bluuebunny/crossref_metadata_2025 huggingface dataset:
Motivational context determines the impact of aversive outcomes on mental effort allocation
Authors: Fahey Mahalia Prater , Yee Debbie M. , Leng Xiamin , Tarlow Maisy , Shenhav Amitai
Published: November 2023

It is well known that people will exert effort on a task if sufficiently motivated, but how they distribute these efforts across different strategies (e.g., efficiency vs. caution) remains uncertain. Past work has shown that people invest effort differently for potential positive outcomes (rewards) versus potential negative outcomes (penalties). However, this research failed to account for differences in the context in which negative outcomes motivate someone - either as punishment or reinforcement. It is therefore unclear whether effort profiles differ as a function of outcome valence, motivational context, or both. Using computational modeling and our novel Multi-Incentive Control Task, we show that the influence of aversive outcomes on one’s effort profile is entirely determined by their motivational context. Participants (N:91) favored increased caution in response to larger penalties for incorrect responses, and favored increased efficiency in response to larger reinforcement for correct responses, whether positively or negatively incentivized.

Statement of Relevance

People have to constantly decide how to allocate their mental effort, and in doing so can be motivated by both the positive outcomes that effort accrues and the negative outcomes that effort avoids. For example, someone might persist on a project for work in the hopes of being promoted or to avoid being reprimanded or even fired. Understanding how people weigh these different types of incentives is critical for understanding variability in human achievement as well as sources of motivational impairments (e.g., in major depression). We show that people not only consider both potential positive and negative outcomes when allocating mental effort, but that the profile of effort they engage under negative incentives differs depending on whether that outcome is contingent on sustaining good performance (negative reinforcement) or avoiding bad performance (punishment). Clarifying the motivational factors that determine effort exertion is an important step for understanding motivational impairments in psychopathology.
Characterization of anOsmrConditional Knockout Mouse Model
Authors: Schwartz Logan S. , Saxl Ruth L. , Stearns Tim , Trowbridge Jennifer J.
Published: November 2023

Oncostatin M (OSM) is a member of the interleukin-6 (IL-6) family of cytokines and has been found to have distinct anti-inflammatory and pro-inflammatory properties in various cellular and disease contexts. OSM signals through two receptor complexes, one of which includes OSMRβ. To investigate OSM-OSMRβ signaling in adult hematopoiesis, we utilized the readily available conditionalOsmrfl/flmouse model B6;129-Osmrtm1.1Nat/J, which is poorly characterized in the literature. This model contains loxP sites flanking exon 2 of theOsmrgene. We crossedOsmrfl/flmice to interferon-inducibleMx1-Cre, which is robustly induced in adult hematopoietic cells. We observed complete recombination of theOsmrflallele and loss of exon 2 in hematopoietic (bone marrow) as well as non-hematopoietic (liver, lung, kidney) tissues. Using a TaqMan assay with probes downstream of exon 2,Osmrtranscript was lower in the kidney but equivalent in bone marrow, lung, and liver fromOsmrfl/flMx1-Cre versusMx1-Cre control mice, suggesting that transcript is being produced despite loss of this exon. Western blots show that liver cells fromOsmrfl/flMx1-Cre mice had complete loss of OSMR protein, while bone marrow, kidney, and lung cells had reduced OSMR protein at varying levels. RNA-seq analysis of a subpopulation of bone marrow cells (hematopoietic stem cells) finds that some OSM-stimulated genes, but not all, are suppressed inOsmrfl/flMx1-Cre cells. Together, our data suggest that the B6;129-Osmrtm1.1Nat/J model should be utilized with caution as loss ofOsmrexon 2 has variable and tissue-dependent impact on mRNA and protein expression.
Robust reprogramming of glia into neurons by inhibition of Notch signaling and NFI factors in adult mammalian retina
Authors: Le Nguyet , Vu Trieu-Duc , Palazzo Isabella , Pulya Ritvik , Kim Yehna , Blackshaw Seth , Hoang Thanh
Published: November 2023

Generation of neurons through direct reprogramming has emerged as a promising therapeutic approach for neurodegenerative diseases. Despite successful applicationsin vitro,in vivoimplementation has been hampered by low efficiency. In this study, we present a highly efficient strategy for reprogramming retinal glial cells into neurons by simultaneously inhibiting key negative regulators. By suppressing Notch signaling through the removal of its central mediatorRbpj,we induced mature Müller glial cells to reprogram into bipolar and amacrine neurons in uninjured adult mouse retinas, and observed that this effect was further enhanced by retinal injury. We found that specific loss of function ofNotch1andNotch2receptors in Müller glia mimicked the effect ofRbpjdeletion on Müller glia-derived neurogenesis. Integrated analysis of multiome (scRNA- and scATAC-seq) and CUT&Tag data revealed that Rbpj directly activates Notch effector genes and genes specific to mature Müller glia while also indirectly represses the expression of neurogenic bHLH factors. Furthermore, we found that combined loss of function ofRbpjandNfia/b/xresulted in a robust conversion of nearly all Müller glia to neurons. Finally, we demonstrated that inducing Müller glial proliferation by AAV (adeno-associated virus)-mediated overexpression of dominant- active Yap supports efficient levels of Müller glia-derived neurogenesis in bothRbpj- andNfia/b/x/Rbpj- deficient Müller glia. These findings demonstrate that, much like in zebrafish, Notch signaling actively represses neurogenic competence in mammalian Müller glia, and suggest that inhibition of Notch signaling andNfia/b/xin combination with overexpression of activated Yap could serve as an effective component of regenerative therapies for degenerative retinal diseases.
Genomic-inferred cross-selection metrics for multi-trait improvement in a recurrent selection breeding program
Authors: Atanda Sikiru Adeniyi , Bandillo Nonoy
Published: November 2023

The major drawback to the implementation of genomic selection in a breeding program is the reduction of additive genetic variance in the long term, primarily due to the Bulmer effect. Increasing genetic gain and retaining additive genetic variance requires optimizing the trade-off between the two competing factors. Our approach integrated index selection in the genomic infer cross-selection (GCS) methods. With this strategy, we identified optimal crosses that simultaneously maximize progeny performance and maintain genetic variance for multiple traits. Using a stochastic simulated recurrent breeding program over a 40-year period, we evaluated different GCS metrics with other factors, such as the number of parents, crosses, and progenies per cross, that influence genetic gain in a breeding program. Across all breeding scenarios, the posterior mean-variance consistently enhances genetic gain when compared to other metrics such as the usefulness criterion, optimal haploid value, mean genomic estimated breeding value, and mean index selection value of the superior parents. In addition, we provide a detailed strategy to optimize the number of parents, crosses, and progenies per cross that maximizes short- and long-term genetic gain in a breeding program.
Spatiotemporal Profiling Unveiling the Cellular Organization Patterns and Local Protumoral Immune Microenvironment Remodeling in Early Lung Adenocarcinoma Progression
Authors: Chen Haojie , Peng Yizhou , Li Yana , Zheng Qiang , Zhao Yue , Liu Pengcheng , Wu Zhigang , Wo Yang , Hong Hui , Sun Yihua , Shao Zhen
Published: November 2023

Spatial cellular organization patterns (COPs) in tumor microenvironment influence the tumor progression and therapeutic response, however, little is known about the cellular composition and functional potential of these multicellular structures during lung adenocarcinoma progression. Here, we integrate spatial transcriptomics with single cell RNA sequencing to characterize the local tumor and immunological landscape of samples from 8 patients with early-stage lung adenocarcinoma at different pathological stages. We identified ten COPs that show distinct associations with local immune states and clinical outcomes, including survival and therapy response. The local infiltration levels of regulatory and dysfunctional immune cells are increased with pathological progression. Cell-to-cell interactions between malignant cells and tumor microenvironment (TME) cells were involved in protumor immune state remodeling. Finally, we detected a group of malignant cells that were specifically located at the tumor boundary, representing a more aggressive state, were involved in the invasion of invasive adenocarcinoma (IAC). Altogether, these results can improve our understanding of the local microenvironment characteristics that underlie LUAD progression and may facilitate the identification of drug targets to prevent invasive progression and biomarkers for diagnosis.
CZ CELL×GENE Discover: A single-cell data platform for scalable exploration, analysis and modeling of aggregated data
Authors:   CZI Single-Cell Biology Program, Abdulla Shibla , Aevermann Brian , Assis Pedro , Badajoz Seve , Bell Sidney M. , Bezzi Emanuele , Cakir Batuhan , Chaffer Jim , Chambers Signe , Michael Cherry J. , Chi Tiffany , Chien Jennifer , Dorman Leah , Garcia-Nieto Pablo , Gloria Nayib , Hastie Mim , Hegeman Daniel , Hilton Jason , Huang Timmy , Infeld Amanda , Istrate Ana-Maria , Jelic Ivana , Katsuya Kuni , Kim Yang Joon , Liang Karen , Lin Mike , Lombardo Maximilian , Marshall Bailey , Martin Bruce , McDade Fran , Megill Colin , Patel Nikhil , Predeus Alexander , Raymor Brian , Robatmili Behnam , Rogers Dave , Rutherford Erica , Sadgat Dana , Shin Andrew , Small Corinn , Smith Trent , Sridharan Prathap , Tarashansky Alexander , Tavares Norbert , Thomas Harley , Tolopko Andrew , Urisko Meghan , Yan Joyce , Yeretssian Garabet , Zamanian Jennifer , Mani Arathi , Cool Jonah , Carr Ambrose
Published: November 2023

Hundreds of millions of single cells have been analyzed to date using high throughput transcriptomic methods, thanks to technological advances driving the increasingly rapid generation of single-cell data. This provides an exciting opportunity for unlocking new insights into health and disease, made possible by meta-analysis that span diverse datasets building on recent advances in large language models and other machine learning approaches. Despite the promise of these and emerging analytical tools for analyzing large amounts of data, a major challenge remains the sheer number of datasets and inconsistent format, data models and accessibility. Many datasets are available via unique portals platforms that often lack interoperability. Here, we present CZ CellxGene Discover(cellxgene.cziscience.com), a data platform that provides curated and interoperable data. This single-cell data resource, available via a free-to-use online data portal, hosts a growing corpus of community contributed data that spans more than 50 million unique cells. Curated, standardized, and associated with consistent cell-level metadata, this collection of interoperable single-cell transcriptomic data is the largest of its kind. A suite of tools and features enables accessibility and reusability of the data via both computational and visual interfaces to allow researchers to rapidly explore individual datasets and perform cross-corpus analysis. This functionality is enabling meta-analyses of tens of millions of cells across studies and tissues and providing global views of human cells at the resolution of single cells.
Fatty acid synthesis promotes inflammasome activation through NLRP3 palmitoylation
Authors: Leishman Stuart , Aljadeed Najd M. , Qian Liyunhe , Cockcroft Shamshad , Behmoaras Jacques , Anand Paras K.
Published: November 2023

Inflammasomes are multi-protein complexes assembled by NOD-like receptor (NLR) family of proteins, which play critical roles in infectious, inflammatory and metabolic diseases. The assembly of the NLRP3 inflammasome is triggered upon recognition of an apt stimulus by the sensor protein, resulting in binding to pro-caspase-1 via the adaptor protein ASC. Inflammasome activation results in the maturation of the precursor forms of cytokines IL-1βand IL-18, along with caspase-1-dependent pyroptosis, a pro-inflammatory form of cell death. Emerging evidence suggests the involvement of lipid metabolism in inflammasome activation; however, the precise mechanisms by which lipids regulate the NLRP3 inflammasome remain ambiguous. A multi-enzyme protein, fatty acid synthase (FASN) is a central regulator of lipid metabolism partaking an essential role in fatty acid biosynthesis pathway by catalysing the production of palmitic acid. Palmitic acid acts as a precursor to long-chain fatty acids and additionally regulates cellular functions by palmitoylation, a process in which palmitate is reversibly added to cysteine residues of target proteins, modifying protein localization and function. Here, we undertook a pharmacological approach to investigate the roles of fatty acid biosynthetic pathway in NLRP3 inflammasome activation. Our results demonstrated that inhibition of FASN in primary mouse and human macrophages abrogates the activation of the NLRP3 inflammasome, resulting in blunted caspase-1 activation. Furthermore, this phenomenon relied on protein palmitoylation asin vitroandin vivoabrogation of palmitoylation similarly reduced NLRP3 activation, which could be restored by exogenously supplementing palmitate in cultured cells. Consequently, an acyl biotin exchange assay corroborated NLRP3 palmitoylation. Notably, activation of the dsDNA sensing AIM2 inflammasome remained unaltered when either FASN or palmitoylation was blocked. These results therefore highlight the pivotal role of FASN and palmitoylation, shedding new mechanistic insights into the activation of the NLRP3 inflammasome.
The hypermorphic PLCγ2 S707Y variant dysregulates microglial cell function – insight into PLCγ2 activation in brain health and disease, and opportunities for therapeutic modulation
Authors: Bull Daniel , Matte Julie C , Navarron Carmen M , McIntyre Rebecca , Whiting Paul , Katan Matilda , Ducotterd Fiona , Magno Lorenza
Published: November 2023

Phospholipase C-gamma 2 (PLCγ2) is highly expressed in hematopoietic and immune cells, where it is a key signalling node enabling diverse cellular functions. Within the periphery, gain-of-function (GOF) PLCγ2 variants, such as the strongly hypermorphic S707Y, cause severe immune dysregulation. The milder hypermorphic mutation PLCγ2 P522R increases longevity and confers protection in central nervous system (CNS) neurodegenerative disorders, implicating PLCγ2 as a novel therapeutic target for treating these CNS indications. Currently, nothing is known about what consequences strong PLCγ2 GOF has on CNS functionality, and more precisely on the specific biological functions of microglia. Using the PLCγ2 S707Y variant as a model of chronic activation we investigated the functional consequences of strong PLCγ2 GOF on human microglia. PLCγ2 S707Y expressing human inducible pluripotent stem cells (hiPSC)-derived microglia exhibited hypermorphic enzymatic activity under both basal and stimulated conditions, compared to PLCγ2 wild type. Despite the increase in PLCγ2 enzymatic activity, the PLCγ2 S707Y hiPSC-derived microglia display diminished functionality for key microglial processes including phagocytosis and cytokine secretion upon inflammatory challenge. RNA sequencing revealed a downregulation of genes related to innate immunity and response, providing molecular support for the phenotype observed. Our data suggests that chronic activation of PLCγ2 elicits a detrimental phenotype that is contributing to unfavourable CNS functions, and informs on the therapeutic window for targeting PLCγ2 in the CNS. Drug candidates targeting PLCγ2 will need to precisely mimic the effects of the PLCγ2 P522R variant on microglial function, but not those of the PLCγ2 S707Y variant.

Highlights

The impact of strongly hypermorphic variants of PLCγ2 have not been studied in brain and yet PLCγ2 is implicated in modifying risk of CNS disorders including Alzheimer’s disease

To address this, we explored the role of the strongly hypermorphic PLCγ2 S707Y variant in hiPSC-derived microglia

S707Y increases PLCγ2 enzymatic activity and intracellular calcium flux

Phagocytosis and cytokine production are diminished in PLCγ2 S707Y microglia

PLCγ2 S707Y downregulates expression of genes related to innate immunity and response

Modulation of PLCγ2 for therapy must recapitulate the positive effects of moderate hypermorphic variants on microglial functions whilst avoiding detrimental effects of strongly hypermorphic variants like PLCγ2 S707Y

Graphical abstract
Mixed signatures for subcritical dynamics in rodent hippocampus during sleep and awake epochs
Authors: Garg Pranjal
Published: November 2023

Neuronal dynamics such as brain criticality have recently been attributed to optimal information processing. Brain criticality attempts to elucidate the collective dynamics of a large number of neurons. It posits that the brain operates near critical to the critical point, although the field is rife with controversies and contrasting evidence. Similar computational capacities are observed during sharp wave ripples in the hippocampus prompting the need to correlate their dynamics. In the current study, we report the measures of avalanche criticality including neuronal avalanches, branching process, crackling noise relation, and deviation from criticality coefficient and Hurst exponents for long-range temporal correlations in rodent hippocampus during sharp wave ripples. We found evidence for mixed subcritical to critical dynamics in the hippocampus and minimal difference between ripple and no ripple times across measured metrics. The evidence demonstrates heterogeneity in signatures of criticality among animals and brain areas, indicating the presence of broad-range neuronal dynamics.
Dynamic encoding of biological motion information in macaque medial superior temporal area
Authors: Feng Tingting , Zhang Bo , Tang Qin , Han Wenhao , Liu Jingxuan , Jiang Yi , Zhang Tao
Published: November 2023

The ability to decipher biological motion information is an essential brain function that develops early in life and is evolutionarily conserved across many species. However, the neuronal encoding of biological motion information remains unclear due to the scarce electrophysiological evidence. In the current study, we tackled this issue by examining whether and how neurons in the monkey medial superior temporal cortex (MST) extract form from biological motion and encode spatial transformations in biological motion. Results revealed that MST neurons are capable of encoding form information and discriminating the horizontal and the vertical mirror transformations of biological motion. More importantly, BM information is dynamically encoded in the modulation strength of evoked spike trains rather than the average firing rate during stimulus presentation. Furthermore, the ability of MST neurons to detect various biological motion features is closely linked with the neuronal selectivity for optic flow patterns.
Intraneuronal binding of amyloid beta with reelin - implications for the onset of Alzheimer’s disease
Authors: Kobro-Flatmoen Asgeir , Omholt Stig W.
Published: November 2023

It was recently shown that in anteriolateral entorhinal cortex layer II neurons (ECLII neurons) in McGill-R-Thy1-APP homozygous transgenic rats (a model commonly used to study Alzheimer’s disease (AD)), the glycoprotein reelin and intracellular amyloid-β(Aβ) engage in a direct protein–protein interaction. Numerous studies of the human brain supported by experimental results from rodent and cell models point to a role for intracellular oligomeric Aβin the onset of AD. If reelin functions as a sink for intracellular Aβand if the binding to reelin makes Aβphysiologically inert, it implies that reelin may prevent the neuron from being exposed to the detrimental effects typically associated with oligomeric Aβ. Considering that reelin expression is extraordinarily high in the major subset of ECLII neurons compared to most other cortical neurons, such a protective role appears very difficult to reconcile with the fact that ECLII is clearly a major cradle for the onset of AD in humans. Here we show that this conundrum may be resolved if ECLII neurons have a much higher maximum production capacity of Aβthan neurons expressing low levels of reelin. We provide a rationale for why this difference has evolved, and argue that the higher maximum production capacity of Aβin ECLII neurons may in a senescent Aβ-inducing physiology predispose these neurons to initiate AD development.

Author summary

Amyloid-βis a small peptide that is widely recognized as one of the main culprits involved in the development of Alzheimer’s disease. It was recently shown that in the major subset of neurons in entorhinal cortex layer II, which expresses high levels of the protein reelin, amyloid-βand reelin bind to each other. These neurons, which are strongly involved in memory formation, are among the first to die in subjects with Alzheimer’s disease. If intracellular amyloid-β, which is clearly involved in the onset of the disease, becomes physiologically inert when it binds to reelin, it implies that reelin can prevent the neuron from being exposed to the detrimental effects of increased levels of amyloid-β. Considering that reelin expression is extraordinarily high in ECLII neurons compared to most other cortical neurons, such a protective role appears very difficult to reconcile with the fact that ECLII constitute the predominant cortical site for initiation of Alzheimer’s disease. Here, we show that this paradox may be resolved if ECLII neurons have a much higher maximum amyloid-βproduction capacity than neurons expressing low levels of reelin. We provide reasons why this difference has evolved and argue that it, in a senescent physiology, predisposes ECLII neurons to initiate the development of Alzheimer’s disease.
Gene and allele specific expression underlying the electric signal divergence in African weakly electric fish
Authors: Cheng Feng , Dennis Alice B. , Baumann Otto , Kirschbaum Frank , Abdelilah-Seyfried Salim , Tiedemann Ralph
Published: November 2023

In the African weakly electric fish genusCampylomormyrus, electric organ discharge (EOD) signals are strikingly different in shape and duration among closely related species, contribute to pre-zygotic isolation and may have triggered an adaptive radiation. We performed mRNA sequencing on electric organs (EOs) and skeletal muscles (SMs; from which the EOs derive) from three species with short (0.4 ms), medium (5 ms), and long (40 ms) EODs and two different cross-species hybrids. We identified 1,444 up-regulated genes in EO shared by all five species/hybrids cohorts, rendering them candidate genes for EO-specific properties inCampylomormyrus. We further identified several candidate genes, includingKCNJ2andKLF5, their up-regulation may contribute to increased EOD duration. Hybrids between a short (C. compressirostris) and a long (C. rhynchophorus) discharging species exhibit EODs of intermediate duration and showed imbalanced expression ofKCNJ2alleles, pointing towards a cis-regulatory difference at this locus, relative to EOD duration.KLF5is a transcription factor potentially balancing potassium channel gene expression, a crucial process for the formation of an EOD. Unraveling the genetic basis of the species-specific modulation of the EOD inCampylomormyrusis crucial for understanding the adaptive radiation of this emerging model taxon of ecological (perhaps even sympatric) speciation.
WTAP, transcriptionally regulated by p65, promotes inflammation through m6A modification and phase separation
Authors: Ge Yong , Chen Rong , Ling Tao , Liu Biaodi , Huang Jingrong , Cheng Youxiang , Lin Yi , Chen Hongxuan , Xie Xiongmei , Xia Guomeng , Luo Guanzheng , Yuan Shaochun , Xu Anlong
Published: November 2023

Emerging evidence has linked dysregulation ofN6-methyladenosine (m6A) to inflammation and inflammatory diseases, but the underlying mechanism still needs investigation. Here, we found that high m6A modification in a variety of hyperinflammatory states is p65-dependent, because Wilms tumor 1 associated protein (WTAP), a key component of the writer complex, is transcriptionally regulated by p65 and its overexpression can lead to higher m6A modification. Mechanistically, upregulated WTAP is more prone to phase separation to facilitate the aggregation of “writer” complex to nuclear speckles and the deposition of m6A marks onto transcriptionally active inflammatory transcripts, thereby accelerating proinflammatory response. Furthermore, myeloid deficiency of WTAP attenuates the severity of LPS-induced sepsis and DSS-induced IBD. Thus, the proinflammatory effect of WTAP is a general risk-increasing mechanism, and interrupting the assembly of m6A writer complex by targeting the phase separation of WTAP to reduce the global m6A level may be a potential and promising therapeutic strategy for alleviating hyperinflammation.
Asymmetric roles for M2-M3 linkers of specific GABAAreceptor subunits in the intrinsic closed-open equilibrium and its modulation by the benzodiazepine diazepam
Authors: Nors Joseph W. , Endres Zachary , Goldschen-Ohm Marcel P.
Published: November 2023

GABAAreceptors (GABAARs) are neurotransmitter-gated ion channels critical for inhibitory synaptic transmission as well as the molecular target for benzodiazepines (BZDs), one of the most widely prescribed class of psychotropic drugs today. Despite structural insight into the conformations underlying functional channel states, the detailed molecular interactions involved in conformational transitions and the physical basis for their modulation by BZDs are not fully understood. We previously identified that alanine substitution at the central residue in the α1 subunit M2-M3 linker (V279A) enhances the efficiency of linkage between the BZD site and the pore gate. Here, we expand on this work by investigating the effect of alanine substitutions at the analogous positions in the M2-M3 linkers of β2 (I275A) and γ2 (V290A) subunits, which together with α1 comprise typical heteromeric α1β2γ2 synaptic GABAARs. We find that these mutations confer subunit-specific effects on the intrinsic pore closed-open equilibrium and its modulation by the BZD diazepam (DZ). The mutations α1(V279A) or γ2(V290A) bias the channel toward a closed conformation, whereas β2(I275A) biases the channel toward an open conformation to the extent that the channel becomes leaky and opens spontaneously in the absence of agonist (e.g., GABA). In contrast, only α1(V279A) enhances the efficiency of DZ-to-pore linkage, whereas mutations in the other two subunits have no effect. These observations show that the central residue in the M2-M3 linkers of distinct subunits in synaptic α1β2γ2 GABAARs contribute asymmetrically to the intrinsic closed-open equilibrium and its modulation by DZ.
Stability of DNA-Methylation Profiles of Biological Aging in Children and Adolescents
Authors: deSteiguer Abby J. , Raffington Laurel , Sabhlok Aditi , Tanksley Peter , Tucker-Drob Elliot M. , Harden K. Paige
Published: November 2023

Background and Objectives

Methylation profile scores (MPSs) index biological aging and aging-related disease in adults and are cross-sectionally associated with social determinants of health in childhood. MPSs thus provide an opportunity to trace how aging-related biology responds to environmental changes in early life. Information regarding the stability of MPSs in early life is currently lacking.

Method

We use longitudinal data from children and adolescents ages 8-18 (N = 428, M age = 12.15 years) from the Texas Twin Project. Participants contributed two waves of salivary DNA-methylation data (mean lag = 3.94 years), which were used to construct four MPSs reflecting multi-system physiological decline and mortality risk (PhenoAgeAccel and GrimAgeAccel), pace of biological aging (DunedinPACE), and cognitive function (Epigenetic-g). Furthermore, we exploit variation among participants in whether they were exposed to the COVID-19 pandemic during the course of study participation, in order to test how a historical period characterized by environmental disruption might affect children’s aging-related MPSs.

Results

All MPSs showed moderate longitudinal stability (test-retestrs = 0.42, 0.44, 0.46, 0.51 for PhenoAgeAccel, GrimAgeAccel, and Epigenetic-g, and DunedinPACE, respectively). No differences in the stability of MPSs were apparent between those whose second assessment took place after the onset of the COVID-19 pandemic vs. those for whom both assessments took place prior to the pandemic.

Conclusions

Aging-related DNA-methylation patterns are less stable in childhood than has been previously observed in adulthood. Further developmental research on the methylome is necessary to understand which environmental perturbations in childhood impact trajectories of biological aging and when children are most sensitive to those impacts.

Article Summary

Methylation profiles of biological aging are less stable in childhood than has been previously observed in adulthood.

What’s Known on This Subject

Methylation profile scores (MPSs) index biological aging in adults and are cross-sectionally associated with social determinants of health in childhood. Aging-related MPSs in adulthood show very high test-retest stability but data on longitudinal stability of MPSs in childhood is sparse.

What This Study Adds

Children’s methylation profiles of biological aging are moderately stable across an approximately four-year period. Methylation profiles are less stable in childhood than in adulthood, suggesting that aging-related biology in childhood might be more responsive to environmental changes than in adulthood.
Tumor microenvironment-induced FOXM1 regulates ovarian cancer stemness
Authors: Battistini Chiara , Kenny Hilary A. , Nieddu Valentina , Melocchi Valentina , Decio Alessandra , Gatto Alessia , Ghioni Mariacristina , Porta Francesca M. , Giavazzi Raffaella , Colombo Nicoletta , Bianchi Fabrizio , Lengyel Ernst , Cavallaro Ugo
Published: November 2023

In ovarian tumors, the omental microenvironment profoundly influences the behavior of cancer cells and sustains the acquisition of stem-like traits, with major impacts on tumor aggressiveness and relapse. Here, we exploit a patient-derived platform of organotypic cultures to study the crosstalk between the tumor microenvironment and ovarian cancer stem cells. The pro-tumorigenic transcription factor FOXM1 is specifically induced by the microenvironment in ovarian cancer stem cells, through activation of FAK/YAP signaling. The microenvironment-induced FOXM1 sustains stemness, and its inactivation reduces cancer stem cells survival in the omental niche and enhances their response to the PARP inhibitor Olaparib. By unveiling the novel role of FOXM1 in ovarian cancer stemness, our findings highlight patient-derived organotypic co-cultures as a powerful tool to capture clinically relevant mechanisms of the microenvironment/stem cells crosstalk, contributing to the identification of tumor vulnerabilities.
Decoding Heterogenous Single-cell Perturbation Responses
Authors: Song Bicna , Liu Dingyu , Dai Weiwei , McMyn Natalie , Wang Qingyang , Yang Dapeng , Krejci Adam , Vasilyev Anatoly , Untermoser Nicole , Loregger Anke , Song Dongyuan , Williams Breanna , Rosen Bess , Cheng Xiaolong , Chao Lumen , Kale Hanuman T. , Zhang Hao , Diao Yarui , Bürckstümmer Tilmann , Siliciano Jenet M. , Li Jingyi Jessica , Siliciano Robert , Huangfu Danwei , Li Wei
Published: November 2023

Understanding diverse responses of individual cells to the same perturbation is central to many biological and biomedical problems. Current methods, however, do not precisely quantify the strength of perturbation responses and, more importantly, reveal new biological insights from heterogeneity in responses. Here we introduce the perturbation-response score (PS), based on constrained quadratic optimization, to quantify diverse perturbation responses at a single-cell level. Applied to single-cell transcriptomes of large-scale genetic perturbation datasets (e.g., Perturb-seq), PS outperforms existing methods for quantifying partial gene perturbation responses. In addition, PS presents two major advances. First, PS enables large-scale, single-cell-resolution dosage analysis of perturbation, without the need to titrate perturbation strength. By analyzing the dose-response patterns of over 2,000 essential genes in Perturb-seq, we identify two distinct patterns, depending on whether a moderate reduction in their expression induces strong downstream expression alterations. Second, PS identifies intrinsic and extrinsic biological determinants of perturbation responses. We demonstrate the application of PS in contexts such as T cell stimulation, latent HIV-1 expression, and pancreatic cell differentiation. Notably, PS unveiled a previously unrecognized, cell-type-specific role of coiled-coil domain containing 6 (CCDC6) in guiding liver and pancreatic lineage decisions, where CCDC6 knockouts drive the endoderm cell differentiation towards liver lineage, rather than pancreatic lineage. The PS approach provides an innovative method for dose-to-function analysis and will enable new biological discoveries from single-cell perturbation datasets.

One sentence summary

We present a method to quantify diverse perturbation responses and discover novel biological insights in single-cell perturbation datasets.
Utility of AlphaMissense predictions in Asparagine Synthetase deficiency variant classification
Authors: Staklinski Stephen J. , Scheben Armin , Siepel Adam , Kilberg Michael S.
Published: November 2023

AlphaMissense is a recently developed method that is designed to classify missense variants into pathogenic, benign, or ambiguous categories across the entire human proteome. Asparagine Synthetase Deficiency (ASNSD) is a developmental disorder associated with severe symptoms, including congenital microcephaly, seizures, and premature death. Diagnosing ASNSD relies on identifying mutations in the asparagine synthetase (ASNS) gene through DNA sequencing and determining whether these variants are pathogenic or benign. Pathogenic ASNS variants are predicted to disrupt the protein’s structure and/or function, leading to asparagine depletion within cells and inhibition of cell growth. AlphaMissense offers a promising solution for the rapid classification of ASNS variants established by DNA sequencing and provides a community resource of pathogenicity scores and classifications for newly diagnosed ASNSD patients. Here, we assessed AlphaMissense’s utility in ASNSD by benchmarking it against known critical residues in ASNS and evaluating its performance against a list of previously reported ASNSD-associated variants. We also present a pipeline to calculate AlphaMissense scores for any protein in the UniProt database. AlphaMissense accurately attributed a high average pathogenicity score to known critical residues within the two ASNS active sites and the connecting intramolecular tunnel. The program successfully categorized 78.9% of known ASNSD-associated missense variants as pathogenic. The remaining variants were primarily labeled as ambiguous, with a smaller proportion classified as benign. This study underscores the potential role of AlphaMissense in classifying ASNS variants in suspected cases of ASNSD, potentially providing clarity to patients and their families grappling with ongoing diagnostic uncertainty.
Differential effects of aging on regional corpus callosum microstructure and the modifying influence of pulse pressure
Authors: Kraft Jessica N , Matijevic Stephanie , Hoagey David A , Kennedy Kristen M , Rodrigue Karen
Published: November 2023

The corpus callosum is composed of several subregions, distinct in cellular and functional organization. This organization scheme may render these subregions differentially vulnerable to the aging process. Callosal integrity may be further compromised by vascular risk factors, which negatively influence white matter health. Here, we test for heterochronicity of aging, hypothesizing an anterior-to-posterior gradient of vulnerability to aging that may be altered by effects of vascular health. In 174 healthy adults across the adult lifespan (mean age=53.56 ± 18.90, range=20-94 years old, 58.62% women), measures of pulse pressure and diffusion-weighted imaging were conducted. A deterministic tractography approach was utilized to extract fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) from each of five callosal subregions, serving as estimates of microstructural health. General linear models tested effects of age, hypertension, and pulse pressure on these metrics. We observed no significant effect of hypertensive diagnosis on callosal microstructure. We found a significant main effect of age and an age x pulse pressure interaction whereby older age and elevated pulse pressure were associated with poorer FA, AD, and RD. Age effects revealed non-linear components and occurred along an anterior-posterior gradient of severity in the callosum. This gradient disappeared when pulse pressure was considered. These results indicate that age-related deterioration across the callosum is regionally variable, and that pulse pressure, a proxy of arterial stiffness, alters this aging pattern.

Significance Statement

Aging is associated with microstructural changes in the corpus callosum, the largest white matter tract in the brain. Additionally, vascular factors, such as hypertension and pulse pressure, affect corpus callosum microstructure. However, it is unclear whether these factors uniformly impact the corpus callosum throughout aging. The current study aimed to characterize patterns of aging and assess the role of hypertension and pulse pressure across different subregions of the corpus callosum. We found an age-related gradient on corpus callosum microstructure, with the most pronounced impact on anterior regions. However, this gradient was not found when pulse pressure was considered. These findings suggest that subregions are differentially sensitive to age-related decline, and pulse pressure modifies and exacerbates these declines.
Gains in soil C storage under anthropogenic N deposition are rapidly lost following its cessation
Authors: Propson Brooke E. , Zak Donald R. , Classen Aimée T. , Burton Andrew J. , Freedman Zachary B.
Published: November 2023

Anthropogenic nitrogen (N) deposition enhanced the global terrestrial carbon (C) sink and partially offset anthropogenic CO2emissions. This was driven by the suppression of microbial activity associated with the breakdown of soil organic matter. However, since the implementation of emission abatement policies in the 1970’s, atmospheric N deposition has declined globally, and the consequences of this decline are unknown. Here, we assessed the response of soil C storage, and associated microbial activities, in a long-term field study that experimentally increased N deposition for 24-years. We measured soil C and N, parameters of microbial activity, and compared effect sizes of soil C in response to, and in recovery from, the N deposition treatment across the history of our experiment (1994-2022). Our results demonstrate that the accumulated C in the organic horizon has been lost and exhibit additional deficits 5-years post-termination of the N deposition treatment. These findings, in part, arise from mechanistic changes in microbial activity. Soil C in the mineral soil was less responsive thus far in recovery. If these organic horizon C dynamics are similar in other temperate forests, the Northern Hemisphere C sink will be reduced and climate warming will be enhanced.
TaxaNorm: a novel taxa-specific normalization approach for microbiome data
Authors: Wang Ziyue , Lloyd Dillon , Zhao Shanshan , Motsinger-Reif Alison
Published: November 2023

Background

In high-throughput sequencing studies, sequencing depth, which quantifies the total number of reads, varies across samples. Unequal sequencing depth can obscure true biological signals of interest and prevent direct comparisons between samples. To remove variability due to differential sequencing depth, taxa counts are usually normalized before downstream analysis. However, most existing normalization methods scale counts using size factors that are sample specific but not taxa specific, which can result in over- or under-correction for some taxa.

Results

We developed TaxaNorm, a novel normalization method based on a zero-inflated negative binomial model. This method assumes the effects of sequencing depth on mean and dispersion vary across taxa. Incorporating the zero-inflation part can better capture the nature of microbiome data. We also propose two corresponding diagnosis tests on the varying sequencing depth effect for validation. We find that TaxaNorm achieves comparable performance to existing methods in most simulation scenarios in downstream analysis and reaches a higher power for some cases. Specifically, it has a well balance on power and false discoveries control. When applying the method in a real dataset, TaxaNorm has improved performance when correcting technical bias.

Conclusion

TaxaNorm considers correcting both sample- and taxon-specific bias by introducing an appropriate regression framework in the microbiome data, which aids in data interpretation and visualization. The ‘TaxaNorm’ R package is freely available through the CRAN repositoryhttps://CRAN.R-project.org/package=TaxaNormand the source code can be downloaded athttps://github.com/wangziyue57/TaxaNorm.
Polygonum Cillinervepolysaccharide inhibits Transmissible gastroenteritis virus by regulating microRNA-181
Authors: Duan Xueqin , Li Huicong , Tan Xuewen , Liu Nishang , Wang Xingchen , Zhang Weimin , Liu Yingqiu , Ma Wuren , Wu Yi , Ma Lin , Fan Yunpeng
Published: November 2023

Transmissible gastroenteritis virus (TGEV) is an important pathogen that can cause changes in the expression profile of cell miRNA. In this study, PCP could treat piglets infected with TGEV by in vivo experiment. High-throughput sequencing technology was used to detect that 9 miRNAs were up-regulated and 17 miRNAs were down-regulated during PCP inhibition of TGEV infection in PK15 cells. Meanwhile, miR-181 was related to the target genes of key proteins of apoptosis pathway. PK15 was treated with different PCP after transfection of miR-181 mimic or inhibitor. Real-time PCR was used to detect the effect of TGEV replication, electron microscopy, TEM and Hoechst fluorescence staining were used to detect the biological function of the treated cells, and western blot (WB) was used to detect the expression of key signaling factors cyt C, caspase 9 and P53 in the apoptotic signaling pathway. The results showed that compared with the control group, 250 μg/mL PCP significantly inhibited the replication of TGEV gRNA and gene N (P< 0.01). PK15 cells in PCP groups (250 and 125 μg/mL) had uniform cell morphology and a small number of floating cells by microscopic, no typical virus structure was observed in 250 μg/mL PCP group under TEM, and apoptosis staining showed that 250 μg/mL PCP significantly reduced the number of apoptotic cells. PCP may inhibit TGEV-induced apoptosis through Caspase-dependent mitochondrial pathway after transfection of miR-181. The above results provided a theoretical basis for further research on the mechanism of PCP anti-TGEV.
Novel hypervariable erythrocyte surface expressed recombinant proteins show promise as serological markers of exposure toPlasmodium falciparuminfection
Authors: Vasileva Hristina , Chopo-Pizarro Ana , Ooko Michael , Dumont Elin , Wu Lindsey , Ssewanyana Isaac , Last Anna , Tetteh Kevin K.A.
Published: November 2023

Malaria caused byPlasmodium spp. leads to significant morbidity and mortality, particularly in Sub-Saharan African countries withPlasmodium falciparumbeing the predominant infectious species. The pathogenesis ofP. falciparumdepends on multiple host and parasitic factors, one of which is the evasion of host immune response due to antigenic variability during the blood stage of infection. The understudied infected erythrocyte expressed protein families STEVOR and RIFIN characterize with antigenic hypervariability and are associated with clinical outcome of the infection and protective acquired immunity based on their topology and localization. We have used two molecular tag methods for successful expression of members of STEVOR and RIFIN protein families as recombinant proteins inE. coliexpression system. We have further established the antigenicity of those recombinants and have used Ugandan cohort samples with variousP. falciparuminfectious status and have compared the seropositivity rate to those recombinants in different age groups against already established short- and long-term markers of infection. We have demonstrated age-dependent immunity acquisition against the tested recombinants, and we have suggested the potential use of STEVOR and RIFIN recombinants as novel markers ofP. falciparuminfection in serosurveillance. Due to the hypervariability of those protein members we propose that further, more extensive research using a library of expressed variants is needed to strengthen the conclusions made in this study.
Replication poison treated BRCA1-deficient breast cancers are prone to MRE11 over-resection resulting in single strand DNA accumulation and mitotic catastrophe
Authors: Tabet Imene , Orhan Esin , Candiello Ermes , Fenou Lise , Velazquez Carolina , Orsetti Beatrice , Rodier Geneviève , Jacot William , Ribeyre Cyril , Sardet Claude , Theillet Charles
Published: November 2023

BRCA1, BRCA2 and RAD51, key players of homologous recombination (HR) repair, are also involved in stalled DNA replication fork protection and repair. BRCA1-deficiency is encountered in 25% of Triple Negative Breast Cancer (TNBC). Here we investigated the sensitivity ofBRCA1-deficient TNBC cell models to gemcitabine a frequently used replication poison that does not alter DNA structure. We show that BRCA1-deficient models, in contrast to their isogenicBRCA1-proficient counterparts, are superiorly sensitive to gemcitabine, accumulate massive levels of single strand DNA (ssDNA), in absence of RPA and RAD51 signals and elevated double strand break (DSB) numbers leading to cell death.

Remarkably, ssDNA accumulation in gemcitabine-treated BRCA1-deficient cells was strongly diminished by the MRE11 inhibitor mirin, while it did not affect ssDNA levels resulting from PARP inhibitor olaparib treatment. The central role of MRE11 DNA resection strongly suggested that replication fork reversal may be important in response to replication poisoning by gemcitabine in BRCA1-deficient models. Furthermore, we demonstrate that gemcitabine-treatedBRCA1-deficient cells showing massive ssDNA accumulation slipped into mitosis and produced mitotic bridges and micronuclei (MN) showing strong BrdU and γH2AX staining. Noticeably these BrdU-positive MN and DNA bridges triggered cGAS sensing.

Our data, thus, strongly suggest that gemcitabine treatment could be beneficial inBRCA1-deficient TNBC both in terms of cancer cell death, but possibly as well in terms of antitumor immune response.