bluuebunny/crossref_metadata_2025 huggingface dataset:
The Occurrence Characteristics of Daytime Irregularities in the Low Latitude Topside F Region at Solar Minimum Revealed by ICON
Authors: Xie Haiyong , Li Guozhu , Zhao Xiukuan , Hu Lianhuan , Sun Wenjie , Li Yi , Ning Baiqi
Published: January 2023

Using observations from the Ionospheric Connection Explorer satellite, the occurrence characteristics of daytime plasma density irregularities in the low latitude topside F region at solar minimum were studied. The results show that the occurrence characteristics of daytime topside irregularities during June solstice resembled those at solar maximum. An interesting phenomenon not reported before is that an occurrence minimum in the local‐time variation occurred around 08:30–10:00 LT, mainly during Equinox in Asia. The topside irregularities appearing after the occurrence minimum were mostly concentrated at low latitudes around ±5°–15°. Based on the total electron content perturbations derived from the ground‐based global navigation satellite system receivers at low latitudes, it was found that the topside irregularities after the occurrence minimum were accompanied with apparent medium‐scale traveling ionospheric disturbances (MSTIDs) at times. Statistically, a good agreement was observed between the local time variations of MSTIDs and of daytime topside irregularities during Equinox in East/Southeast Asia. We suggest that the daytime irregularities in the low latitude topside F region were not totally the remnants of nighttime equatorial plasma bubbles. Especially for the daytime irregularities during Equinox in Asia, they could be MSTIDs appearing at topside F region.
Monitoring the 2021 Cumbre Vieja Volcanic Eruption Using Satellite Multisensor Data Fusion
Authors: Weisz Elisabeth , Menzel W. Paul
Published: January 2023

Multisensor satellite data fusion merges measurements or products from imaging and sounding instruments with different spatial, spectral, and temporal resolution to obtain more comprehensive information about key atmospheric variables and processes. Here, data from low Earth and geostationary orbits, such as the Joint Polar Satellite Systems and Geostationary Operational Environmental Satellites platforms, respectively, are integrated using spatial‐temporal fusion to enhance the detection of trace gas emissions from volcanoes. Not only does this yield trace gas information with improved spatial detail but, more importantly, the fusion product is also made available at significantly increased temporal resolution to help monitor the variable dispersion of trace gas emissions. The emission and dispersion of volcanic sulfur dioxide and ash plumes from the Cumbre Vieja volcano (Canary Islands, Spain) eruptions in October 2021 are studied through the synergistic exploitation of measurements and products from the Visible Infrared Imaging Radiometer Suite, the Cross‐track Infrared Sounder, the TROPOspheric Monitoring Instrument, and the Advanced Baseline Imager. Fusion results show increased spatial and temporal detail and describe evolution and directionality of the volcanic ash plumes; the potential benefits range from improved air quality monitoring to better guidance from aircraft safety systems.
Mathematical Modeling of the Neuronal Processes in Sugar Addiction
Authors: Almeida Andre , Celaymanian Hamed , Seel Natalie , Zak Boris , Noori Hamid R.
Published: January 2023

It has already been demonstrated that the body responds to enhanced intake of sugar and is conducive to a natural form of addiction. There are substantial neurochemical changes in the brain (especially dopamine and acetylcholine systems) similar to other addictive drugs. A mathematical model comprised by a system of delayed leaky integrate-and-*re equations is established to simulate the eff*ects of sugar on a reward-circuitry. Simulations with Neuron suggest agreement with the neurobiological hypotheses of hyperactivity of neural systems due to binge sugar intake.
Data Management Plan for Monogram BioSciences
Authors: Petropoulos Christos
Published: January 2023

This is the data plan for access to data underlying published reports by Monogram BioSciences.
Mutations in pathways depending on BRCA1 and BRCA2 may increase cancer risks from an environmental carcinogen
Authors: Friedenson Bernard
Published: January 2023

Recently, the President’s Cancer Panel [2008-2009] protested that preventive action is not taken when uncertainty exists about potential harm from a chemical, because the US regulatory approach demands that a hazard be incontrovertibly demonstrated. It is now incontrovertible that formaldehyde increases risks for leukemias. Evidence is also strong that formaldehyde causes some types of DNA damage in humans that are known to require repairs mediated by BRCA1/2 containing pathways. Homologous recombination repairs require BRCA1/2, Fanconi and ATM proteins in these pathways. Biallelic BRCA2 mutations interfere with these repairs and are clearly associated with leukemias, especially myeloid leukemias. Fanconi anemia homozygotes have very high risks for acute myeloid leukemias. Disabling BRCA1/2 related DNA repair processes prevents repair of formaldehyde related DNA damage in laboratory cells. DNA-protein cross links result in the accumulation of DNA double strand breaks in homologous recombination-deficient but not homologous recombination -proficient cells. ATM heterozygotes have increased risks for some leukemias that have been linked to formaldehyde in normal individuals. Weaker evidence suggests increased risk for rare nasopharyngeal or sinonasal cancers in heterozygous BRCA1/2 mutation carriers and in ATM mutation carriers.Formaldehyde is a pervasive environmental carcinogen that is theoretically more likely to cause malignancy in carriers of mutations that disable protective repair pathways. Because of this potential for harm, it is prudent for mutation carriers to immediately avoid formaldehyde, especially high level exposure. The EPA recommends four basic “Steps to Reduce Exposure” for everyone.
BioPAX Support in CellDesigner
Authors: Muruganujan Anushya , Mi Huaiyu
Published: January 2023

BioPAX is a pathway data exchange language that is widely used by pathway database resources. Here we describe a mechanism that allows users to curate pathway data in diagrams using CellDesigner, a pathway graphical editing tool, and save the pathway data in BioPAX format. We used this mechanism to create BioPAX files for all 165 pathways from the PANTHER database. In addition, we are also working on graphically visualizing BioPAX data by importing them into CellDesigner.
*100 Semi-supercentenarians and older as a proposed sample set for the Archon Genomics X PRIZE Validation Protocol*
Authors: Perls Thomas , Barzilai Nir
Published: January 2023

The "Archon Genomics X PRIZE Validation Protocol":http://precedings.nature.com/documents/5731/version/1 has been posted in part to solicit comments from the scientific community. Here, we suggest 100 subjects age >=105 years as the source of DNAs for the competition.
Off-line memory reprocessing in a recurrent neuronal network formed by unsupervised learning
Authors: Jitsev Jenia , von der Malsburg Christoph
Published: January 2023

In the visual cortex, memory traces for complex objects are embedded into a scaffold of feed-forward and recurrent connectivity of the hierarchically organized visual pathway. Strong evidence suggests that consolidation of the memory traces in such a memory network depends on an off-line reprocessing done in the sleep state or during restful waking. It remains largely unclear, what plasticity mechanisms are involved in this consolidation process and what changes are induced in the network during memory reprocessing in the off-line regime. Here we focus on the functional consequences off-line reprocessing has in a hierarchical recurrent neuronal network that learns different person identities from natural face images in an unsupervised manner. Due to the inherently self-exciting, but competitive unit dynamics, the two-layered network is able to self-generate sparse activity even in the absence of external input in an off-line regime. In this regime, the network replays the memory content established during preceding on-line learning. Remarkably, this off-line memory replay turns out to be highly beneficial for the network recognition performance. The benefit is articulated after the off-line regime in a strong boost of identity recognition rate on the alternative face views to which the network has not been exposed during learning. Performance of both network layers is affected by the boost. Surprisingly, the positive effect is independent of synapse-specific plasticity, relying completely on a synapse-unspecific mechanism of homeostatic activity regulation that tunes network unit excitability. Comparing further a purely feed-forward configuration of the network with its fully recurrent original version reveals a stronger boost in recognition performance for the latter after the off-line reprocessing. These findings suggest that the off-line memory reprocessing enhances generalization capability of the hierarchical recurrent network by improving communication of contextual cues mediated via recurrent lateral and top-down connectivity.
Analyzing local image statistics via maximum-entropy constructions
Authors: Victor Jonathan , Thengone Daniel , Conte Mary
Published: January 2023

Because the space of signals that the visual system encounters is high-dimensional, investigations of visual processing and perception must utilize a sampling strategy. One kind of approach begins with a class of models for input-output relations, and then chooses a stimulus ensemble such as white noise that enables efficient determination of model parameters. A second kind of approach begins with the explicit recognition that it is important to understand the visual system in the context of the inputs under which it functions and evolves; this motivates the use of naturalistic stimulus ensembles. Neither approach alone is sufficient: models built from ensembles such as white noise provide only a fair account of responses to natural scenes, and the complex statistical structure of naturalistic stimuli makes it difficult to isolate computational mechanisms.Here we present a step in the direction of bridging this gap. Our starting point is a recent analysis of the multipoint correlations of natural images (Tkačik et al., 2010) which showed that four-point correlations in specific configurations (“gliders”) capture the informative local statistics in binarized natural images. We focus on one such glider, 2x2 windowpanes. The corresponding set of image statistics has ten parameters, and we determine a set of coordinates for this space that are calibrated for equal salience to an ideal observer. Via maximum-entropy constructions, we generate ensembles that isolate the individual coordinates and coordinate pairs. We then characterize the perceptual salience of these image statistics, alone and in combination, via a texture-segmentation task (Chubb et al., 2004). Three main findings emerge. First, observers are sensitive to image statistics of low and high-order. Second, the pattern of sensitivities, which is not simply order-by-order, is remarkably constant across observers. Third, image statistics interact at a perceptual level in a way that suggests an approximately Euclidean metric.
Predicting Temporal Patterns In The Environment: Toward Primitive Mechanisms Of Learning, Memory, And Generalization
Authors: Jones Matthew , Curran Tim , Mozer Michael , Wilder Matt
Published: January 2023

Across a wide range of cognitive tasks, recent experience influences subsequent behavior. For example, when individuals repeatedly perform a speeded two-alternative choice task, response latencies vary dramatically based on the immediately preceding sequence. These sequential dependencies (SDs) have been interpreted as adaptation to the statistical structure of an uncertain, changing environment (e.g., Jones & Sieck, 2003; Mozer, Kinoshita, & Shettel, 2007; Yu & Cohen, 2009), and can shed light on how individuals learn and represent structure in binary stimulus sequences. Heretofore, theories have posited that SDs arise from rapidly (exponentially) decaying memory traces of various environmental statistics (e.g., Cho et al., 2002; Yu & Cohen, 2009).We present a series of experiments and a model that place SDs on a fundamentally different foundation. We show that: (1) decay of recent experience can follow a power function curve, not an exponential, linking the SD literature to a rich literature on human declarative memory; (2) the simple trace-based mechanism underlying existing accounts is inadequate, but incremental memory adjustments may be explained via error correction, linking the SD literature to the rich literature on human associative learning; and (3) distinct but interacting subsystems are found in the brain that jointly predict upcoming environmental events.We conducted three behavioral studies with EEG recordings of individuals performing discrimination of spatial location and motion coherence. Identifying the onset of the lateralized readiness potential (LRP) in an event-related EEG analysis, we are able to decompose the total response latency into two intervals—pre and post LRP onset—and to examine SDs in stimulus and response processing separately. We find evidence for two distinct mechanisms, one reflecting incremental learning of stimulus repetition rate (i.e., the probability that successive stimuli will match), and the other reflecting incremental learning of response baserates. The data cannot be explained by a model that assumes these rates are based on independent traces, and calls for an account in which the two rates jointly predict future stimuli via error-correction learning.By manipulating the autocorrelation structure of the sequences (from a positive to a negative autocorrelation, indicated on the graphs by blue and red lines, respectively), we obtained evidence for incremental learning occurring over hundreds of trials, which is parsimoniously explained by a memory with power function decay. Together, the results highlight a tension between the two broad and well established classes of trace-based memory models and learning models based on error correction. Two attempts at reconciling these approaches via modeling are discussed.
The neuron as a population of ion channels: the emergence of a stochastic and history dependent mode
Authors: Soudry Daniel , Meir Ron
Published: January 2023

Experiments show that synaptically isolated cortical neurons, stimulated with periodic extra-cellular current pulses for long durations, respond in a complex irregular and history dependent manner - over a large range of timescales (from seconds to days). With the aim of finding a biophysical explanation to these results, we developed a general novel scheme to analytically solve conductance based Hodgkin-Huxley like models under pulse stimulation, and derived closed-form expressions for the transient behavior, firing rates and firing patterns of the neuron. Using this approach we were able to reproduce most experimental results using only slow sodium inactivation - with the important exceptions of the irregular behavior and the large range of timescales. By ruling out chaotic behavior, we proved that both of these features could not occur in deterministic conductance based models - even when using an arbitrary large number of gating variables (accounting for potassium activation, changes in ion concentrations, etc.). Additionally, we showed channel noise is highly likely to play a very significant role in the neuronal dynamics, and to be the cause of the observed irregularity. Finally, we came to the conclusion that, even when taking into account ion channel stochasticity, current conductance based models cannot reproduce the experimentally observed very slow changes in the neuronal response, necessitating the introduction of long term processes such as ion channel regularization.
Learning a Bayesian prior in interval timing
Authors: Sohn Hansem , Lee Sang-Hun
Published: January 2023

Behavioral studies on perceptual learning (PL) often attributed an improvement in task performance to an enhancement in sensory processing of stimuli. However, the framework of Bayesian inference suggests that perceptual improvements can arise from learning-induced changes either in a likelihood function or in a prior expectation for sensory input. We developed and adapted Bayesian observer models to long-term changes in interval timing (IT) performance by human subjects to assess relative contributions of the prior and likelihood to PL of IT.While subjects were viewing a small bar that drifted for a while and disappeared, we estimated subjective time intervals ([DELTA]Ts) from subjects’ natural reactions to the reappearance of the invisible bar at a designated location, with the speed and distance of invisible motion varied trial to trial. Ten subjects performed this task over 10 daily sessions for [DELTA]Ts ranging from 0.5 to 6.5 sec.In terms of timing accuracy, the trend that short and long [DELTA]Ts were overestimated and underestimated, respectively, was evident in all subjects and became stronger over sessions. In contrast, timing precision gradually improved over session for the entire set of sampled [DELTA]Ts. These seemingly contradictory dynamics of PL in accuracy and precision were captured simultaneously by Bayesian models, in which subjective timing is determined jointly by the prior and likelihood function for IT. The best among several nested models was a simple model in which only a single Gaussian function and a single coefficient of variance were set free to describe the prior and the likelihood functions, respectively. Interestingly, it was the spread of the prior, not the likelihood, that changed steadily in the model fit to the across-session data, suggesting that the improvements in timing precision observed in our and previous studies arose as the prior became sharpened through massive training.
Cholinergic innervation is necessary to shift reward timing activity in rodent visual cortex
Authors: Roach Emma , Hussain Shuler Marshall
Published: January 2023

While the biological analogue of prediction error has been well characterized in the midbrain dopaminergic system, the possibility of other neuromodulatory systems acting as global reinforcers is a topic of much debate. Reward timing, the phenomenon by which single unit responses in primary visual cortex (V1)reflect an operantly learned stimulus‐reward interval, offers a tractable preparation to investigate reinforcement learning in vivo: theoretical work suggests that reward timing results from the interaction of stimulus‐evoked recurrent network activity and a global reinforcement signal that indicates the time of received reward. We hypothesized that this signal is conveyed by cholinergic neurons arising from the basal forebrain (BF), a strong candidate system that projects globally to most cortical regions, has a known role in plasticity, and is involved in attention and the representation of salience. To test the necessity of such a signal in entraining reward timing in V1, rats were trained on an initial stimulus‐reward contingency, received a neurotoxin in V1 that eliminated BF cholinergic terminals, and subsequently trained on a second contingency. We found that extracellular single unit recordings from V1 of lesioned animals, but not saline‐infused controls, failed to show shifted neural reports of reward that matched the new contingency. Importantly, neurons of lesioned animals continued to display intervals associated with the initial contingency, arguing that cholinergic input is required to learn, but not to express, reward timing activity.
Predictive context biases perceptual selection during binocular rivalry
Authors: Denison Rachel , Silver Michael
Published: January 2023

Prediction may be a fundamental principle of sensory processing, such that the brain continuously generates predictions about forthcoming sensory information. However, little is known about how prediction contributes to the selection of a conscious percept from among competing alternatives. Here, we used binocular rivalry to investigate the effects of prediction on perceptual selection. In binocular rivalry, incompatible images presented to the two eyes result in a perceptual alternation between the images, even though the visual stimuli remain constant. If predictive signals influence the competition between neural representations of rivalrous images, this influence should generate a bias in perceptual selection that depends on predictive context. To manipulate predictive context, we developed a novel binocular rivalry paradigm in which orthogonal rivalrous test gratings were immediately preceded by rotating gratings presented identically to the two eyes. One of the rivalrous gratings had an orientation that was consistent with the preceding rotation direction (it was the expected next image in the series), and the other had an inconsistent orientation. We found that human observers were more likely to perceive the consistent grating, suggesting that predictive context biased selection in favor of the predicted percept. This prediction effect depended on only recent stimulus history, and it could be dissociated from another stimulus history effect related to orientation-specific adaptation. Since binocular rivalry between orthogonal gratings is thought to be resolved at an early stage of visual processing, these results suggest that predictive signals may exist at low levels of the visual processing hierarchy and that these signals can bias conscious perception. In the future, this paradigm could be used to test whether visual percepts are generated from the combination of prior information and incoming sensory information according to Bayesian principles.
Ten reasons NOT to fix the numerical value of the Avogadro constant
Authors: Wheatley Nigel
Published: January 2023

This discussion paper, circulated in advance of the 17th meeting of the Consultative Committee for Amount of Substance, addresses the proposed redefinition of the mole in terms of a fixed numerical value for the Avogadro constant. It gives ten reasons why the Avogadro constant should not be given a fixed numerical value in the International System of Units, noting that there would be no metrological benefit from such a change, and that the proposed redefinition would be more conceptually complex that the current one and divorced from practical measurement and historical background. As the conditions for redefinition of the kilogram have not been met, and no mise en pratique has been produced for the proposed new definition, the paper concludes that the proposal should be rejected.
Dnmt1/Tet2-mediated changes in Cmip methylation regulate the development of nonalcoholic fatty liver disease by controlling the Gbp2-Pparγ-CD36 axis
Authors: Lee Jangho , Song Ji-Hye , Park Jae-Ho , Chung Min-Yu , Lee Seung-Hyun , Jeon Sae-Bom , Park So Hee , Hwang Jin-Taek , Choi Hyo-Kyoung
Published: January 2023

Dynamic alteration of DNA methylation leads to various human diseases, including nonalcoholic fatty liver disease (NAFLD). Although C-Maf-inducing protein (Cmip) has been reported to be associated with NAFLD, its exact underlying mechanism remains unclear. Here, we aimed to elucidate this mechanism in NAFLD in vitro and in vivo. We first identified alterations in the methylation status of theCmipintron 1 region in mouse liver tissues with high-fat high-sucrose diet-induced NAFLD. Knockdown of DNA methyltransferase (Dnmt) 1 significantly increased Cmip expression. Chromatin immunoprecipitation assays of AML12 cells treated with oleic and palmitic acid (OPA) revealed that Dnmt1 was dissociated and that methylation of H3K27me3 was significantly decreased in theCmipintron 1 region. Conversely, the knockdown of Tet methylcytosine dioxygenase 2 (Tet2) decreased Cmip expression. Following OPA treatment, the CCCTC-binding factor (Ctcf) was recruited, and H3K4me3 was significantly hypermethylated. IntravenousCmipsiRNA injection ameliorated NAFLD pathogenic features inob/obmice. Additionally,PparγandCd36expression levels were dramatically decreased in the livers ofob/obmice administered siCmip, and RNA sequencing revealed that Gbp2 was involved.Gbp2knockdown also induced a decrease inPparγandCd36expression, resulting in the abrogation of fatty acid uptake into cells. Our data demonstrate that Cmip and Gbp2 expression levels are enhanced in human liver tissues bearing NAFLD features. We also show that Dnmt1–Trt2/Ctcf-mediated reversible modulation ofCmipmethylation regulates the Gbp2–Pparγ–Cd36 signaling pathway, indicating the potential ofCmipas a novel therapeutic target for NAFLD.
Impaired OTUD7A-dependent Ankyrin regulation mediates neuronal dysfunction in mouse and human models of the 15q13.3 microdeletion syndrome
Authors: Unda Brianna K. , Chalil Leon , Yoon Sehyoun , Kilpatrick Savannah , Irwin Courtney , Xing Sansi , Murtaza Nadeem , Cheng Anran , Brown Chad , Afonso Alexandria , McCready Elizabeth , Ronen Gabriel M. , Howe Jennifer , Caye-Eude Aurélie , Verloes Alain , Doble Brad W. , Faivre Laurence , Vitobello Antonio , Scherer Stephen W. , Lu Yu , Penzes Peter , Singh Karun K.
Published: January 2023

Copy number variations (CNVs) are associated with psychiatric and neurodevelopmental disorders (NDDs), and most, including the recurrent 15q13.3 microdeletion disorder, have unknown disease mechanisms. We used a heterozygous 15q13.3 microdeletion mouse model and patient iPSC-derived neurons to reveal developmental defects in neuronal maturation and network activity. To identify the underlying molecular dysfunction, we developed a neuron-specific proximity-labeling proteomics (BioID2) pipeline, combined with patient mutations, to target the 15q13.3 CNV genetic driverOTUD7A.OTUD7Ais an emerging independent NDD risk gene with no known function in the brain, but has putative deubiquitinase function. The OTUD7A protein–protein interaction network included synaptic, axonal, and cytoskeletal proteins and was enriched for ASD and epilepsy risk genes (Ank3, Ank2, SPTAN1, SPTBN1). The interactions between OTUD7A and Ankyrin-G (Ank3) and Ankyrin-B (Ank2) were disrupted by an epilepsy-associatedOTUD7AL233F variant. Further investigation of Ankyrin-G in mouse and human 15q13.3 microdeletion and OTUD7AL233F/L233Fmodels revealed protein instability, increased polyubiquitination, and decreased levels in the axon initial segment, while structured illumination microscopy identified reduced Ankyrin-G nanodomains in dendritic spines. Functional analysis of human 15q13.3 microdeletion and OTUD7AL233F/L233Fmodels revealed shared and distinct impairments to axonal growth and intrinsic excitability. Importantly, restoring OTUD7A or Ankyrin-G expression in 15q13.3 microdeletion neurons led to a reversal of abnormalities. These data reveal a critical OTUD7A-Ankyrin pathway in neuronal development, which is impaired in the 15q13.3 microdeletion syndrome, leading to neuronal dysfunction. Furthermore, our study highlights the utility of targeting CNV genes using cell type-specific proteomics to identify shared and unexplored disease mechanisms across NDDs.
A distal super-enhancer activates oncogenic ETS2 via recruiting MECOM in inflammatory bowel disease and colorectal cancer
Authors: Chen Yongheng , Ying Ying , Wang Maolin , Ma Canjie , Jia Min , Shi Liang , Wang Shilan , Zheng Xiangyi , Chen Wei , Shu Xing-sheng
Published: January 2023

Abnormal activities of distal cis-regulatory elements (CREs) contribute to the initiation and progression of cancer. Gain of super-enhancer (SE), a highly active distal CRE, is essential for the activation of key oncogenes in various cancers. However, the mechanism of action for most tumor-specific SEs still largely remains elusive. Here, we report that a candidate oncogeneETS2was activated by a distal SE in inflammatory bowel disease (IBD) and colorectal cancer (CRC). The SE physically interacted with theETS2promoter and was required for the transcription activation ofETS2. Strikingly, theETS2-SE activity was dramatically upregulated in both IBD and CRC tissues when compared to normal colon controls and was strongly correlated with the level ofETS2expression. The tumor-specific activation ofETS2-SE was further validated by increased enhancer RNA transcription from this region in CRC. Intriguingly, a known IBD-risk SNP resides in theETS2-SE and the genetic variant modulated the level ofETS2expression through affecting the binding of an oncogenic transcription factor MECOM. Silencing ofMECOMinduced significant downregulation ofETS2in CRC cells, and the level ofMECOMandETS2correlated well with each other in CRC and IBD samples. Functionally, MECOM and ETS2 were both required for maintaining the colony-formation and sphere-formation capacities of CRC cells and MECOM was crucial for promoting migration. Taken together, we uncovered a novel disease-specific SE that distantly drives oncogenicETS2expression in IBD and CRC and delineated a mechanistic link between non-coding genetic variation and epigenetic regulation of gene transcription.
A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer
Authors: Tietscher Sandra , Wagner Johanna , Anzeneder Tobias , Langwieder Claus , Rees Martin , Sobottka Bettina , de Souza Natalie , Bodenmiller Bernd
Published: January 2023

Immune checkpoint therapy in breast cancer remains restricted to triple negative patients, and long-term clinical benefit is rare. The primary aim of immune checkpoint blockade is to prevent or reverse exhausted T cell states, but T cell exhaustion in breast tumors is not well understood. Here, we use single-cell transcriptomics combined with imaging mass cytometry to systematically study immune environments of human breast tumors that either do or do not contain exhausted T cells, with a focus on luminal subtypes. We find that the presence of a PD-1highexhaustion-like T cell phenotype is associated with an inflammatory immune environment with a characteristic cytotoxic profile, increased myeloid cell activation, evidence for elevated immunomodulatory, chemotactic, and cytokine signaling, and accumulation of natural killer T cells. Tumors harboring exhausted-like T cells show increased expression of MHC-I on tumor cells and of CXCL13 on T cells, as well as altered spatial organization with more immature rather than mature tertiary lymphoid structures. Our data reveal fundamental differences between immune environments with and without exhausted T cells within luminal breast cancer, and show that expression of PD-1 and CXCL13 on T cells, and MHC-I – but not PD-L1 – on tumor cells are strong distinguishing features between these environments.
Molecular subtypes of ALS are associated with differences in patient prognosis
Authors: Eshima Jarrett , O’Connor Samantha A. , Marschall Ethan ,   NYGC ALS Consortium, Bowser Robert , Plaisier Christopher L. , Smith Barbara S.
Published: January 2023

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease with poorly understood clinical heterogeneity, underscored by significant differences in patient age at onset, symptom progression, therapeutic response, disease duration, and comorbidity presentation. We perform a patient stratification analysis to better understand the variability in ALS pathology, utilizing postmortem frontal and motor cortex transcriptomes derived from 208 patients. Building on the emerging role of transposable element (TE) expression in ALS, we consider locus-specific TEs as distinct molecular features during stratification. Here, we identify three unique molecular subtypes in this ALS cohort, with significant differences in patient survival. These results suggest independent disease mechanisms drive some of the clinical heterogeneity in ALS.
Structure of the Sec14 domain of Kalirin reveals a distinct class of lipid-binding module in RhoGEFs
Authors: Li Yunfeng , Pustovalova Yulia , Doukov Tzanko I. , Hoch Jeffrey C. , Mains Richard E. , Eipper Betty A. , Hao Bing
Published: January 2023

Gated entry of lipophilic ligands into the enclosed hydrophobic pocket in stand-alone Sec14 domain proteins often links lipid metabolism to membrane trafficking. Similar domains occur in multidomain mammalian proteins that activate small GTPases and regulate actin dynamics. The neuronal RhoGEF Kalirin, a central regulator of cytoskeletal dynamics, contains a Sec14 domain (KalbSec14) followed by multiple spectrin-like repeats and catalytic domains. Previous studies demonstrated that Kalirin lacking its Sec14 domain fails to maintain cell morphology or dendritic spine length, yet whether and how KalbSec14interacts with lipids remain unknown. Here, we report the structural and biochemical characterization of KalbSec14. KalbSec14adopts a closed conformation, sealing off the canonical ligand entry site, and instead employs a surface groove to bind a limited set of lysophospholipids. The low-affinity interactions of KalbSec14with lysolipids are expected to serve as a general model for the regulation of Rho signaling by other Sec14-containing Rho activators.
Automatic purpose-driven basis set truncation for time-dependent Hartree–Fock and density-functional theory
Authors: Han Ruocheng , Mattiat Johann , Luber Sandra
Published: January 2023

Real-time time-dependent density-functional theory (RT-TDDFT) and linear response time-dependent density-functional theory (LR-TDDFT) are two important approaches to simulate electronic spectra. However, the basis sets used in such calculations are usually the ones designed mainly for electronic ground state calculations. In this work, we propose a systematic and robust scheme to truncate the atomic orbital (AO) basis set employed in TDDFT and TD Hartree–Fock (TDHF) calculations. The truncated bases are tested for both LR- and RT-TDDFT as well as RT-TDHF approaches, and provide an acceleration up to an order of magnitude while the shifts of excitation energies of interest are generally within 0.2 eV. The procedure only requires one extra RT calculation with 1% of the total propagation time and a simple modification on basis set file, which allows an instant application in any quantum chemistry package supporting RT-/LR-TDDFT calculations. Aside from the reduced computational effort, this approach also offers valuable insight into the effect of different basis functions on computed electronic excitations and further ideas on the design of basis sets for special purposes.
Benchmarking commonly used software suites and analysis workflows for DIA proteomics and phosphoproteomics
Authors: Lou Ronghui , Cao Ye , Li Shanshan , Lang Xiaoyu , Li Yunxia , Zhang Yaoyang , Shui Wenqing
Published: January 2023

A plethora of software suites and multiple classes of spectral libraries have been developed to enhance the depth and robustness of data-independent acquisition (DIA) data processing. However, how the combination of a DIA software tool and a spectral library impacts the outcome of DIA proteomics and phosphoproteomics data analysis has been rarely investigated using benchmark data that mimics biological complexity. In this study, we create DIA benchmark data sets simulating the regulation of thousands of proteins in a complex background, which are collected on both an Orbitrap and a timsTOF instruments. We evaluate four commonly used software suites (DIA-NN, Spectronaut, MaxDIA and Skyline) combined with seven different spectral libraries in global proteome analysis. Moreover, we assess their performances in analyzing phosphopeptide standards and TNF-α-induced phosphoproteome regulation. Our study provides a practical guidance on how to construct a robust data analysis pipeline for different proteomics studies implementing the DIA technique.
Inhibition of histone methyltransferase Smyd3 rescues NMDAR and cognitive deficits in a tauopathy mouse model
Authors: Williams Jamal B. , Cao Qing , Wang Wei , Lee Young-Ho , Qin Luye , Zhong Ping , Ren Yong , Ma Kaijie , Yan Zhen
Published: January 2023

Pleiotropic mechanisms have been implicated in Alzheimer’s disease (AD), including transcriptional dysregulation, protein misprocessing and synaptic dysfunction, but how they are mechanistically linked to induce cognitive deficits in AD is unclear. Here we find that the histone methyltransferase Smyd3, which catalyzes histone H3 lysine 4 trimethylation (H3K4me3) to activate gene transcription, is significantly elevated in prefrontal cortex (PFC) of AD patients and P301S Tau mice, a model of tauopathies. A short treatment with the Smyd3 inhibitor, BCI-121, rescues cognitive behavioral deficits, and restores synaptic NMDAR function and expression in PFC pyramidal neurons of P301S Tau mice. Fbxo2, which encodes an E3 ubiquitin ligase controlling the degradation of NMDAR subunits, is identified as a downstream target of Smyd3. Smyd3-induced upregulation of Fbxo2 in P301S Tau mice is linked to the increased NR1 ubiquitination. Fbxo2 knockdown in PFC leads to the recovery of NMDAR function and cognitive behaviors in P301S Tau mice. These data suggest an integrated mechanism and potential therapeutic strategy for AD.
Direct and indirect effects of the COVID-19 pandemic on mortality in Switzerland
Authors: Riou Julien , Hauser Anthony , Fesser Anna , Althaus Christian L. , Egger Matthias , Konstantinoudis Garyfallos
Published: January 2023

The direct and indirect impact of the COVID-19 pandemic on population-level mortality is of concern to public health but challenging to quantify. Using data for 2011–2019, we applied Bayesian models to predict the expected number of deaths in Switzerland and compared them with laboratory-confirmed COVID-19 deaths from February 2020 to April 2022 (study period). We estimated that COVID-19-related mortality was underestimated by a factor of 0.72 (95% credible interval [CrI]: 0.46–0.78). After accounting for COVID-19 deaths, the observed mortality was −4% (95% CrI: −8 to 0) lower than expected. The deficit in mortality was concentrated in age groups 40–59 (−12%, 95%CrI: −19 to −5) and 60–69 (−8%, 95%CrI: −15 to −2). Although COVID-19 control measures may have negative effects, after subtracting COVID-19 deaths, there were fewer deaths in Switzerland during the pandemic than expected, suggesting that any negative effects of control measures were offset by the positive effects. These results have important implications for the ongoing debate about the appropriateness of COVID-19 control measures.
A population-based matched cohort study of major congenital anomalies following COVID-19 vaccination and SARS-CoV-2 infection
Authors: Calvert Clara , Carruthers Jade , Denny Cheryl , Donaghy Jack , Hopcroft Lisa E. M. , Hopkins Leanne , Goulding Anna , Lindsay Laura , McLaughlin Terry , Moore Emily , Taylor Bob , Loane Maria , Dolk Helen , Morris Joan , Auyeung Bonnie , Bhaskaran Krishnan , Gibbons Cheryl L. , Katikireddi Srinivasa Vittal , O’Leary Maureen , McAllister David , Shi Ting , Simpson Colin R. , Robertson Chris , Sheikh Aziz , Stock Sarah J. , Wood Rachael
Published: January 2023

Evidence on associations between COVID-19 vaccination or SARS-CoV-2 infection and the risk of congenital anomalies is limited. Here we report a national, population-based, matched cohort study using linked electronic health records from Scotland (May 2020-April 2022) to estimate the association between COVID-19 vaccination and, separately, SARS-CoV-2 infection between six weeks pre-conception and 19 weeks and six days gestation and the risk of [1] any major congenital anomaly and [2] any non-genetic major congenital anomaly. Mothers vaccinated in this pregnancy exposure period mostly received an mRNA vaccine (73.7% Pfizer-BioNTech BNT162b2 and 7.9% Moderna mRNA-1273). Of the 6731 babies whose mothers were vaccinated in the pregnancy exposure period, 153 had any anomaly and 120 had a non-genetic anomaly. Primary analyses find no association between any vaccination and any anomaly (adjusted Odds Ratio [aOR] = 1.01, 95% Confidence Interval [CI] = 0.83-1.24) or non-genetic anomalies (aOR = 1.00, 95% CI = 0.81-1.22). Primary analyses also find no association between SARS-CoV-2 infection and any anomaly (aOR = 1.02, 95% CI = 0.66-1.60) or non-genetic anomalies (aOR = 0.94, 95% CI = 0.57-1.54). Findings are robust to sensitivity analyses. These data provide reassurance on the safety of vaccination, in particular mRNA vaccines, just before or in early pregnancy.
Formation and degradation of strongly reducing cyanoarene-based radical anions towards efficient radical anion-mediated photoredox catalysis
Authors: Kwon Yonghwan , Lee Jungwook , Noh Yeonjin , Kim Doyon , Lee Yungyeong , Yu Changhoon , Roldao Juan Carlos , Feng Siyang , Gierschner Johannes , Wannemacher Reinhold , Kwon Min Sang
Published: January 2023

Cyanoarene-based photocatalysts (PCs) have attracted significant interest owing to their superior catalytic performance for radical anion mediated photoredox catalysis. However, the factors affecting the formation and degradation of cyanoarene-based PC radical anion (PC•‒) are still insufficiently understood. Herein, we therefore investigate the formation and degradation of cyanoarene-based PC•‒ under widely-used photoredox-mediated reaction conditions. By screening various cyanoarene-based PCs, we elucidate strategies to efficiently generate PC•‒ with adequate excited-state reduction potentials (Ered*) via supra-efficient generation of long-lived triplet excited states (T1). To thoroughly investigate the behavior of PC•‒ in actual photoredox-mediated reactions, a reductive dehalogenation is carried out as a model reaction and identified the dominant photodegradation pathways of the PC•‒. Dehalogenation and photodegradation of PC•‒ are coexistent depending on the rate of electron transfer (ET) to the substrate and the photodegradation strongly depends on the electronic and steric properties of the PCs. Based on the understanding of both the formation and photodegradation of PC•‒, we demonstrate that the efficient generation of highly reducing PC•‒ allows for the highly efficient photoredox catalyzed dehalogenation of aryl/alkyl halides at a PC loading as low as 0.001 mol% with a high oxygen tolerance. The present work provides new insights into the reactions of cyanoarene-based PC•‒ in photoredox-mediated reactions.
Wireless dielectrophoresis trapping and remote impedance sensing via resonant wireless power transfer
Authors: Ertsgaard Christopher T. , Kim Minki , Choi Jungwon , Oh Sang-Hyun
Published: January 2023

Nearly all biosensing platforms can be described using two fundamental steps—collection and detection. Target analytes must be delivered to a sensing element, which can then relay the transduced signal. For point-of-care technologies, where operation is to be kept simple, typically the collection step is passive diffusion driven—which can be slow or limiting under low concentrations. This work demonstrates an integration of both active collection and detection by using resonant wireless power transfer coupled to a nanogap capacitor. Nanoparticles suspended in deionized water are actively trapped using wireless dielectrophoresis and positioned within the most sensitive fringe field regions for wireless impedance-based detection. Trapping of 40 nm particles and larger is demonstrated using a 3.5 VRMS, 1 MHz radiofrequency signal delivered over a distance greater than 8 cm from the nanogap capacitor. Wireless trapping and release of 1 µm polystyrene beads is simultaneously detected in real-time over a distance of 2.5 cm from the nanogap capacitor. Herein, geometric scaling strategies coupled with optimal circuit design is presented to motivate combined collection and detection biosensing platforms amenable to wireless and/or smartphone operation.
Dysregulation of PRMT5 in chronic lymphocytic leukemia promotes progression with high risk of Richter’s transformation
Authors: Hing Zachary A. , Walker Janek S. , Whipp Ethan C. , Brinton Lindsey , Cannon Matthew , Zhang Pu , Sher Steven , Cempre Casey B. , Brown Fiona , Smith Porsha L. , Agostinelli Claudio , Pileri Stefano A. , Skinner Jordan N. , Williams Katie , Phillips Hannah , Shaffer Jami , Beaver Larry P. , Pan Alexander , Shin Kyle , Gregory Charles T. , Ozer Gulcin H. , Yilmaz Selen A. , Harrington Bonnie K. , Lehman Amy M. , Yu Lianbo , Coppola Vincenzo , Yan Pearlly , Scherle Peggy , Wang Min , Pitis Philip , Xu Chaoyi , Vaddi Kris , Chen-Kiang Selina , Woyach Jennifer , Blachly James S. , Alinari Lapo , Yang Yiping , Byrd John C. , Baiocchi Robert A. , Blaser Bradley W. , Lapalombella Rosa
Published: January 2023

Richter’s Transformation (RT) is a poorly understood and fatal progression of chronic lymphocytic leukemia (CLL) manifesting histologically as diffuse large B-cell lymphoma. Protein arginine methyltransferase 5 (PRMT5) is implicated in lymphomagenesis, but its role in CLL or RT progression is unknown. We demonstrate herein that tumors uniformly overexpress PRMT5 in patients with progression to RT. Furthermore, mice with B-specific overexpression of hPRMT5 develop a B-lymphoid expansion with increased risk of death, and Eµ-PRMT5/TCL1 double transgenic mice develop a highly aggressive disease with transformation that histologically resembles RT; where large-scale transcriptional profiling identifies oncogenic pathways mediating PRMT5-driven disease progression. Lastly, we report the development of a SAM-competitive PRMT5 inhibitor, PRT382, with exclusive selectivity and optimal in vitro and in vivo activity compared to available PRMT5 inhibitors. Taken together, the discovery that PRMT5 drives oncogenic pathways promoting RT provides a compelling rationale for clinical investigation of PRMT5 inhibitors such as PRT382 in aggressive CLL/RT cases.
A new extended single-switch high gain DC–DC boost converter for renewable energy applications
Authors: Mansour Arafa S. , Zaky Mohamed S.
Published: January 2023

High-gain DC/DC converters are considered one of the most important components of green energy systems. Large numbers of these converters are used for increasing the voltage gain by using an extreme duty cycle. However, it increases losses and the cost, degrades the system performance, and hence obtains a low efficiency. In this article, a new design of a high-gain DC/DC boost converter is proposed. This converter has the potential to be used in low input voltage applications that need a high voltage gain such as systems powered by solar photovoltaic panels and fuel cells. The new topology is characterized by its simplicity of operation, high voltage gain, better efficiency, continuity of the input current, reduced number of inductors and capacitors, and can be extended to get higher gains. The converter structure, principle of operation, and design consideration of inductors and capacitors are presented in detail. Derivation of power losses and efficiency is presented. A laboratory prototype is implemented, and various experimental tests are given. The achievement of the suggested design is confirmed and compared with other recent high-gain converters.