bluuebunny/crossref_metadata_2025 huggingface dataset:
Epigenetic Modifier Kdm6a/Utx Controls the Specification of Hypothalamic Neuronal Subtypes in a Sex-Dependent Manner
Authors: Cabrera Zapata Lucas E. , Cambiasso María Julia , Arevalo Maria Angeles
Published: July 2022

Kdm6a is an X chromosome-linked H3K27me2/3 demethylase that promotes chromatin accessibility and gene transcription and is critical for tissue/cell-specific differentiation. Previous results showed higher Kdm6a levels in XX than in XY hypothalamic neurons and a female-specific requirement for Kdm6a in mediating increased axogenesis before brain masculinization. Here we explored the sex-specific role of Kdm6a in the specification of neuronal subtypes in the developing hypothalamus. Hypothalamic neuronal cultures were established from sex-segregated E14 mouse embryos and transfected with siRNAs to knockdown Kdm6a expression (Kdm6a-KD). We evaluated by immunofluorescence the effect of Kdm6a-KD on Ngn3, a bHLH transcription factor regulating neuronal sub-specification in hypothalamus. Kdm6a-KD decreased Ngn3 expression in females but not in males, abolishing basal sex differences. Then, we analyzed Kdm6a-KD effect on Ascl1, Pomc, Npy, Sf1, Gad1 and Th expression by RT-qPCR. While Kdm6a-KD downregulated Ascl1 in both sexes equally, we found sex-specific results for Pomc, Npy and Th. Pomc and Th expressed higher in female than in male neurons and Kdm6a-KD reduced their levels only in females, while Npy expressed higher in male than in female neurons and Kdm6a-KD upregulated its expression only in females. Identical results were found by immunofluorescence for Pomc and Npy neuropeptides. Finally, using ChIP-qPCR we found higher H3K27me3 levels at Ngn3, Pomc and Npy promoters in male neurons, in line with Kdm6a higher expression and demethylase activity in females. These results indicate that Kdm6a plays a key sex-specific role in controlling the differentiation of neuronal populations regulating food intake and energy homeostasis.
On the functional role of gamma synchronization in the retinogeniculate system of the cat
Authors: Neuenschwander Sergio , Rosso Giovanne , Branco Natalia , Freitag Fabio , Tehovnik Edward J. , Schmidt Kerstin E. , Baron Jerome
Published: July 2022

Abstract

Fast gamma oscillations, generated within the retina, and transmitted to the cortex via the lateral geniculate nucleus (LGN), are thought to carry information about stimulus size and continuity. This hypothesis relies mainly on studies carried out under anesthesia and the extent to which it holds under more naturalistic conditions remains unclear. Using multi-electrode recordings of spiking activity in the retina and the LGN of the cat, we show that visually driven gamma oscillations are absent for awake states and are highly dependent on halothane (or isoflurane). Under ketamine, responses were non-oscillatory, as in the awake condition. Response entrainment to the monitor refresh was commonly observed up to 120 Hz and was superseded by the gamma oscillatory responses induced by halothane. Given that retinal gamma oscillations are contingent upon halothane anesthesia and absent in the awake cat, such oscillations should be considered artifactual, thus playing no functional role in vision.
Muscle synergies are flexibly recruited during gait pattern exploration using motor control-based biofeedback
Authors: Spomer Alyssa M. , Yan Robin Z. , Schwartz Michael H. , Steele Katherine M.
Published: July 2022

Understanding how the central nervous system coordinates diverse motor outputs has been a topic of extensive investigation. While it is generally accepted that a small set of synergies underlies many common activities, such as walking, whether synergies are equally robust across a broader array of gait patterns or can be flexibly modified remains unclear. Here, we evaluated the extent to which synergies changed as nondisabled adults (n = 14) explored gait patterns using custom biofeedback. Secondarily, we used Bayesian Additive Regression Trees to identify factors which were predictive of synergy modulation. Participants performed 41.1 ± 8.0 gait patterns using biofeedback, during which synergy recruitment changed depending on the type and magnitude of gait pattern modification. Specifically, a consistent set of synergies was recruited to accommodate small deviations from baseline, but additional synergies emerged for larger gait changes. Synergy complexity was similarly modulated; complexity decreased for 82.6% of the attempted gait patterns, however, distal gait mechanics were highly predictive of these changes. In particular, greater ankle dorsiflexion moments and knee flexion through stance, as well as greater knee extension moments at initial contact corresponded to a reduction in synergy complexity. Taken together, these results suggest that the central nervous system preferentially adopts a low-dimensional, largely invariant control strategy, but can modify that strategy to produce diverse gait patterns. Beyond improving understanding of how synergies are recruited during gait, study outcomes may also help identify parameters that can be targeted with interventions to alter synergies and improve motor control following neurological injury.
To praise or to blame? Neural signals predict divergent responses to moral hypocrisy
Authors: Liu Jinting , Yang Jiamiao , Cui Fang
Published: July 2022

Moral hypocrisy is common in society and could be discouraged if observers always respond negatively. Understanding the observers’ responses to moral hypocrisy is critical for promoting genuine morality. This study took the perspective from the observers and compared their behavioral and neural responses to moral hypocrisy versus clear moral/immoral acts. Behaviorally, we found that claiming to help but avoiding the cost of help (i.e., moral hypocrisy) was endorsed as more moral than rejecting to help and even received monetary praise from 40% of observers. Neurally, moral hypocrisy versus clear moral acts elicited reduced responses in the reward system (e.g., ventromedial prefrontal cortex) and increased responses in regions responsible for disgust (e.g., anterior insula). The neural signals together with the interplay to the mentalizing network (e.g., temporoparietal junction) predicted divergent responses, even five months later. Our findings provide behavioral and neural accounts of how hypocrisy is perceived and why it prevails.

Significance Statement

From the perspective of a third-party observer, this study showed that moral hypocrisy is indeed deceptive and induces observers’ divergent responses of praise or blame.

Claiming to help but avoiding the cost of help (i.e., moral hypocrisy) was considered more moral than rejecting to help and even received monetary praise from 40% of observers.

Using fMRI, this study revealed that the divergent behavioral responses to moral hypocrisy could be predicted and classified by the activations of the reward system (e.g., ventromedial prefrontal cortex) and regions responsible for disgust (e.g., anterior insula) as well as the functional connectivity with the mentalizing network (e.g., right temporoparietal junction), even five months later.
A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for HIV-associated tuberculous meningitis (The LASER-TBM Trial)
Authors: Davis Angharad G , Wasserman Sean , Stek Cari , Maxebengula Mpumi , Liang C. Jason , Stegmann Stephani , Koekemoer Sonya , Jackson Amanda , Kadernani Yakub , Bremer Marise , Daroowala Remy , Aziz Saalikha , Goliath Rene , Sai Louise Lai , Sihoyiya Thandi , Denti Paolo , Lai Rachel PJ , Crede Thomas , Naude Jonathan , Szymanski Patryk , Vallie Yakoob , Banderker Ismail Abbas , Moosa Muhammed S , Raubenheimer Peter , Candy Sally , Offiah Curtis , Wahl Gerda , Vorster Isak , Maartens Gary , Black John , Meintjes Graeme , Wilkinson Robert J
Published: July 2022

Background

Drug regimens which include intensified antibiotics alongside effective anti-inflammatory therapies may improve outcomes in Tuberculous Meningitis (TBM). Safety data on their use in combination and in the context of HIV is needed to inform clinical trial design.

Methods

We conducted a phase 2 open-label parallel-design RCT to assess safety of high-dose rifampicin, linezolid and aspirin in HIV-associated TBM. Participants were randomised (1.4:1:1) to three treatment arms (arm 1, standard of care (SOC); arm 2 SOC + additional rifampicin (up to 35mg/kg/day)) + linezolid 1200mg/day reducing after 28/7 to 600mg/day; arm 3, as per arm 2 + aspirin 1000mg/day) for 56 days, when the primary outcome of adverse events of special interest (AESI) or death was assessed.

Results

52 participants were randomised. 59% had mild disease (MRC Grade 1) vs 39% (Grade 2) vs 2% (Grade 3). 33% of participants had microbiologically-confirmed TBM; vs 41% ‘possible’ or 25% ‘probable’. AESI or death occurred in 10/16 (arm 3) vs 4/14 (arm 2) vs 6/20 (arm 1) (p=0.083). The cumulative proportion of AESI or death (Kaplan-Meier method) demonstrated worse outcomes in arm 3 vs arm 1 (p=0.04), however only one event in arm 3 was attributable to aspirin and was mild. There was no difference in efficacy (Modified Rankin Scale) at day 56 between the three arms.

Conclusions

High-dose rifampicin and adjunctive linezolid can safely be added to SOC in HIV-associated TBM. Larger studies are required to evaluate whether potential toxicity associated with these interventions, particularly aspirin, is outweighed by mortality or morbidity benefit.

In this phase 2a randomised control trial we demonstrate that high-doserifampicin and adjunctive linezolid is safe in adult HIV-associated tuberculous meningitis. Larger studies are required to evaluate potential toxicity with aspirin, in relation to benefit on morbidity and mortality.
Prediction of celiac disease associated epitopes and motifs in a protein
Authors: Tomer Ritu , Patiyal Sumeet , Dhall Anjali , Raghava Gajendra P. S.
Published: July 2022

Celiac disease (CD) is an autoimmune gastrointestinal disorder which causes immune-mediated enteropathy against gluten. The gluten immunogenic peptides have the potential to trigger immune responses which leads to damage the small intestine. HLA-DQ2 and HLA-DQ8 are major alleles that bind to epitope/antigenic region of gluten and induce celiac disease. There is a need to identify CD associated epitopes in protein-based foods and therapeutics. In addition, prediction of CD associated epitope/peptide is also required for developing antigen-based immunotherapy against celiac disease. In this study, computational tools have been developed to predict CD associated epitopes and motifs. Dataset used in this study for training, testing and evaluation contain experimentally validated CD associated and non-CD associate peptides. Our analysis support existing hypothesis that proline (P) and glutamine (Q) are highly abundant in CD associated peptides. A model based on density of P&Q in peptides has been developed for predicting CD associated which achieve maximum AUROC 0.98. We discovered CD associated motifs (e.g., QPF, QPQ, PYP) which occurs specifically in CD associated peptides. We also developed machine learning based models using peptide composition and achieved maximum AUROC 0.99. Finally, we developed ensemble method that combines motif-based approach and machine learning based models. The ensemble model-predict CD associated motifs with 100% accuracy on an independent dataset, not used for training. Finally, the best models and motifs has been integrated in a web server and standalone software package “CDpred”. We hope this server anticipate the scientific community for the prediction, designing and scanning of CD associated peptides as well as CD associated motifs in a protein/peptide sequence (https://webs.iiitd.edu.in/raghava/cdpred/).

Key Points

Celiac disease is one of the prominent autoimmune diseases

Gluten immunogenic peptides are responsible for celiac disease

Mapping of celiac disease associated epitopes and motifs on a proteins

Identification of proline and glutamine rich regions

A web server and software package for predicting CD associate peptides

Author’s Biography

Ritu Tomer is currently working as Ph.D. in Computational Biology from Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.

Sumeet Patiyal is currently working as Ph.D. in Computational biology from Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.

Anjali Dhall is currently working as Ph.D. in Computational Biology from Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.

Gajendra P. S. Raghava is currently working as Professor and Head of Department of Computational Biology, Indraprastha Institute of Information Technology, New Delhi, India.
Soil bacterial and fungal communities show within field heterogeneity that varies by land management and distance metric
Authors: Seaton Fiona M. , Griffiths Rob I. , Goodall Tim , Lebron I , Norton Lisa R.
Published: July 2022

Increasing interest in the use of microbial metrics to evaluate soil health raises the issue of how fine-scale heterogeneity can affect microbial community measurements. Here we analyse bacterial and fungal communities of over 100 soil samples across 17 pasture farms and evaluate beta diversity at different scales. We find large variation in microbial communities between different points in the same field, and if Aitchison distance is used we find that within-field variation is as high as between-farm variation. However, if Bray-Curtis or Jaccard distance are used this variation is partially explained by differences in soil pH and vegetation and is higher under mob grazing for fungi. Hence, field scale variation in microbial communities can impact the evaluation of soil health.
Deciphering structural asymmetry of the habenula in the human brain
Authors: Abuduaini Yilamujiang , Pu Yi , Thompson Paul M. , Kong Xiang-Zhen
Published: July 2022

Functional laterality of the habenula has been suggested in both animal models and the humans. Understanding this evolutionarily conserved brain feature is of fundamental importance and has been attracting attention due to its potential role in human cognition and a variety of neuropsychiatric disorders such as depression and schizophrenia. Deciphering structural asymmetry of the human habenula remains to be challenging. Here, we present a large-scale meta-analysis of the left-right differences in the habenular volume in the human brain with 52 datasets (N = 1,427), and also assessed the potential moderating effects of the sampling variability and other methodological factors. Results showed significant heterogeneity in the left-right differences across the datasets, which seems to be mainly due to different MRI scanners and segmentation approaches used. While little evidence was found for the volume asymmetry across all the datasets, the most pronounced and significant leftward asymmetry was found in the datasets from 3 T scanners and when using manual segmentation approaches. We did not find significant disorder-related differences relative to healthy controls in either the left-right asymmetry or the unilateral volume. This study not only provides useful data for future studies of brain imaging and methodological developments related to precision habenula measurements, but also helps to understand potential roles of habenular laterality in health and disorders.
Anticipation of appetitive operant action induces sustained dopamine release in the nucleus accumbens
Authors: Goedhoop Jessica , Arbab Tara , Willuhn Ingo
Published: July 2022

The mesolimbic dopamine system is implicated in signaling reward-related information as well as in actions that generate rewarding outcomes. These implications are commonly investigated in either Pavlovian or operant reinforcement paradigms, where only the latter requires instrumental action. To parse contributions of reward- and action-related information to dopamine signals, we directly compared the two paradigms: rats underwent either Pavlovian or operant conditioning while dopamine release was measured in the nucleus accumbens, a brain region central for processing this information. Task conditions were identical with the exception of the operant-lever response requirement. Rats in both groups released the same quantity of dopamine at the onset of the reward-predictive cue. However, only the operant-conditioning group showed a subsequent, sustained plateau in dopamine concentration throughout the entire five-second cue presentation (preceding the required action). This dopamine “ramp” was unaffected by probabilistic reward delivery, occurred exclusively prior to operant actions, and was not related to task performance or task acquisition, as it persisted throughout the two-week daily behavioral training. Instead, the ramp flexibly increased in duration with longer cue presentation, seemingly modulating the initial cue-onset triggered dopamine release (i.e., the reward-prediction error (RPE) signal), as both signal amplitude and sustain diminished when reward timing was made more predictable. Thus, our findings suggest that RPE and action components of dopamine release can be differentiated temporally into phasic and ramping/sustained signals, respectively, where the latter depends on the former and presumably reflects the anticipation or incentivization of appetitive action, conceptually akin to motivation.

Significance Statement

It is unclear whether the components of dopamine signals that are related to reward-associated information and reward-driven approach behavior can be separated. Most studies investigating the dopamine system utilize either Pavlovian or operant conditioning, which both involve the delivery of reward and necessitate appetitive approach behavior. Thus, used exclusively, neither paradigm can disentangle the contributions of these components to dopamine release. However, by combining both paradigms in the same study, we find that anticipation of a reward-driven operant action induces a modulation of reward-prediction-associated dopamine release, producing so-called “dopamine ramps”. Therefore, our findings provide new insight into dopamine ramps, and suggest that dopamine signals integrate reward and appetitive action in a temporally distinguishable, yet dependent, manner.
Integrated Analysis of T cell Repertoire and Transcriptome Identifies Mechanisms of Regulatory T cell (Treg) Suppression of Acute Graft-versus-Host-Disease
Authors: Lohmeyer Juliane K. , Hirai Toshihito , Turkoz Mustafa , Buhler Stephane , Ramos Teresa Lopes , Köhler Natalie , Baker Jeanette , Ji Xuhuai , Villard Jean , Chalandon Yves , Simonetta Federico , Negrin Robert S.
Published: July 2022

CD4+FOXP3+ regulatory T cells have demonstrated efficacy in graft-versus-host disease (GvHD) prevention and treatment. Preclinical and clinical studies indicate that Treg are able to protect from GvHD without interfering with the graft-versus-tumor (GvT) effect of hematopoietic cell transplantation (HCT), although the underlying molecular mechanisms are largely unknown. To elucidate Treg suppressive function during in vivo suppression of acute GvHD, we performed paired T cell receptor (TCRα, TCRβ genes) repertoire sequencing and RNA sequencing analysis on conventional T cells (Tcon) and Treg before and after transplantation in an MHC major-mismatch mouse model of HCT. We show that both Treg and Tcon underwent clonal restriction and that Treg did not interfere with the activation of alloreactive Tcon clones and the breadth of their TCR repertoire, however, markedly suppressed their expansion. Transcriptomic analysis revealed that Treg predominantly affected the transcriptome of CD4 Tcon and to a lesser extent of CD8 Tcon, modulating the transcription of genes encoding pro- and anti-inflammatory molecules as well as enzymes involved in metabolic processes, inducing a switch from glycolysis to oxidative phosphorylation. Finally, Treg did not interfere with the induction of gene sets involved in the GvT effect. Our results shed light into the mechanisms of acute GvHD suppression by Treg and will support the clinical translation of this immunoregulatory approach.

Key Points

- Regulatory T cells modulate conventional T cells transcriptome during GvHD suppression by affecting several, non-redundant pathways.

- Regulatory T cells undergo activation and clonal expansion during GvHD suppression.
Widespread of horizontal gene transfer events in eukaryotes
Authors: Li Kun , Yan Fazhe , Duan Zhongqu , Adelson David L. , Wei Chaochun
Published: July 2022

Horizontal gene transfer (HGT) is the transfer of genetic material between distantly related organisms. While most genes in prokaryotes can be horizontally transferred, HGT events in eukaryotes are considered as rare, particularly in mammals. Here we reported the identification of HGT regions (HGTs), which are genomic sequence fragments indicating the occurrence of HGT events, in human, mouse, cow, lizard, frog, zebrafish, fruit fly, nematode, Arabidopsis and yeast. By comparing the genomes of these 10 representative eukaryotes with 1,496 eukaryotic genomes, 16,098 bacteria and 11,695 viruses, we found between 10 and 243 non-redundant HGTs per species, and most of these HGTs were previously unknown. These HGTs have transformed their host genomes with various numbers of copies and have impacted hundreds, even thousands of genes. We listed several examples of HGTs and proposed some possible routes that HGT events occurred. Further analysis showed that the majority of the 1,496 eukaryotes with full length genome sequences also contain HGTs. Our findings reveal that HGT is widespread in eukaryotic genomes, and HGT is a ubiquitous driver of genome evolution for eukaryotes.
Modifying the trajectory of epicardial leads can substantially reduce MRI-induced RF heating in pediatric patients with a cardiac implantable electronic device
Authors: Jiang Fuchang , Bhusal Bhumi , Nguyen Bach , Monge Michael , Webster Gregory , Kim Daniel , Bonmassar Giorgio , Popsecu Andrada R. , Golestanirad Laleh
Published: July 2022

Purpose

Infants and children with congenital heart defects, inherited arrhythmia syndromes, and congenital cardiac conduction disorders often receive epicardial implantable electronic devices. Unfortunately, once an epicardial device is implanted, the patient is no longer eligible to receive MRI exams due to an elevated risk of RF heating. Here we show that a simple modification in the trajectory of epicardial leads can substantially and reliably reduce RF heating during MRI at 1.5 T, with benefits extending to abandoned leads.

Methods

Electromagnetic simulations were performed to assess RF heating of two common epicardial lead trajectories exhibiting different degrees of coupling with MRI incident electric fields. Experiments in anthropomorphic phantoms implanted with commercial cardiac implantable electronic devices (CIEDs) confirmed the findings.

Results

Simulations of an epicardial lead with a trajectory where the excess length of the lead was looped and placed on the anterior surface of the heart showed a 9-fold reduction in 0.1g-averaged SAR compared to the lead with excess length looped on the inferior surface of the heart. Repeated experiments with a commercial epicardial device confirmed the results, showing a 16-fold reduction in the average temperature rise for fully implanted systems with leads following low-SAR trajectories, and a 20-fold reduction in RF heating on an abandoned lead.

Conclusion

Surgical modification of epicardial lead trajectory can substantially reduce RF heating at 1.5 T, with benefits extending to abandoned leads.
Antithymocyte globulin inhibits CD8+ T cell effector functions via the paracrine induction of PDL-1 on monocytes
Authors: Copic Dragan , Direder Martin , Klas Katharina , Bormann Daniel , Laggner Maria , Ankersmit Hendrik Jan , Mildner Michael
Published: July 2022

Antithymocyte globulins (ATG) are T cell depleting antibodies used in solid organ transplantation for induction therapy in sensitized patients with high risk of graft rejection. Previously described effects besides depletion of T cells suggest additional modes of action and identified further cellular targets. Here, we examined the transcriptional changes arising in immune cells from human blood after ex vivo stimulation with ATG on a single cell level to uncover additional mechanisms by which ATG regulates T cell activity and effector functions. Analysis of the paracrine factors present in plasma of ATG-treated whole blood revealed high levels of chemokines and cytokines including Interferon-γ (IFN-γ). Furthermore, we identify an increase of surface expression of programmed cell death 1 ligand 1 (PDL-1) on monocytes mediated by the released paracrine factors. In addition, we show that this induction is dependent on activation of JAK/STAT signaling via binding of IFN-γ to Interferon-γ receptor 1 (IFN-γR1). Lastly, we demonstrate that the modulation of the immune-regulatory axis of Programmed cell death protein 1 (PD1) on activated CD8+ T cells with PDL-1 found on monocytes mediated by ATG potently inhibits effector functions including proliferation and granzyme B release of activated T cells. Together our findings represent a novel mode of action by which ATG exerts its immunosuppressive effects.

One Sentence Summary

ATG increases PDL-1 on CD14+-monocytes and inhibits T cell effector functions.
Long Noncoding RNA MALAT1 is Dynamically Regulated in Leader Cells during Collective Cancer Invasion
Authors: Zhu Ninghao , Ahmed Mona , Liao Joseph C. , Wong Pak Kin
Published: July 2022

Cancer cells invade collectively with leader-follower organization. However, how leader cells are regulated during the dynamic invasion process remains poorly understood. Using a FRET nanobiosensor that tracks lncRNA dynamics in live single cells, we monitored the spatiotemporal distribution of lncRNA during collective cancer invasion. We show that lncRNA MALAT1 is dynamically regulated in the invading fronts of cancer cells and patient-derived organoids. The abundance, diffusivity, and distribution of MALAT1 transcripts are distinct between leader and follower cells. MALAT1 expression increases when a cell acquires the leader cell role and decreases when the migration process stops. Transient knockdown of MALAT1 prevents the formation of leader cells and abolishes the migration of cancer cells. Taken together, our single cell analysis suggests MALAT1 dynamically regulates leader cells during collective cancer invasion.
ADOLESCENT EXPOSURE TO LOW-DOSE THC DISRUPTS ENERGY BALANCE AND ADIPOSE ORGAN HOMEOSTASIS IN ADULTHOOD
Authors: Lin Lin , Jung Kwang-Mook , Le Johnny , Colleluori Georgia , Wood Courtney , Lee Hye-Lim , Palese Francesca , Squire Erica , Su Shiqi , Torrens Alexa , Fotio Yannick , Tang Lingyi , Yu Clinton , Yang Qin , Huang Lan , DiPatrizio Nicholas , Jang Cholsoon , Cinti Saverio , Piomelli Daniele
Published: July 2022

One of cannabis’ most iconic effects is the stimulation of hedonic high-calorie eating – the ‘munchies’ – yet habitual cannabis users are on average leaner than non-users. We asked whether this unexpected phenotype might result from lasting changes in energy balance established during adolescence, when habitual use of the drug often begins. We found that daily low-dose administration of cannabis’ intoxicating constituent, Δ9-tetrahydrocannabinol (THC), to adolescent mice causes an adult metabolic phenotype characterized by reduced fat mass, increased lean mass and utilization of fat as fuel, partial resistance to diet-induced obesity and dyslipidemia, and enhanced thermogenesis. Multi-omics analyses revealed that this phenotype is associated with multiple molecular anomalies in the adipose organ, which include ectopic overexpression of muscle-associated proteins and heightened anabolic processing. Thus, adolescent exposure to THC may promote an enduring ‘pseudo-lean’ state that superficially resembles healthy leanness but might in fact be rooted in adipose organ dysfunction.
Individual differences in oxycodone addiction-like behaviors in a large cohort of heterogeneous stock (HS) rats
Authors: Kallupi Marsida , de Guglielmo Giordano , Carrette Lieselot LG , Simpson Sierra , Kononoff Jenni , Kimbrough Adam , Smith Lauren C , Shankar Kokila , Avelar Alicia , Conlisk Dana , Brennan Molly , Tieu Lani , Sedighim Sharona , Boomhower Brent , Maturin Lisa , Fannon McKenzie J , Martinez Angelica , Crook Caitlin , Dirik Selen , Velarde Nathan , Schweitzer Paul , Bonnet-Zahedi Selene , Othman Dyar N. , Sichel Benjamin , Guess Kwynn , Peng Beverly , Hu Andrew S. , Chun Lucas E. , Milan Kristel , Lau Justin , Zheng Yicen , Vang Ashley , Solberg Woods Leah C. , Palmer Abraham A. , George Olivier
Published: July 2022

Family and twin studies demonstrate that genetic factors determine 20-60% of the vulnerability to opioid use disorder. However, the genes/alleles that mediate the risk of developing addiction-related behaviors, including the sensitivity to the analgesic efficacy of opioids, the development of tolerance, dependence, and escalation of oxycodone taking and seeking, have been ill-defined, thus hindering efforts to design pharmacological interventions to enable precision medicine strategies. Here we characterized oxycodone addiction-like behaviors in heterogeneous stock (HS) rats, that show high genetic diversity that mimics the high genetic variability in humans. HS rats were allowed to self-administer oxycodone for two h/daily for four days (ShA) and then moved to 12h/daily (LgA) for 14 days. Animals were screened for motivation to self-administer oxycodone using a progressive-ratio (PR) schedule of reinforcement and for the development of withdrawal-induced hyperalgesia and tolerance to the analgesic effects of oxycodone using the von-Frey and tail immersion tests, respectively. To reduce cohort-specific effects, we used cohorts of 46-60 rats and normalized the response level within cohorts using a Z-score. To take advantage of the four opioid-related behaviors and further identify subjects that are consistently vulnerable vs. resilient to compulsive oxycodone use, we computed an Addiction Index by averaging normalized responding (Z-scores) for the four behavioral tests. Results showed high individual variability between vulnerable and resilient rats, likely to facilitate the detection of gene variants associated with vulnerable vs. resilient individuals. Such data will have considerable translational value for designing follow-up studies in humans.
Enhanced Single RNA Imaging Reveals Dynamic Gene Expression in Live Animals
Authors: Hu Yucen , Xu Jingxiu , Gao Erqing , Fan Xueyuan , Wei Jieli , Xu Suhong , Ma Weirui
Published: July 2022

Imaging endogenous mRNAs in live animals is technically challenging. Here we describe an MS2 based signal Amplification with Suntag System that enables live-cell RNA imaging of high temporal resolution and with 8xMS2 stem-loops, which overcomes the obstacle of inserting a 1,300 nt 24xMS2 into the genome for the imaging of endogenous mRNAs. Using this tool we were able to image the activation of gene expression and the dynamics of endogenous mRNAs in the epidermis of live C. elegans.
Tumor landscape of epithelial ovarian cancer highlights that EGR1 drives tumor invasion at single-cell resolution
Authors: Zhang Yuanfu , Sun Shu , Qi Yue , Dai Yifan , Hao Yangyang , Xin Mengyu , Xu Rongji , Chen Hongyan , Wu Xiaoting , Liu Qian , Kong Congcong , Zhang Guangmei , Wang Peng , Guo Qiuyan
Published: July 2022

Identifying underlying molecular mechanisms and biomarkers of epithelial ovarian carcinoma (EOC) proliferation and metastasis remains challenging. Patients of EOC are usually diagnosed at an advanced stage and the availability of invasion-related targets is limited. Herein, we explored the single-cell RNA sequencing (scRNA-seq) dataset of EOC and defined tumor physiological reprograming compared to bulk RNA-seq. The energy metabolism and anti-apoptotic pathway was found as critical contributors to intratumor heterogeneity. Moreover, hypoxia, oxidative phosphorylation (OXPHOS) and glycolysis were positively correlated, which have biologically activity trajectories during epithelial mesenchymal transition (EMT). The HMGH1, EGR1 and RUNX1 were found to be critical inducers of the EMT process in EOC. Experimental validation revealed that suppressed EGR1 decreased the expression of FAS and HSPG2 and associating with EMT progression in EOC. In tumor microenvironment (TME), CAFs were found have significant contribution to tumor immune infiltration and metastasis and accumulation of CAFs was associated with poorer patient survival. In conclusion, physiological features and molecular mechanisms in the TME of EOC were revealed and provided effective targets for the suppression of tumor metastasis.
Cryptochrome-Timeless structure reveals circadian clock timing mechanisms
Authors: Lin Changfan , Feng Shi , DeOliveira Cristina C. , Crane Brian R.
Published: July 2022

Circadian rhythms influence many behaviors and diseases1, 2. They arise from oscillations in gene expression caused by repressor proteins that directly inhibit transcription of their own genes. The fly circadian clock offers a valuable model for studying these processes, wherein Timeless (TIM) plays a critical role in mediating nuclear entry of the transcriptional repressor Period (PER) and the photoreceptor Cryptochrome (CRY) entrains the clock by triggering TIM degradation in light2, 3. The cryo-EM structure of the CRY:TIM complex reveals how a light-sensing cryptochrome recognizes its target. CRY engages a continuous core of N-terminal TIM armadillo (ARM) repeats, resembling how photolyases recognize damaged DNA, and binds a C-terminal TIM helix reminiscent of the interactions between light-insensitive CRYs and their partners in mammals. The structure highlights how the CRY flavin cofactor undergoes conformational changes that couple to large-scale rearrangements at the molecular interface, and how a phosphorylated segment in TIM may impact clock period by regulating the binding of importin-α and the nuclear import of TIM:PER4, 5. Moreover, the structure reveals that the TIM N-terminus inserts into the restructured CRY pocket to replace the autoinhibitory C-terminal tail released by light, thereby providing a possible explanation for how the LS-TIM polymorphism adapts flies to different climates6, 7.
Neural contributions to reduced fluid intelligence across the adult lifespan
Authors: Mitchell Daniel J. , Mousley Alexa L. S. , Shafto Meredith A. , Cam-CAN  , Duncan John
Published: July 2022

Fluid intelligence – the ability to solve novel, complex problems – declines steeply during healthy human aging. Using functional magnetic resonance imaging (fMRI), fluid intelligence has been repeatedly associated with activation of a frontoparietal brain network, and focal damage to these regions suggests that fluid intelligence depends on their integrity. It is therefore possible that age-related functional differences in frontoparietal activity contribute to the reduction in fluid intelligence. This paper reports on analysis of the Cambridge Centre for Ageing and Neuroscience (Cam-CAN) data, a large, population-based, healthy, adult lifespan cohort. The data support a model in which age-related differences in fluid intelligence are partially mediated by the responsiveness of frontoparietal regions to novel problem-solving. We first replicate a prior finding of such mediation using an independent sample. We then precisely localise the mediating brain regions, and show that mediation is specifically associated with voxels most activated by cognitive demand, but not with voxels suppressed by cognitive demand. We quantify the robustness of this result to potential unmodelled confounders, and estimate the causal direction of the effects. Finally, exploratory analyses suggest that neural mediation of age-related differences in fluid intelligence is moderated by the variety of regular physical activities, more reliably than by their frequency or duration. An additional moderating role of the variety of non-physical activities emerged when controlling for head motion. A better understanding of the mechanisms that link healthy aging with lower fluid intelligence may suggest strategies for mitigating such decline.

Significance Statement

Global populations are living longer, driving urgency to understand age-related cognitive declines. Fluid intelligence is of prime importance, because it reflects performance across many domains, and declines especially steeply during healthy aging. Despite consensus that fluid intelligence is associated with particular frontoparietal brain regions, little research has investigated suggestions that under-responsiveness of these regions mediates age-related decline. We replicate a recent demonstration of such mediation, showing specific association with brain regions most activated by cognitive demand, and robustness to moderate confounding by unmodelled variables. By showing that this mediation model is moderated by the variety of regular physical activities, more reliably than by their frequency or duration, we identify a potential modifiable lifestyle factor that may help promote successful aging.
Galectin-8 is a major ligand of LILRB4 prompting MDSC functions in the tumor microenvironment
Authors: Wang Yiting , Sun Yufan , Deng Shouyan , Song Teng , Wang Yungang , Xu Jie
Published: July 2022

The LILRB4 myeloid receptor has been implicated in an immunosuppressive microenvironment, with specific antibodies under preclinical or clinical development for tumor immunotherapy. However, it remains largely unknown which natural ligand may trigger LILRB4 to expand myeloid derived suppressive cells (MDSC), and the relevant downstream signaling pathways are also under debate. Here we show that Galectin-8 is a high-affinity functional ligand of LILRB4, and its ligation induces MDSC by activating STAT3 as well as inhibiting NF-κB. Importantly, Galectin-8 but not APOE could induce MDSC, and both ligands bind LILRB4 in a non-competitive manner. Antibodies recognizing a defined epitope on LILRB4 could efficiently block Galectin-8 binding and neutralize its effects on MDSC induction and relevant signaling pathways. Galectin-8 expression promoted B16 tumor growth in mice, and knockout of LILRB4 attenuated tumor growth in this context. The LILRB4-specific Galectin-8 blocking antibody efficiently suppressed MDSC expansion and tumor growthin vivo. These results identify Galectin-8 as a functionally important ligand of LILRB4, highlighting the blockade of LILRB4-Galectin-8 interaction as a promising strategy for cancer immunotherapy.
Conserved and transcript-specific functions of the RESC factors, RESC13 and RESC14, in kinetoplastid RNA editing
Authors: Sortino Katherine , Tylec Brianna L. , Chen Runpu , Sun Yijun , Read Laurie K.
Published: July 2022

Uridine insertion/deletion RNA editing is an extensive post-transcriptional modification of mitochondrial mRNAs in kinetoplastid organisms, includingTrypanosoma brucei. This process is carried out usingtrans-acting gRNAs and complex protein machinery. The essential RNA Editing Substrate Binding Complex (RESC) serves as the scaffold that modulates protein and RNA interactions during editing, and contains the Guide RNA Binding Complex (GRBC), the RNA Editing Mediator Complexes (REMCs), and organizer proteins. Despite the importance of RESC in editing, the functions of each protein comprising this complex are not completely understood. Here, we further define the roles of a REMC protein, RESC13, and a RESC organizer, RESC14, using high-throughput sequencing on two large pan-edited mRNAs, A6 and COIII. When comparing our analyses to that of a previously published small pan-edited mRNA, RPS12, we find that RESC13 has conserved functions across the three transcripts with regards to editing initiation, gRNA utilization, gRNA exchange, and restricting the formation of long mis-edited junctions that likely arise from its ability to modulate RNA structure. However, RESC13 does have transcript-specific effects on the types of long junctions whose formation it restricts. RESC14 has a conserved effect on gRNA utilization across the three transcripts analyzed, but has transcript-specific effects on editing initiation, gRNA exchange, and junction formation. Our data suggest that transcript-specific effects of both proteins are due to differences in transcript length and sequences as well as transcript-specific protein interactions. These findings highlight the importance of studying multiple transcripts to determine the function of editing factors.
Calculating temperature-dependent X-ray structure factors of α-quartz with an extensible Python 3 package
Authors: Sutter John P. , Pittard James , Filik Jacob , Baron Alfred Q. R.
Published: July 2022

The design of X-ray optics based on diffraction from crystals depends on the accurate calculation of the structure factors of their Bragg reflections over a wide range of temperatures. In general, the temperature dependence of the lattice parameters, the atomic positions and the atomic thermal vibrations is both anisotropic and nonlinear. Implemented here is a software package for precise and flexible calculation of structure factors for dynamical diffraction. α-Quartz is used as an example because it presents the challenges mentioned above and because it is being considered for use in high-resolution X-ray spectroscopy. The package is designed to be extended easily to other crystals by adding new material files, which are kept separate from the package's stable core. Python 3 was chosen as the language to allow the easy integration of this code into existing packages. The importance of a correct anisotropic treatment of the atomic thermal vibrations is demonstrated by comparison with an isotropic Debye model. Discrepancies between the two models can be as much as 5% for strong reflections and considerably larger (even to the level of 100%) for weak reflections. A script for finding Bragg reflections that backscatter X-rays of a given energy within a given temperature range is demonstrated. The package and example scripts are available on request. Also discussed, in detail, are the various conventions related to the proper description of chiral quartz.
A semi-supervised deep-learning approach for automatic crystal structure classification
Authors: Lolla Satvik , Liang Haotong , Kusne A. Gilad , Takeuchi Ichiro , Ratcliff William
Published: July 2022

The structural solution problem can be a daunting and time-consuming task. Especially in the presence of impurity phases, current methods, such as indexing, become more unstable. In this work, the novel approach of semi-supervised learning is applied towards the problem of identifying the Bravais lattice and the space group of inorganic crystals. The reported semi-supervised generative deep-learning model can train on both labeled data, i.e. diffraction patterns with the associated crystal structure, and unlabeled data, i.e. diffraction patterns that lack this information. This approach allows the models to take advantage of the troves of unlabeled data that current supervised learning approaches cannot, which should result in models that can more accurately generalize to real data. In this work, powder diffraction patterns are classified into all 14 Bravais lattices and 144 space groups (the number is limited due to sparse coverage in crystal structure databases), which covers more crystal classes than other studies. The reported models also outperform current deep-learning approaches for both space group and Bravais lattice classification using fewer training data.
Crystallographic phase retrieval method for liquid crystal bicontinuous phases: indicator-based method
Authors: Oka Toshihiko
Published: July 2022

An indicator-based crystallographic phase retrieval method has been developed for diffraction data of bicontinuous cubic phases of lyotropic liquid crystals. Such liquid crystals have large structural disorder; the number of independent Bragg reflections that can be observed is limited. This paper proposes two indicators to identify plausible combination(s) of crystallographic phases, i.e. electron-density distribution. The indicators are based on the characteristics of the liquid crystals: amphiphilic molecules diffuse mainly in the direction parallel to polar–nonpolar interfaces and the electron density in the direction parallel to the interfaces is averaged. One indicator is the difference between the maximum and minimum electron density, and the other is calculated from the Hessian matrix of the electron density. Using test data, the electron densities were calculated for all possible phase combinations and indicators were obtained. The results indicated that the electron densities with the minimum indicators were close to the true electron density. Therefore, this method is effective for phase retrieval. The accuracy of the phase retrieval decreased when the volume fraction of the region including the triply periodic minimal surface increased.
Advancing right to health considerations in national responses against health sector corruption: the case for action
Authors: Alexiadou Elisavet Athanasia
Published: July 2022

Purpose

Health sector corruption constitutes a pervasive challenge and a major obstacle to the equitable enjoyment of the right to health by exacerbating health inequalities within societies, while often eroding public trust primarily amid public health crises that threaten human security. The purpose of this paper is to examine the value of advancing right to health considerations in national legislative and regulatory responses against health sector corruption.

Design/methodology/approach

This paper builds on existing evidence, with focusing attention on international standards that are relevant to the topic under discussion. The literature research included publicly available reports, peer-reviewed studies and other documents primarily of human rights bodies at the United Nations level.

Findings

Advancing right to health considerations in national responses against health sector corruption offers comprehensive guidance for the deployment of a strong regulatory anti-corruption framework for action by the governments as part of their health rights obligations. Essentially, the implementation of such a national framework for action, encompassing accountability, participatory decision-making and transparency, constitutes a necessary and an important step towards maintaining well-functioning health systems and a robust social pressure for continued political commitment with the ultimate goal the provision of equitable access to quality health services at all times.

Originality/value

By using a rights-based approach, the paper identifies a national framework for state action consisting of legal obligations and tools towards guiding governments, while at the same time empowering civil society groups to demand the implementation of core human rights principles of transparency, participation and accountability within health system governance. It provides insights for the future development, reinforcement and/or reform of national law, policies and practices towards minimizing and eradicating vulnerabilities to health sector corruption.