Miracle-dz/UniFAR-FTUs huggingface dataset:
Individual-Specific Areal-Level Parcellations Improve Functional Connectivity Prediction of Behavior

Resting-state functional MRI (rs-fMRI) allows estimation of individual-specific cortical parcellations. We have previously developed a multi-session hierarchical Bayesian model (MS-HBM) for estimating high-quality individual-specific network-level parcellations. Here, we extend the model to estimate individual-specific areal-level parcellations. While network-level parcellations comprise spatially distributed networks spanning the cortex, the consensus is that areal-level parcels should be spatially localized, i.e., should not span multiple lobes. There is disagreement about whether areal-level parcels should be strictly contiguous or comprise multiple non-contiguous components, therefore we considered three areal-level MS-HBM variants spanning these range of possibilities. Individual-specific MS-HBM parcellations estimated using 10min of data generalized better than other approaches using 150min of data to out-of-sample rs-fMRI and task-fMRI from the same individuals. Resting-state functional connectivity (RSFC) derived from MS-HBM parcellations also achieved the best behavioral prediction performance. Among the three MS-HBM variants, the strictly contiguous MS-HBM (cMS-HBM) exhibited the best resting-state homogeneity and most uniform within-parcel task activation. In terms of behavioral prediction, the gradient-infused MS-HBM (gMS-HBM) was numerically the best, but differences among MS-HBM variants were not statistically significant. Overall, these results suggest that areal-level MS-HBMs can capture behaviorally meaningful individual-specific parcellation features beyond group-level parcellations. Multi-resolution trained models and parcellations are publicly available (https://github.com/ThomasYeoLab/CBIG/tree/master/stable_projects/brain_parcellation/Kong2022_ArealMSHBM).
The impact of Spike mutations on SARS-CoV-2 neutralization

Multiple SARS-CoV-2 vaccines have shown protective efficacy, which is most likely mediated by neutralizing antibodies recognizing the viral entry protein, Spike. Antibodies from SARS-CoV-2 infection neutralize the virus by focused targeting of Spike and there is limited serum cross-neutralization of the closely-related SARS-CoV. As new SARS-CoV-2 variants are rapidly emerging, exemplified by the B.1. 1.7, 501Y.V2 and P.1 lineages, it is critical to understand if antibody responses induced by infection with the original SARS-CoV-2 virus or the current vaccines will remain effective against virus variants. In this study we evaluate neutralization of a series of mutated Spike pseudotypes including a B.1. 1.7 Spike pseudotype. The analyses of a panel of Spike-specific monoclonal antibodies revealed that the neutralizing activity of some antibodies was dramatically reduced by Spike mutations. In contrast, polyclonal antibodies in the serum of patients infected in early 2020 remained active against most mutated Spike pseudotypes. The majority of serum samples were equally able to neutralize the B.1. 1.7 Spike pseudotype, however potency was reduced in a small number of samples (3 of 36) by 5–10-fold. This work highlights that changes in the SARS-CoV-2 Spike can alter neutralization sensitivity and underlines the need for effective real-time monitoring of emerging mutations and their impact on vaccine efficacy.
Cynandione A Alleviates Neuropathic Pain Through α7-nAChR-Dependent IL-10/β-Endorphin Signaling Complexes

Cynandione A, an acetophenone isolated from Cynanchum Wilfordii Radix, exhibits antineuropathic pain effect. This study further explored the target molecule and signaling mechanisms underlying cynandione-A-induced antineuropathic pain. Intrathecal injection of cynandione A significantly attenuated mechanical allodynia in neuropathic rats and substantially increased spinal expression of IL-10 and β-endorphin but not dynorphin A. Cynandione A treatment also enhanced expression of IL-10 and β-endorphin but not α7 nicotinic acetylcholine receptors (nAChRs) in cultured microglia. The IL-10 antibody attenuated cynandione-A-induced spinal or microglial gene expression of β-endorphin and mechanical allodynia, whereas the β-endorphin antiserum blocked cynandione-A-induced mechanical antiallodynia but not spinal or microglial IL-10 gene expression. The α7 nAChR antagonist methyllycaconitine significantly reduced cynandione-A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. Furthermore, cynandione A stimulated microglial phosphorylation of PKA, p38, and CREB in an α7-nAChR-dependent manner, and treatment with their inhibitors attenuated cynandione-A-induced mechanical antiallodynia and spinal or microglial expression of IL-10 and β-endorphin. In addition, cynandione A stimulated spinal phosphorylation of the transcription factor STAT3, which was inhibited by methyllycaconitine, the PKA activation inhibitor or IL-10 antibody. The STAT3 inhibitor NSC74859 also abolished cynandione-A-induced mechanical antiallodynia and spinal expression of β-endorphin. These findings suggest that cynandione A suppresses neuropathic pain through α7-nAChR-dependent IL-10/β-endorphin signaling pathway in spinal microglia.
Low photorespiratory capacity is sufficient to block the induction of high photosynthetic capacity in high light

The induction of high photosynthetic capacity (i.e., the CO2− and light-saturated maximum photosynthetic rate) in HL is a shared response among many herbaceous dicot plants. The increase in photosynthetic capacity following a shift to growth in high light (HL) was measured across a large panel of Arabidopsis thaliana ecotypes revealing substantial ecotypic variation in photosynthetic capacity acclimation to HL. Metabolomic data quantified during the HL shift for a strongly acclimating ecotype and a weakly acclimating ecotype identified differences between the ecotypes in primary nitrogen (N) assimilation, photorespiration, and triose-phosphate utilization pathways after the HL shift. Based on these results, rates of N assimilation and photorespiration were measured using metabolic indicators for these pathways across the full ecotype panel. N assimilation and photorespiration rates early in the HL shift were found to positively correlate with the magnitude of induction of photosynthetic capacity later in HL shift. Shifting ecotypes into HL growth conditions under non-photorespiratory conditions was sufficient to convert non-acclimating ecotypes and also photorespiratory mutants into strongly acclimating ecotypes. This work supports a model where high photorespiratory capacity, and thus the ability to maintain high photorespiration rates, prevents a negative photorespiration-dependent signal that blocks the induction of high photosynthetic capacity in HL.
Hinge Influences in Murine IgG Binding to Cryptococcus neoformans Capsule

Decades of studies on antibody structure led to the tenet that the V region binds antigens while the C region interacts with immune effectors. In some antibodies, however, the C region affects affinity and/or specificity for the antigen. One such case is that of the 3E5 antibodies, a family of monoclonal murine IgGs in which the mIgG3 isotype has different fine specificity to the Cryptococcus neoformans capsule polysaccharide than the other mIgG isotypes. Our group serendipitously found another pair of mIgG1/mIgG3 antibodies based on the 2H1 hybridoma to the C. neoformans capsule that recapitulated the differences observed with 3E5. In this work, we report the molecular basis of the constant domain effects on antigen binding using recombinant antibodies. As with 3E5, immunofluorescence experiments show a punctate pattern for 2H1-mIgG3 and an annular pattern for 2H1-mIgG1. Also as observed with 3E5, 2H1-mIgG3 bound on ELISA to both acetylated and non-acetylated capsular polysaccharide, whereas 2H1-mIgG1 only bound well to the acetylated form, consistent with differences in fine specificity. In engineering hybrid mIgG1/mIgG3 antibodies, we found that switching the 2H1-mIgG3 hinge for its mIgG1 counterpart changed the immunofluorescence pattern to annular, but a 2H1-mIgG1 antibody with a mIgG3 hinge still had an annular pattern. The hinge is thus necessary but not sufficient for these changes in binding to the antigen. This important role for the constant region in binding of antibodies to the antigen could affect the design of therapeutic antibodies and our understanding of their function in immunity. Key points Key point 1- 2H1 antibodies recapitulate differences between mIgG isotypes observed with 3E5. Key point 2 – The hinge region is necessary but not sufficient for these differences. Key point 3 - The antibody constant region can also play a role in mIgG binding to antigen.
Universal DNA Methylation Age Across Mammalian Tissues

Aging is often perceived as a degenerative process resulting from random accrual of cellular damage over time. Despite this, age can be accurately estimated by epigenetic clocks based on DNA methylation profiles from almost any tissue of the body. Since such pan-tissue epigenetic clocks have been successfully developed for several different species, we hypothesized that one can build pan-mammalian clocks that measure age in all mammalian species. To address this, we generated data using 11,754 methylation arrays, each profiling up to 36 thousand cytosines in highly-conserved stretches of DNA, from 59 tissue-types derived from 185 mammalian species. From these methylation profiles, we constructed three age predictors, each with a single mathematical formula, termed universal pan-mammalian clocks that are accurate in estimating the age (r>0.96) of any mammalian tissue. Deviations between epigenetic age and chronological age relate to mortality risk in humans, mutations that affect the somatotropic axis in mice, and caloric restriction. We characterized specific cytosines, whose methylation levels change with age across most mammalian species. These cytosines are greatly enriched in polycomb repressive complex 2-binding sites, are located in regions that gradually lose chromatin accessibility with age and are proximal to genes that play a role in mammalian development, cancer, human obesity, and human longevity. Collectively, these results support the notion that aging is indeed evolutionarily conserved and coupled to developmental processes across all mammalian species - a notion that was long-debated without the benefit of this new compelling evidence. SUMMARY This study identifies and characterizes evolutionarily conserved cytosines implicated in the aging process across mammals and establishes pan mammalian epigenetic clocks.
Decreased cell stiffness facilitates cell detachment and cell migration from breast cancer spheroids in 3D collagen matrices of different rigidity

Tumour-cell detachment is a critical early event in the metastatic cascade. Although several mechanisms have been reported, the role of cell mechanical properties in facilitating cell detachment and migration is not well understood. We, therefore, investigated how cells alter intracellular stiffness during these processes.MDA-MB-231 cells were embedded as 10,000-cell spheroids in 2 and 4 mg/ml collagen matrices. Using mitochondrial-based particle tracking microrheology (PTM), the intracellular stiffness of cells that have migrated different distances from the spheroid were assessed. Here, 0dC, 4dC and 6dC represented no, medium and high migration, respectively.For 2 and 4 mg/ml collagen matrices, the MSD and cell stiffness of 0dC cells were larger than for migrated 4dC and 6dC cells. The MSD of 4dC and 6dC cells were similar; however, the cell stiffness of 4dC cells was smaller than that of 6dC cells. The stiffness of 0dC cells was lower for higher matrix concentration and rigidity compared to lower matrix rigidity, whereas matrix rigidity did not affect the stiffness of 4dC and 6dC cells.PTM was capable of quantifying intracellular mechanics during tumour detachment and migration in 3D environments. Based on our findings, it is proposed that decreased cell stiffness drives cellular detachment and migration. Increased matrix rigidity physically hinders migration and cells need to either soften or remodel the environment to migrate. The finding that matrix rigidity did not affect the stiffness of migrated cells suggests that cells facilitate migration by remodelling their environment through cleavage of matrix proteins.
The Acetylcholine-Activated Potassium Current Inhibitor XAF-1407 Terminates Persistent Atrial Fibrillation in Goats

Aims: The acetylcholine-activated inward rectifier potassium current (IKACh) has been proposed as an atrial-selective target for the treatment of atrial fibrillation (AF). Using a novel selective IKACh inhibitor XAF-1407, the study investigates the effect of IKACh inhibition in goats with pacing-induced, short-term AF. Methods: Ten goats (57 ± 5 kg) were instrumented with pericardial electrodes. Electrophysiological parameters were assessed at baseline and during intravenous infusion of XAF-1407 (0.3, 3.0 mg/kg) in conscious animals before and after 2 days of electrically induced AF. Following a further 2 weeks of sustained AF, cardioversion was attempted with either XAF-1407 (0.3 followed by 3 mg/kg) or with vernakalant (3.7 followed by 4.5 mg/kg), an antiarrhythmic drug that inhibits the fast sodium current and several potassium currents. During a final open chest experiment, 249 unipolar electrograms were recorded on each atrium to construct activation patterns and AF cardioversion was attempted with XAF-1407. Results: XAF-1407 prolonged atrial effective refractory period by 36 ms (45%) and 71 ms (87%) (0.3 and 3.0 mg/kg, respectively; pacing cycle length 400 ms, 2 days of AF-induced remodeling) and showed higher cardioversion efficacy than vernakalant (8/9 vs. 5/9). XAF-1407 caused a minor decrease in the number of waves per AF cycle in the last seconds prior to cardioversion. Administration of XAF-1407 was associated with a modest increase in QTc (<10%). No ventricular proarrhythmic events were observed. Conclusion: XAF-1407 showed an antiarrhythmic effect in a goat model of AF. The study indicates that IKACh represents an interesting therapeutic target for treatment of AF. To assess the efficacy of XAF-1407 in later time points of AF-induced remodeling, follow-up studies with longer period of AF maintenance would be necessary.
MicroRNA-30e-5p Regulates SOCS1 and SOCS3 During Bacterial Infection

Host innate immunity is the major player against continuous microbial infection. Various pathogenic bacteria adopt the strategies to evade the immunity and show resistance toward the various established therapies. Despite the advent of many antibiotics for bacterial infections, there is a substantial need for the host-directed therapies (HDTs) to combat the infection. HDTs are recently being adopted to be useful in eradicating intracellular bacterial infection. Changing the innate immune responses of the host cells alters pathogen’s ability to reside inside the cell. MicroRNAs are the small non-coding endogenous molecules and post-transcriptional regulators to target the 3’UTR of the messenger RNA. They are reported to modulate the host’s immune responses during bacterial infections. Exploiting microRNAs as a therapeutic candidate in HDTs upon bacterial infection is still in its infancy. Here, initially, we re-analyzed the publicly available transcriptomic dataset of macrophages, infected with different pathogenic bacteria and identified significant genes and microRNAs common to the differential infections. We thus identified and miR-30e-5p, to be upregulated in different bacterial infections which enhances innate immunity to combat bacterial replication by targeting key negative regulators such as SOCS1 and SOCS3 of innate immune signaling pathways. Therefore, we propose miR-30e-5p as one of the potential candidates to be considered for additional clinical validation toward HDTs.
Calming the Storm: Natural Immunosuppressants as Adjuvants to Target the Cytokine Storm in COVID-19

The COVID-19 pandemic has caused a global health crisis, with no specific antiviral to treat the infection and the absence of a suitable vaccine to prevent it. While some individuals contracting the SARS-CoV-2 infection exhibit a well coordinated immune response and recover, others display a dysfunctional immune response leading to serious complications including ARDS, sepsis, MOF; associated with morbidity and mortality. Studies revealed that in patients with a dysfunctional immune response, there is a massive cytokine and chemokine release, referred to as the ‘cytokine storm’. As a result, such patients exhibit higher levels of pro-inflammatory/modulatory cytokines and chemokines like TNFα, INFγ, IL-1β, IL-2, IL-4, IL-6, IL-7, IL-9, IL-10, IL-12, IL-13, IL-17, G-CSF, GM-CSF, MCSF, HGF and chemokines CXCL8, MCP1, IP10, MIP1α and MIP1β. Targeting this cytokine storm is a novel, promising treatment strategy to alleviate this excess influx of cytokines observed at the site of infection and their subsequent disastrous consequences. Natural immunosuppressant compounds, derived from plant sources like curcumin, luteolin, piperine, resveratrol are known to inhibit the production and release of pro-inflammatory cytokines and chemokines. This inhibitory effect is mediated by altering signal pathways like NF-κB, JAK/STAT, MAPK/ERK that are involved in the production and release of cytokines and chemokines. The use of these natural immunosuppressants as adjuvants to ameliorate the cytokine storm; in combination with antiviral agents and other treatment drugs currently in use presents a novel, synergistic approach for the treatment and effective cure of COVID-19. This review briefly describes the immunopathogenesis of the cytokine storm observed in SARS-CoV-2 infection and details some natural immunosuppressants that can be used as adjuvants in treating COVID-19 disease.
The Relationship Between the Implementation of Statutory Preventative Measures, Perceived Susceptibility of COVID-19, and Personality Traits in the Initial Stage of Corona-Related Lockdown: A German and Austrian Population Online Survey

Background: Particularly during the early and middle stages of the COVID-19 pandemic, a population's compliance with precautionary measures (e.g., hygiene rules, smart working, travel restrictions, and quarantine) is paramount in preventing the virus from spreading. Objective: The investigation and documentation of different socio-demographic and personality-specific factors in regards to preventative measures and consequent specific health behaviors during the COVID-19 pandemic, based on the Health Belief Model. Method: An online survey was conducted on N = 3,006 individuals living in Germany and Austria during the early stages of lockdown. The questionnaire consisted of a self-administered section, exploring the dimensions posited in the Health Belief Model: perceived severity, perceived susceptibility, perceived barriers, perceived benefits of health-promoting measures, and engagement in health-promoting behaviors. Additionally, the following standardized scales were used to record personality determinants: the Stress Coping Style Questionnaire SVF 78 to evaluate coping and processing strategies in stressful circumstances, the Positive and Negative Affect Schedule (PANAS) to assess the emotional state induced by the coronavirus crisis, the UI-18 scale to diagnose the intolerance of uncertainty, and the State-Trait Anxiety Inventory (STAI) to assess anxiety. Results: In line with the Health Belief model, four groups were created based on perceived susceptibility and engagement in health-promoting behaviors, and consequently studied in relation to personality determinants. Those four groups differed significantly in regards to almost all personality dimensions (p ≤ 0.005). Group 1 (n = 450) shows a reduced engagement with protective measures and displays underestimation of the COVID-19-pandemic. Group 2 (n = 984) displays many positive personality variables and high compliance with protective measures. Group 3 (n = 468) perceives the subjective risk of disease as high, but high emotional discomfort and stress caused by the protective measures leads to the activation of a complex fear defense. Group 4 (n = 1,004) is highly anxious and therefore compliant. Conclusion: This typification has implications for establishing the appropriate support systems. This is particularly important to encourage compliance with preventive regulations within the groups, which showed poor abidance for several reasons. For Group 1, further education on the realistic threat and efficient protective measures is as central as the fostering of empathy for others; with its resource-conscious exemplary behavior Group 2 could be used as a positive social role model. Group 3 would benefit from promoting self-care, while Group 4 requires information on psychosocial assistance availability in order to mitigate the high stress to which the group members are subjected.
Anterior expansion and posterior addition to the notochord mechanically coordinate embryo axis elongation

During development the embryo body progressively elongates from head-to-tail along the anterior-posterior (AP) axis. Multiple tissues contribute to this elongation through a combination of convergence and extension and/or volumetric growth. How force generated by the morphogenesis of one tissue impacts the morphogenesis of other axial tissues to achieve an elongated axis is not well understood. The notochord, a rod-shaped tissue possessed by all vertebrates, runs across the entire length of the somitic compartment and is flanked on either side by the developing somites in the segmented region of the axis and presomitic mesoderm in the posterior. Cells in the notochord undergo an expansion that is constrained by a stiff sheath of extracellular matrix, that increases the internal pressure in the notochord allowing it to straighten and elongate. Therefore, it is appropriately positioned to play a role in mechanically elongating the somitic compartment. Here, we use multi-photon mediated cell ablation to remove specific regions of the developing notochord and quantify the impact on axis elongation. We show that anterior notochord cell expansion generates a force that displaces notochord cells posteriorly relative to adjacent axial tissues and contributes to the elongation of segmented tissue during post-tailbud stages of development. Crucially, unexpanded cells derived from progenitors at the posterior end of the notochord provide resistance to anterior notochord cell expansion, allowing for force generation across the AP axis. Therefore, notochord cell expansion beginning in the anterior, and addition of cells to the posterior notochord, act as temporally coordinated morphogenetic events that shape the zebrafish embryo AP axis.
Flow Injection Analysis of Benzene Using an Amperometric Bacterial Biosensor

Abstract A bacterial biosensor integrated within a flow injection analysis (FIA) system has been developed for the detection of benzene, based on its aerobic catabolism by Pseudomonas putida ML2. P. putida ML2 cells were immobilised between two cellulose acetate membranes and fixed onto a Clark dissolved oxygen electrode. Biosensor responses were investigated with the FIA system, resulting in a linear detection range between 0.01–0.1 mM benzene. A response and baseline recovery time of 6 and 10–15 min, respectively, was obtained. A stable and reproducible sensor response has been found up to 28 days of use based on the same bacterial membrane, and the sensor has shown a high specificity to benzene, with a negligible response to other benzene‐related compounds. Its ease of operation, rapid and sensitive response, and cost‐effective production, demonstrate that the P. putida ML2 biosensor has potential applications for the analysis of samples containing benzene. The optimisation of the biosensor‐flow injection system is described.