An episode of seronegative autoimmune hepatitis is followed a few days or months later by aplastic anemia or full aplasia. This autoimmune disease could be due to a regulation defect in the immune response to a viral trigger, in a genetically predisposed individual. Other causes of hepatitis or aplastic anemia have to be ruled out. Steroids and azathioprine usually control the liver damage but do not prevent the development of aplastic anemia. Aplastic anemia is treated with either hematopoietic stem cell transplantation in patients with a sibling donor or anti‐thymocyte globulins and cyclosporine. We propose guidelines to explore and treat this rare disease. We emphasize on the necessary close collaboration between hepatologists and hematologists.
From Malignant Thyroid Teratoma to Thyroblastoma: Evolution of a Newly-recognized DICER1-associated Malignancy
Authors: Rooper Lisa M.
Published: September 2022

Thyroblastoma is a novel thyroid malignancy included in the 5th Edition WHO Classification of Endocrine and Neuroendocrine Tumours. The majority of tumors now classified as thyroblastoma were originally regarded to be malignant thyroid teratomas. However, these neoplasms were recently recognized as a separate entity based on a distinctive constellation of primitive multilineage elements, including immature thyroid epithelium, undifferentiated or rhabdomyoblastic spindle cell proliferations, and neuroepithelial blastema, as well as recurrent DICER1 hotspot mutations. Thyroblastoma is an aggressive tumor that leads to death from disease in ~50% of patients, making it essential to differentiate this entity from a wide range of other thyroid tumors that show overlapping histologic features or DICER1 mutations. This review aims to provide a practical overview of the background, clinicopathologic features, molecular underpinnings, and differential diagnosis of this recently-described and molecularly-defined entity.
Radiomics and Deep Learning for Disease Detection in Musculoskeletal Radiology
Authors: Fritz Benjamin , Yi Paul H. , Kijowski Richard , Fritz Jan
Published: September 2022

Radiomics and machine learning–based methods offer exciting opportunities for improving diagnostic performance and efficiency in musculoskeletal radiology for various tasks, including acute injuries, chronic conditions, spinal abnormalities, and neoplasms. While early radiomics-based methods were often limited to a smaller number of higher-order image feature extractions, applying machine learning-based analytic models, multifactorial correlations, and classifiers now permits big data processing and testing thousands of features to identify relevant markers. A growing number of novel deep learning–based methods describe magnetic resonance imaging– and computed tomography–based algorithms for diagnosing anterior cruciate ligament tears, meniscus tears, articular cartilage defects, rotator cuff tears, fractures, metastatic skeletal disease, and soft tissue tumors. Initial radiomics and deep learning techniques have focused on binary detection tasks, such as determining the presence or absence of a single abnormality and differentiation of benign versus malignant. Newer-generation algorithms aim to include practically relevant multiclass characterization of detected abnormalities, such as typing and malignancy grading of neoplasms. So-called delta-radiomics assess tumor features before and after treatment, with temporal changes of radiomics features serving as surrogate markers for tumor responses to treatment. New approaches also predict treatment success rates, surgical resection completeness, and recurrence risk. Practice-relevant goals for the next generation of algorithms include diagnostic whole-organ and advanced classification capabilities. Important research objectives to fill current knowledge gaps include well-designed research studies to understand how diagnostic performances and suggested efficiency gains of isolated research settings translate into routine daily clinical practice. This article summarizes current radiomics- and machine learning–based magnetic resonance imaging and computed tomography approaches for musculoskeletal disease detection and offers a perspective on future goals and objectives.
Neuropathology and neuroanatomy of TDP-43 amyotrophic lateral sclerosis
Authors: Del Tredici Kelly , Braak Heiko
Published: September 2022

Purpose of review

Intracellular inclusions consisting of the abnormal TDP-43 protein and its nucleocytoplasmic mislocalization in selected cell types are hallmark pathological features of sALS. Descriptive (histological, morphological), anatomical, and molecular studies all have improved our understanding of the neuropathology of sporadic amyotrophic lateral sclerosis (sALS). This review highlights some of the latest developments in the field.

Recent findings

Increasing evidence exists from experimental models for the prion-like nature of abnormal TDP-43, including a strain-effect, and with the help of neuroimaging-based studies, for spreading of disease along corticofugal connectivities in sALS. Progress has also been made with respect to finding and establishing reliable biomarkers (neurofilament levels, diffusor tensor imaging).

The latest findings may help to elucidate the preclinical phase of sALS and to define possible mechanisms for delaying or halting disease development and progression.
Profile likelihood-based parameter and predictive interval analysis guides model choice for ecological population dynamics
Authors: Simpson Matthew J , Walker Shannon A , Studerus Emma N , McCue Scott W , Murphy Ryan J , Maclaren Oliver J
Published: September 2022

Calibrating mathematical models to describe ecological data provides important insight via parameter estimation that is not possible from analysing data alone. When we undertake a mathematical modelling study of ecological or biological data, we must deal with the trade-off between data availability and model complexity. Dealing with the nexus between data availability and model complexity is an ongoing challenge in mathematical modelling, particularly in mathematical biology and mathematical ecology where data collection is often not standardised, and more broad questions about model selection remain relatively open. Therefore, choosing an appropriate model almost always requires case-by-case consideration. In this work we present a straightforward approach to quantitatively explore this trade-off using a case study exploring mathematical models of coral reef regrowth after some ecological disturbance, such as damage caused by a tropical cyclone. In particular, we compare a simple single species ordinary differential equation (ODE) model approach with a more complicated two-species coupled ODE model. Univariate profile likelihood analysis suggests that the both models are practically identifiable. To provide additional insight we construct and compare approximate prediction intervals using a new parameter-wise prediction approximation, confirming both the simple and complex models perform similarly with regard to making predictions. Our approximate parameter-wise prediction interval analysis provides explicit information about how each parameter affects the predictions of each model. Comparing our approximate prediction intervals with a more rigorous and computationally expensive evaluation of the full likelihood shows that the new approximations are reasonable in this case. All algorithms and software to support this work are freely available as jupyter notebooks onGitHubso that they can be adapted to deal with any other ODE-based models.
MyD88-TLR4-dependent choroid plexus activation precedes perilesional inflammation and edema in intracerebral hemorrhage
Authors: Akeret Kevin , Buzzi Raphael M. , Thomson Bart R. , Schwendinger Nina , Klohs Jan , Schulthess Nadja , Baselgia Livio , Hansen Kerstin , Regli Luca , Vallelian Florence , Hugelshofer Michael , Schaer Dominik J.
Published: September 2022

The functional neurological outcome of patients with intracerebral hemorrhage (ICH) strongly relates to the degree of secondary brain injury (ICH-SBI) evolving within days after the initial bleeding. Different mechanisms including the incitement of inflammatory pathways, dysfunction of the blood–brain barrier (BBB), activation of resident microglia, and an influx of blood-borne immune cells, have been hypothesized to contribute to ICH-SBI. Yet, the spatiotemporal interplay of specific inflammatory processes within different brain compartments has not been sufficiently characterized, limiting potential therapeutic interventions to prevent and treat ICH-SBI. Using a whole-blood injection model in mice, we systematically characterized the spatial and temporal dynamics of inflammatory processes after ICH using 7-Tesla magnetic resonance imaging (MRI), spatial RNA sequencing (spRNAseq), functional BBB assessment, and immunofluorescence average-intensity-mapping. We identified a pronounced early response of the choroid plexus (CP) peaking at 12 to 24h, that was characterized by inflammatory cytokine expression, epithelial and endothelial expression of leukocyte adhesion molecules, and the accumulation of leukocytes. In contrast, we observed a delayed secondary reaction pattern at the injection site (striatum) peaking at 96h, defined by gene expression corresponding to perilesional leukocyte infiltration and correlating to the delayed signal alteration seen on MRI. Pathway analysis revealed a dependence of the early inflammatory reaction in the CP on toll-like receptor 4 (TLR4) signaling via myeloid differentiation factor 88 (MyD88). TLR4 and MyD88 knockout mice corroborated this observation, lacking the early upregulation of adhesion molecules and leukocyte infiltration within the CP 24h after whole-blood injection. In conclusion, we report a biphasic brain reaction pattern after ICH with a MyD88-TLR4-dependent early inflammatory response of the CP, preceding inflammation, edema and leukocyte infiltration at the lesion site. Pharmacological targeting of the early CP-activation might harbor the potential to modulate the development of ICH-SBI.

Graphical abstract

Akeret, Buzzi et al. characterized the spatiotemporal dynamics after striatal whole blood injection in mice using magnetic resonance imaging (MRI), spatial RNA sequencing (spRNAseq), functional blood-brain barrier (BBB) assessment, and immunofluorescence average intensity mapping (IF). They report a biphasic brain reaction pattern with an early MyD88-TLR4-dependent inflammatory response of the CP, which preceded secondary inflammation and leukocyte infiltration at the perilesional site.
Many but not all deep neural network audio models capture brain responses and exhibit correspondence between model stages and brain regions
Authors: Tuckute Greta , Feather Jenelle , Boebinger Dana , McDermott Josh H.
Published: September 2022

Models that predict brain responses to stimuli provide one measure of understanding of a sensory system, and have many potential applications in science and engineering. Deep artificial neural networks have emerged as the leading such predictive models of the visual system, but are less explored in audition. Prior work provided examples of audio-trained neural networks that produced good predictions of auditory cortical fMRI responses and exhibited correspondence between model stages and brain regions, but left it unclear whether these results generalize to other neural network models, and thus how to further improve models in this domain. We evaluated model-brain correspondence for publicly available audio neural network models along with in-house models trained on four different tasks. Most tested models out-predicted previous filter-bank models of auditory cortex, and exhibited systematic model-brain correspondence: middle stages best predicted primary auditory cortex while deep stages best predicted non-primary cortex. However, some state-of-the-art models produced substantially worse brain predictions. Models trained to recognize speech in background noise produced better brain predictions than models trained to recognize speech in quiet, potentially because hearing in noise imposes constraints on biological auditory representations. The training task influenced the prediction quality for specific cortical tuning properties, with best overall predictions resulting from models trained on multiple tasks. The results generally support the promise of deep neural networks as models of audition, though they also indicate that current models do not explain auditory cortical responses in their entirety.
Combined absence of TRP53 target genes ZMAT3, PUMA and p21 cause a high incidence of cancer in mice
Authors: Brennan Margs S. , Brinkmann Kerstin , Healey Geraldine , Gangoda Lahiru , Strasser Andreas , Herold Marco J. , Janic Ana
Published: September 2022

Transcriptional activation of target genes is essential for TP53-mediated tumour suppression, though the roles of many TP53-activated target genes in tumour suppression remains poorly understood. Knockdown of ZMAT3 in haematopoietic stem/progenitor cells by shRNA caused leukaemia only with the concomitant absence of the pro-apoptotic BCL-2 family member PUMA and the CDK inhibitor p21. We were interested to further investigate the role of ZMAT3 in tumour suppression beyond the haematopoietic system. Therefore, we generated Zmat3 knockout and compound gene knockout mice, lacking Zmat3 and p21, Zmat3 and Puma or all three genes. Puma−/−p21−/−Zmat3−/− triple knockout mice developed tumours at a significantly higher frequency compared to wild type, Puma−/−Zmat3−/− or p21−/− Zmat3−/−deficient mice. Interestingly, we observed that the triple and Puma−/−Zmat3−/− double deficient animals succumbed to lymphoma, while p21−/−Zmat3−/− animals developed mainly solid cancers. This analysis suggests that in addition to ZMAT3 loss, additional TRP53-regulated processes must be disabled simultaneously for TRP53-mediated tumour suppression to fail. Interestingly, our findings also reveal that the absence of different TRP53 regulated tumour suppressive processes changes the tumour spectrum, which suggests that different TRP53 tumour suppressive pathways are more critical in different tissues.
Low HER2 enables dedifferentiation and transformation of normal breast epithelial cells via chromatin opening
Authors: Hayat A , Carter EP , King HW , Ors A , Doe A , Teijeiro SA , Charrot S , Godinho S , Cutillas P , Mohammed H , Grose RP , Ficz G
Published: September 2022

Overexpression of the human epidermal growth factor 2 (HER2) protein in breast cancer patients is a predictor of poor prognosis and resistance to therapies. Despite significant advances in the development of targeted therapies and improvements in the 5-year survival rate of metastatic HER2-positive breast cancer patients, a better understanding of the disease at an early stage is needed to prevent its progression. Here, we used an inducible breast cancer transformation system that allows investigation of early molecular changes at high temporal resolution. HER2 overexpression to similar levels as those observed in a subtype of HER2 positive breast cancer patients induced transformation of MCF10A cells and resulted in gross morphological changes, increased anchorage-independent growth of cells, and altered transcriptional programme of genes associated with oncogenic transformation. Global phosphoproteomic analysis during the first few hours of HER2 induction predominantly detected an increase in protein phosphorylation. Intriguingly, this correlated with a wave of chromatin opening, as measured by ATAC-seq on acini isolated from 3D cell culture. We observed that HER2 overexpression leads to reprogramming of many distal regulatory regions and promotes reprogramming-associated heterogeneity. We found that a subset of cells acquired a dedifferentiated breast stem-like phenotype, making them likely candidates for malignant transformation. Our data show that this population of cells, which counterintuitively enriches for relatively low HER2 protein abundance and increased chromatin accessibility, possesses transformational drive, resulting in increased anchorage-independent growth in vitro compared to cells not displaying a stem-like phenotype. Our data provide a discovery platform for signalling to chromatin pathways in HER2-driven cancers, offering an opportunity for biomarker discovery and identification of novel drug targets.
Wolbachiagenomics reveals a potential for a nutrition-based symbiosis in blood-sucking Triatomine bugs
Authors: Filée Jonathan , Agésilas-Lequeux Kenny , Lacquehay Laurie , Bérenger Jean Michel , Dupont Lise , Mendonça Vagner , da Rosa João Aristeu , Harry Myriam
Published: September 2022

The nutritional symbiosis promoted by bacteria is a key determinant for adaptation and evolution of many insect lineages. A complex form of nutritional mutualism that arose in blood-sucking insects critically depends on diverse bacterial symbionts that supplement the diet of their nutrient-poor hosts with B vitamins. For instance, the triatomine bugRhodnius prolixus, one of the main vectors of the Chagas disease in humans, is known to maintain a nutritional symbiosis with the gut symbiontsRhodococcus rhodnii.

In this study, we show thatWolbachiasymbionts are also widely distributed in theRhodniusgenus. We have screened a large set ofRhodniusblood-sucking bugs samples belonging to 17 different species and to the three phylogenetic groups,prolixus, pallescensandpictipes. We assembled 13 genomes ofWolbachiainfecting eightRhodniusspecies fromprolixusandpictipesgroups. We demonstrate that theseWolbachiabelong to supergroup F and are closely related toWolbachiainfecting the bedbugCimex lectularius(wCle). Although bedbugs and triatomines are very distantly related hemipteran bugs, the genomes of their respectiveWolbachiawere highly similar, suggesting recent horizontal host switches. We also show thatRhodnius Wolbachiagenomes infecting theprolixusgroup encode intact biotin operon, the hallmark of nutritional symbiosis in bedbugs. This operon is lacking from all the otherWolbachiainfectingR. pictipes. Finally, host genome analyses provide evidence of massiveWolbachia-to-Rhodniusgene transfers in almost samples, providing footprints of past infections that support a widespread and probably ancient symbiotic association betweenWolbachiaand triatomine bugs.

Our results suggest that bothWolbachiaandR. rhodniigut symbionts and theirRhodniushost maintain a highly prevalent symbiotic relationship, in which the vertically-inheritedWolbachiahas the metabolic potantial to ensure or complement, the nutritional mutualism provided by the gut symbionts. Specific loss of the biotin operon in some symbiont genomes suggests that the boundaries between obligatory mutualism, facultative mutualism and parasitism inWolbachiaare transient and fluid, supporting a dynamic process of transition and reversion from one state to another.
An RNA binding module of SWI/SNF is required for activation of cell-type specific enhancers and super-enhancers in early development
Authors: Saha Dhurjhoti , Animireddy Srinivas , Lee Junwoo , Lin Yuan-chi , Feola Kyle , Jain Abhinav K , Lu Yue , Liu Bin , Bartholomew Blaine
Published: September 2022

The mammalian SWI/SNF complex is an ATP-dependent chromatin remodeler and master regulator in development that when mutated is the cause for several human diseases including cancer. Although SWI/SNF is highly enriched at enhancers and its basic chromatin remodeling activities have been studied for over 30 years, there is little known about how it regulates enhancer activity or enhancer-promoter interactions. We find a putative RNA binding module located near the C-terminus of the catalytic subunit of SWI/SNF required for SWI/SNF recruitment to cell-type specific enhancers and super-enhancers in naïve and cell lineage primed pluripotent cells. The AT-hook is required for acquisition of the active histone marks H3K27ac and H3K4me1 and recruitment of the MLL3/4 co-activator to these enhancers and super-enhancers. Consistent with changes in enhancer architecture, loss of the AT-hook interferes with activation of genes involved in cell lineage priming as well as genes normally activated in naïve pluripotent cells.
Genomic loss of the HSP70cA gene in the vertebrate lineage
Authors: Merchant Alisha , Ramirez Bradly I. , Reyes Melinda N. , Van Dysocheata , Martinez-Colin Marilin , Ojo Damilola O. , Mazuca Esmeralda L. , De La O Heidi J. , Glenn Abigayle M. , Lira Claudia G. , Ehsan Hashimul , Yu Ermeng , Kaneko Gen
Published: September 2022

Metazoan 70 kDa heat shock protein (HSP70) genes have been classified into four lineages: cytosolic A (HSP70cA), cytosolic B (HSP70cB), endoplasmic reticulum (HSP70er), and mitochondria (HSP70m). Because previous studies have identified no HSP70cA genes in vertebrates, we hypothesized that this gene has lost on the evolutionary path to vertebrates. To test this hypothesis, the present study conducted a comprehensive database search followed by phylogenetic and synteny analyses. The HSP70cA gene was present in invertebrates and animals that belong to subphyla of Chordata, Cephalochordata (lancelets) and Tunicata (tunicates). However, the genomes of early vertebrates in the subphylum Craniata (lamprey, hagfish, elephant shark, and coelacanth) contained only HSP70cB genes, suggesting the loss of the HSP70cA gene in the early period of vertebrate evolution. Synteny analysis using available genomic resources indicated that the synteny around the HSP70 genes was generally conserved between tunicates, but it was largely different between tunicates and lamprey. These results suggest the presence of dynamic chromosomal rearrangement in early vertebrates, which possibly caused the loss of the HSP70cA gene in the vertebrate lineage.
Di-valent siRNA Mediated Silencing of MSH3 Blocks Somatic Repeat Expansion in Mouse Models of Huntington’s Disease
Authors: O’Reilly Daniel , Belgrad Jillian , Ferguson Chantal , Summers Ashley , Sapp Ellen , McHugh Cassandra , Mathews Ella , Buchwald Julianna , Ly Socheata , Moreno Dimas Echeverria , Kennedy Zachary , Hariharan Vignesh , Monopoli Kathryn , Yang X. William , Carroll Jeffery , DiFiglia Marian , Aronin Neil , Khvorova Anastasia
Published: September 2022

Huntington’s Disease (HD) is a severe neurodegenerative disorder caused by expansion of the CAG trinucleotide repeat tract in the huntingtin gene. Inheritance of expanded CAG repeats is needed for HD manifestation, but further somatic expansion of the repeat tract in non-dividing cells, particularly striatal neurons, hastens disease onset. Called somatic repeat expansion, this process is mediated by the mismatch repair (MMR) pathway. Among MMR components identified as modifiers of HD onset, MutS Homolog 3 (MSH3) has emerged as a potentially safe and effective target for therapeutic intervention. Here, we identify fully chemically modified short interfering RNA (siRNA) that robustly silence MSH3in vitroandin vivo. When synthesized in a di-valent scaffold, siRNA-mediated silencing of MSH3 effectively blocked CAG repeat expansion in striatum of two HD mouse models without impacting tumor-associated microsatellite instability. Our findings establish a novel paradigm for treating patients with HD and other repeat expansion diseases.

One Sentence Summary

Silencing MSH3 in the CNS of two models of Huntington’s disease using di-valent siRNA blocks disease-accelerating somatic expansion of CAG repeats.
Single-molecule identification of the target RNAs of different RNA binding proteins simultaneously in cells
Authors: Flamand Mathieu N. , Ke Ke , Tamming Renee , Meyer Kate D.
Published: September 2022

RNA-binding proteins (RBPs) regulate nearly every aspect of mRNA processing and are important regulators of gene expression in cells. However, current methods for transcriptome-wide identification of RBP targets are limited since they examine only a single RBP at a time and since they do not provide information on the individual RNA molecules that are bound by a given RBP. Here, we overcome these limitations by developing TRIBE-STAMP, an approach for single-molecule detection of the target RNAs of two RNA binding proteins simultaneously in cells. We apply TRIBE-STAMP to the cytoplasmic m6A reader proteins YTHDF1, 2, and 3 and discover that individual mRNA molecules can be bound by more than one YTHDF protein throughout their lifetime, providing new insights into the function of YTHDF proteins in cells. TRIBE-STAMP is a highly versatile approach that enables single-molecule analysis of the targets of RBP pairs simultaneously in the same cells.
Cryo-EM structure of the type III-E CRISPR-Cas effector gRAMP in complex with TPR-CHAT
Authors: Wang Shuo , Guo Minghui , Zhu Yuwei , Lin Zhiying , Huang Zhiwei
Published: September 2022

The type III-E CRISPR-Cas effector protein, named gRAMP, is the largest single-unit CRISPR-Cas effector. A caspase-like peptidase (TPR-CHAT) gene often co-occurs with gRAMP gene clusters. However, the exact mechanism of the recognition and cleavage of target RNA of Sb-gRAMP, as well as the molecular architecture of the CRISPR-guided caspase complex, remains unclear. Here, we report the cryo-EM structures of the type III-E effector Sb-gRAMP-crRNA in a complex with TPR-CHAT, with and without target ssRNA at 3.0 and 2.9 Å, respectively. The overall structure of the gRAMP-crRNA-ssRNA-TPR-CHAT complex adopts an “L”-shaped conformation, consisting of a copy of gRAMP, a copy of TPR-CHAT, a 37-nt crRNA, and an 18-nt target ssRNA. The data presented in this manuscript reveal the mechanism of recognition of crRNA and target ssRNA by gRAMP, also, this work reports the structure of the CRISPR type III-E effector in complex with the binding partner TPR-CHAT, which provides vital clues for elucidating the functional relation between the CRISPR-Cas system and caspase peptidase.
Neuronal representation of a working memory-based decision strategy in the motor and prefrontal cortico-basal ganglia loops
Authors: Yoshizawa Tomohiko , Ito Makoto , Doya Kenji
Published: September 2022

While animal and human decision strategies are typically explained by model-free and model-based reinforcement learning, their choice sequences often follow simple procedures based on working memory of past actions and rewards. Here we address how working memory-based choice strategies, such as win-stay-lose-switch (WSLS), are represented in the prefrontal and motor cortico-basal ganglia loops by simultaneous recording of neuronal activities in the dorsomedial striatum (DMS), the dorsolateral striatum (DLS), the medial prefrontal cortex (mPFC), and the primary motor cortex (M1). In order to compare neuronal representations when rats employ working memory-based strategies, we developed a new task paradigm, a continuous/intermittent choice task, consisting of choice and no-choice trials. While the continuous condition (CC) consisted of only choice trials, in the intermittent condition (IC), a no-choice trial was inserted after each choice trial to disrupt working memory of the previous choice and reward. Behaviors in CC showed high proportions of win-stay and lose-switch choices, which could be regarded as “a noisy WSLS strategy.” Poisson regression of neural spikes revealed encoding specifically in CC of the previous action and reward before action choice and prospective coding of WSLS action during action execution. A striking finding was that the DLS and M1 in the motor cortico-basal ganglia loop carry substantial WM information about previous choices, rewards, and their interactions, in addition to current action coding.

Significance Statement

Working memory-based decision strategies, such as win-stay-lose-switch (WSLS), are widely observed in humans and animals. To address neuronal bases of these strategies, we recorded neuronal activities of rat prefrontal and motor cortico-basal ganglia loops during continuous/intermittent choice tasks. The rat choice strategy was a noisy WSLS in the continuous choice condition, whereas non-WSLS was selected in the intermittent choice condition. In the continuous choice condition, the primary motor cortex and the dorsolateral striatum in the motor loop more strongly conveyed information about previous choices, rewards, and their interactions than the medial prefrontal cortex and the dorsomedial striatum in the prefrontal loop. These results demonstrate that the motor cortico-basal ganglia loop contributes to working memory-based decision strategies.
Changes in sex differences in neuroanatomical structure and cognitive behavior across the life span
Authors: Juraska Janice M.
Published: September 2022

Sex differences occur in the structure and function of the rat cerebral cortex and hippocampus, which can change from the juvenile period through old age. Although the evidence is incomplete, it appears that in at least some portions of the cortex these differences develop due to the rise of ovarian hormones at puberty and are potentially not dependent on the perinatal rise in testosterone, which is essential for sexual differentiation of the hypothalamus and sexual behavior. During aging of female rats, the presence of continued ovarian hormone secretion after cessation of the estrous cycle also influences sex differences in neuroanatomical structure and cognitive behavior, resulting in nullification or reversal of sex differences seen in younger adults. Sex differences can be altered by experience in a stimulating environment during the juvenile/adolescent period, and sex differences in performance even can be affected by the parameters of a task. Thus, broad generalizations about differences such as “spatial ability” are to be avoided. It is clear that to understand how the brain produces behavior, sex and hormones have to be taken into account.