The fasciola cinereum of the hippocampal tail as an interventional target in epilepsy.

Targeted tissue ablation involving the anterior hippocampus is the standard of care for patients with drug-resistant mesial temporal lobe epilepsy. However, a substantial proportion continues to suffer from seizures even after surgery. We identified the fasciola cinereum (FC) neurons of the posterior hippocampal tail as an important seizure node in both mice and humans with epilepsy. Genetically defined FC neurons were highly active during spontaneous seizures in epileptic mice, and closed-loop optogenetic inhibition of these neurons potently reduced seizure duration. Furthermore, we specifically targeted and found the prominent involvement of FC during seizures in a cohort of six patients with epilepsy. In particular, targeted lesioning of the FC in a patient reduced the seizure burden present after ablation of anterior mesial temporal structures. Thus, the FC may be a promising interventional target in epilepsy.

Acetylcholine receptor based chemogenetics engineered for neuronal inhibition and seizure control assessed in mice.

Epilepsy is a prevalent disorder involving neuronal network hyperexcitability, yet existing therapeutic strategies often fail to provide optimal patient outcomes. Chemogenetic approaches, where exogenous receptors are expressed in defined brain areas and specifically activated by selective agonists, are appealing methods to constrain overactive neuronal activity. We developed BARNI (Bradanicline- and Acetylcholine-activated Receptor for Neuronal Inhibition), an engineered channel comprised of the α7 nicotinic acetylcholine receptor ligand-binding domain coupled to an α1 glycine receptor anion pore domain. Here we demonstrate that BARNI activation by the clinical stage α7 nicotinic acetylcholine receptor-selective agonist bradanicline effectively suppressed targeted neuronal activity, and controlled both acute and chronic seizures in male mice. Our results provide evidence for the use of an inhibitory acetylcholine-based engineered channel activatable by both exogenous and endogenous agonists as a potential therapeutic approach to treating epilepsy.

Metabolic programs of T cell tissue residency empower tumour immunity.

Tissue resident memory CD8+ T (TRM) cells offer rapid and long-term protection at sites of reinfection1. Tumour-infiltrating lymphocytes with characteristics of TRM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting TRM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memory CD8+ T cell populations. We found that memory CD8+ T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate-cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where TRM cells interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memory T cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of TRM cell metabolism, we reveal how these programs can be leveraged to fuel memory CD8+ T cell formation in the context of acute infections and enhance antitumour immunity.

Neuroprotection in Cerebral Cortex Induced by the Pregnancy Hormone Estriol.

In multiple sclerosis (MS), demyelination occurs in the cerebral cortex, and cerebral cortex atrophy correlates with clinical disabilities. Treatments are needed in MS to induce remyelination. Pregnancy is protective in MS. Estriol is made by the fetoplacental unit, and maternal serum estriol levels temporally align with fetal myelination. Here, we determined the effect of estriol treatment on the cerebral cortex in the preclinical model of MS, experimental autoimmune encephalomyelitis (EAE). Estriol treatment initiated after disease onset decreased cerebral cortex atrophy. Neuropathology of the cerebral cortex showed increased cholesterol synthesis proteins in oligodendrocytes, more newly formed remyelinating oligodendrocytes, and increased myelin in estriol-treated EAE mice. Estriol treatment also decreased the loss of cortical layer V pyramidal neurons and their apical dendrites and preserved synapses. Together, estriol treatment after EAE onset reduced atrophy and was neuroprotective in the cerebral cortex.

Genetic alterations in peritoneal metastatic tumors predicted the outcomes for hyperthermic intraperitoneal chemotherapy.

Introduction: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) are considered for patients with peritoneal metastasis (PM). However, patients selection that relies on conventional prognostic factors is not yet optimal. In this study, we performed whole exome sequencing (WES) to establish tumor molecular characteristics and expect to identify prognosis profiles for PM management. Methods: In this study, blood and tumor samples were collected from patients with PM before HIPEC. Tumor molecular signatures were determined using WES. Patient cohort was divided into responders and non-responders according to 12-month progression-free survival (PFS). Genomic characteristics between the two cohorts were compared to study potential targets. Results: In total, 15 patients with PM were enrolled in this study. Driver genes and enriched pathways were identified from WES results. AGAP5 mutation was found in all responders. This mutation was significantly associated with better OS (p = 0.00652). Conclusions: We identified prognostic markers that might be useful to facilitate decision-making before CRS/HIPEC.

Inflammatory bone marrow signaling in pediatric acute myeloid leukemia distinguishes patients with poor outcomes.

High levels of the inflammatory cytokine IL-6 in the bone marrow are associated with poor outcomes in pediatric acute myeloid leukemia (pAML), but its etiology remains unknown. Using RNA-seq data from pre-treatment bone marrows of 1489 children with pAML, we show that > 20% of patients have concurrent IL-6, IL-1, IFNα/ß, and TNFα signaling activity and poorer outcomes. Targeted sequencing of pre-treatment bone marrow samples from affected patients (n = 181) revealed 5 highly recurrent patterns of somatic mutation. Using differential expression analyses of the most common genomic subtypes (~60% of total), we identify high expression of multiple potential drivers of inflammation-related treatment resistance. Regardless of genomic subtype, we show that JAK1/2 inhibition reduces receptor-mediated inflammatory signaling by leukemic cells in-vitro. The large number of high-risk pAML genomic subtypes presents an obstacle to the development of mutation-specific therapies. Our findings suggest that therapies targeting inflammatory signaling may be effective across multiple genomic subtypes of pAML.

Is nature relatedness associated with better mental health? An exploratory study on Vietnamese university students.

OBJECTIVE: This study aims to examine the relationship between nature relatedness (NR) on subjective positive well-being (life satisfaction) and mental disorders (depression, stress, and anxiety) in Vietnamese university students. PARTICIPANTS: 340 Hue University students voluntarily took part in the survey. METHODS: The Nature Relatedness Scale, Depression, Anxiety, and Stress Scale and Satisfaction with Life Scale were used. Bivariate correlation, single regression, and moderation analysis were conducted to investigate the relationship between NR and the mental health of university students and the moderating role of NR. RESULTS: Higher levels of NR significantly predicted higher levels of life satisfaction but did not significantly predict fewer symptoms of depression, anxiety, and stress. NR significantly moderated the link between life satisfaction and depression, anxiety, and stress. CONCLUSIONS: The findings of this study imply that efforts to enhance students' mental health should include efforts to promote their NR.

Oral desensitization therapy for peanut allergy induces dynamic changes in peanut-specific immune responses.

BACKGROUND: The PALISADE study, an international, phase 3 trial of peanut oral immunotherapy (POIT) with AR101, resulted in desensitization in children and adolescents who were highly allergic to peanut. An improved understanding of the immune mechanism induced in response to food allergen immunotherapy would enable more informed and effective therapeutic strategies. Our main purpose was to examine the immunological changes in blood samples from a subset of peanut-allergic individuals undergoing oral desensitization immunotherapy with AR101. METHODS: Blood samples obtained as part of enrollment screening and at multiple time points during PALISADE study were used to assess basophil and CD4+ T-cell reactivity to peanut. RESULTS: The absence of clinical reactivity to the entry double-blinded placebo-controlled peanut challenge (DBPCFC) was accompanied by a significantly lower basophil sensitivity and T-cell reactivity to peanut compared with DBPCFC reactors. At baseline, peanut-reactive TH2A cells were observed in many but not all peanut-allergic patients and their level in peripheral blood correlates with T-cell reactivity to peanut and with serum peanut-specific IgE and IgG4 levels. POIT reshaped circulating peanut-reactive T-cell responses in a subset-dependent manner. Changes in basophil and T-cell responses to peanut closely paralleled clinical benefits to AR101 therapy and resemble responses in those with lower clinical sensitivity to peanut. However, no difference in peanut-reactive Treg cell frequency was observed between groups. CONCLUSION: Oral desensitization therapy with AR101 leads to decreased basophil sensitivity to peanut and reshapes peanut-reactive T effector cell responses supporting its potential as an immunomodulatory therapy.

Temporal patterns of synchrony in a pyramidal-interneuron gamma (PING) network.

Synchronization in neural systems plays an important role in many brain functions. Synchronization in the gamma frequency band (30-100 Hz) is involved in a variety of cognitive phenomena; abnormalities of the gamma synchronization are found in schizophrenia and autism spectrum disorder. Frequently, the strength of synchronization is not high, and synchronization is intermittent even on short time scales (few cycles of oscillations). That is, the network exhibits intervals of synchronization followed by intervals of desynchronization. Neural circuit dynamics may show different distributions of desynchronization durations even if the synchronization strength is fixed. We use a conductance-based neural network exhibiting pyramidal-interneuron gamma rhythm to study the temporal patterning of synchronized neural oscillations. We found that changes in the synaptic strength (as well as changes in the membrane kinetics) can alter the temporal patterning of synchrony. Moreover, we found that the changes in the temporal pattern of synchrony may be independent of the changes in the average synchrony strength. Even though the temporal patterning may vary, there is a tendency for dynamics with short (although potentially numerous) desynchronizations, similar to what was observed in experimental studies of neural synchronization in the brain. Recent studies suggested that the short desynchronizations dynamics may facilitate the formation and the breakup of transient neural assemblies. Thus, the results of this study suggest that changes of synaptic strength may alter the temporal patterning of the gamma synchronization as to make the neural networks more efficient in the formation of neural assemblies and the facilitation of cognitive phenomena.

Detrimental impacts of mixed-ion radiation on nervous system function.

Galactic cosmic radiation (GCR), composed of highly energetic and fully ionized atomic nuclei, produces diverse deleterious effects on the body. In researching the neurological risks of GCR exposures, including during human spaceflight, various ground-based single-ion GCR irradiation paradigms induce differential disruptions of cellular activity and overall behavior. However, it remains less clear how irradiation comprising a mix of multiple ions, more accurately recapitulating the space GCR environment, impacts the central nervous system. We therefore examined how mixed-ion GCR irradiation (two similar 5-6 beam combinations of protons, helium, oxygen, silicon and iron ions) influenced neuronal connectivity, functional generation of activity within neural circuits and cognitive behavior in mice. In electrophysiological recordings we find that space-relevant doses of mixed-ion GCR preferentially alter hippocampal inhibitory neurotransmission and produce related disruptions in the local field potentials of hippocampal oscillations. Such underlying perturbation in hippocampal network activity correspond with perturbed learning, memory and anxiety behavior.

Deep brain optogenetics without intracranial surgery.

Achieving temporally precise, noninvasive control over specific neural cell types in the deep brain would advance the study of nervous system function. Here we use the potent channelrhodopsin ChRmine to achieve transcranial photoactivation of defined neural circuits, including midbrain and brainstem structures, at unprecedented depths of up to 7 mm with millisecond precision. Using systemic viral delivery of ChRmine, we demonstrate behavioral modulation without surgery, enabling implant-free deep brain optogenetics.

Transcriptional readout of neuronal activity via an engineered Ca2+-activated protease.

Molecular integrators, in contrast to real-time indicators, convert transient cellular events into stable signals that can be exploited for imaging, selection, molecular characterization, or cellular manipulation. Many integrators, however, are designed as complex multicomponent circuits that have limited robustness, especially at high, low, or nonstoichiometric protein expression levels. Here, we report a simplified design of the calcium and light dual integrator FLARE. Single-chain FLARE (scFLARE) is a single polypeptide chain that incorporates a transcription factor, a LOV domain-caged protease cleavage site, and a calcium-activated TEV protease that we designed through structure-guided mutagenesis and screening. We show that scFLARE has greater dynamic range and robustness than first-generation FLARE and can be used in culture as well as in vivo to record patterns of neuronal activation with 10-min temporal resolution.

Buildup and bistability in auditory streaming as an evidence accumulation process with saturation.

A repeating triplet-sequence ABA- of non-overlapping brief tones, A and B, is a valued paradigm for studying auditory stream formation and the cocktail party problem. The stimulus is "heard" either as a galloping pattern (integration) or as two interleaved streams (segregation); the initial percept is typically integration then followed by spontaneous alternations between segregation and integration, each being dominant for a few seconds. The probability of segregation grows over seconds, from near-zero to a steady value, defining the buildup function, BUF. Its stationary level increases with the difference in tone frequencies, DF, and the BUF rises faster. Percept durations have DF-dependent means and are gamma-like distributed. Behavioral and computational studies usually characterize triplet streaming either during alternations or during buildup. Here, our experimental design and modeling encompass both. We propose a pseudo-neuromechanistic model that incorporates spiking activity in primary auditory cortex, A1, as input and resolves perception along two network-layers downstream of A1. Our model is straightforward and intuitive. It describes the noisy accumulation of evidence against the current percept which generates switches when reaching a threshold. Accumulation can saturate either above or below threshold; if below, the switching dynamics resemble noise-induced transitions from an attractor state. Our model accounts quantitatively for three key features of data: the BUFs, mean durations, and normalized dominance duration distributions, at various DF values. It describes perceptual alternations without competition per se, and underscores that treating triplets in the sequence independently and averaging across trials, as implemented in earlier widely cited studies, is inadequate.

Connecting Pathological Cellular Mechanisms to Large-Scale Seizure Structures.

Epilepsy is a neurological disorder characterized by recurrent seizures, where abnormal electrical activity begins in a local brain area and propagates before terminating. In a recent study, Liou and colleagues used multiscale computational modeling to gain mechanistic insights into clinical seizure dynamics based on cellular-level biophysical properties.

Neurological Impairments in Mice Subjected to Irradiation and Chemotherapy.

Radiotherapy, surgery and the chemotherapeutic agent temozolomide (TMZ) are frontline treatments for glioblastoma multiforme (GBM). However beneficial, GBM treatments nevertheless cause anxiety or depression in nearly 50% of patients. To further understand the basis of these neurological complications, we investigated the effects of combined radiotherapy and TMZ chemotherapy (combined treatment) on neurological impairments using a mouse model. Five weeks after combined treatment, mice displayed anxiety-like behaviors, and at 15 weeks both anxiety- and depression-like behaviors were observed. Relevant to the known roles of the serotonin axis in mood disorders, we found that 5HT1A serotonin receptor levels were decreased by ∼50% in the hippocampus at both early and late time points, and a 37% decrease in serotonin levels was observed at 15 weeks postirradiation. Furthermore, chronic treatment with the selective serotonin reuptake inhibitor fluoxetine was sufficient for reversing combined treatment-induced depression-like behaviors. Combined treatment also elicited a transient early increase in activated microglia in the hippocampus, suggesting therapy-induced neuroinflammation that subsided by 15 weeks. Together, the results of this study suggest that interventions targeting the serotonin axis may help ameliorate certain neurological side effects associated with the clinical management of GBM to improve the overall quality of life for cancer patients.

Mental health among Vietnamese urban late adolescents: The association of parenting styles.

The aim of this study was to explore the correlation between parental styles and mental problems among Vietnamese high school students. In total, 16.4 percent of 757 eligible participants reported mental difficulties. Findings showed that being female and in grade 12 were risk factors to mental problems while living in Hue city was likely as a protective factor. The father's warmth reduced the risk of having mental problems among adolescents, while an overprotective mother increased the risk. There was no correlation between authoritarianism of both mother and father and mental difficulties. These results suggest that a parenting program for parents might reduce the risk of mental problems among Vietnamese youth.

Identifying residual hotspots and mapping lower respiratory infection morbidity and mortality in African children from 2000 to 2017.

Lower respiratory infections (LRIs) are the leading cause of death in children under the age of 5, despite the existence of vaccines against many of their aetiologies. Furthermore, more than half of these deaths occur in Africa. Geospatial models can provide highly detailed estimates of trends subnationally, at the level where implementation of health policies has the greatest impact. We used Bayesian geostatistical modelling to estimate LRI incidence, prevalence and mortality in children under 5 subnationally in Africa for 2000-2017, using surveys covering 1.46 million children and 9,215,000 cases of LRI. Our model reveals large within-country variation in both health burden and its change over time. While reductions in childhood morbidity and mortality due to LRI were estimated for almost every country, we expose a cluster of residual high risk across seven countries, which averages 5.5 LRI deaths per 1,000 children per year. The preventable nature of the vast majority of LRI deaths mandates focused health system efforts in specific locations with the highest burden.

Ufd1 phosphorylation at serine 229 negatively regulates endoplasmic reticulum-associated degradation by inhibiting the interaction of Ufd1 with VCP.

Misfolded proteins in the endoplasmic reticulum (ER) are removed through multistep processes termed ER-associated degradation (ERAD). Valosin-containing protein (VCP) plays a crucial role in ERAD as the interaction of ubiquitin fusion degradation protein 1 (Ufd1) with VCP via its SHP box motif (228F-S-G-S-G-N-R-L235) is required for ERAD. However, the mechanisms by which the VCP-Ufd1 interaction is regulated are not well understood. Here, we found that the serine 229 residue located in the Ufd1 SHP box is phosphorylated in vitro and in vivo by cyclic adenosine monophosphate-dependent protein kinase A (PKA), with this process being enhanced by either forskolin (an adenylyl cyclase activator) or calyculin A (a protein phosphatase inhibitor). Moreover, a phosphomimetic mutant (S229D) of Ufd1 as well as treatment by forskolin, calyculin A, or activated PKA strongly reduced Ufd1 binding affinity for VCP. Consistent with this, the Ufd1 S229D mutant significantly inhibited ERAD leading to the accumulation of ERAD substrates such as a tyrosinase mutant (C89R) and 3-hydroxy-3-methylglutaryl coenzyme A reductase. However, a non-phosphorylatable Ufd1 mutant (S229A) retained VCP-binding ability and was less effective in blocking ERAD. Collectively, our results support that Ufd1 S229 phosphorylation status mediated by PKA serves as a key regulatory point for the VCP-Ufd1 interaction and functional ERAD.

Histone deacetylase 6 inhibitor tubastatin A attenuates angiotensin II-induced hypertension by preventing cystathionine γ-lyase protein degradation.

Cystathionine γ-lyase (CSEγ) is a hydrogen sulfide (H2S)-producing enzyme. Endothelial H2S production can mediate vasodilatory effects, contributing to the alleviation of hypertension (high blood pressure). Recent studies have suggested a role of histone deacetylase 6 (HDAC6) in hypertension, although its underlying mechanisms are poorly understood. Here, we addressed the potential regulation of CSEγ by HDAC6 in angiotensin II (AngII)-induced hypertension and its molecular details focusing on CSEγ posttranslational modification. Treatment of mice with a selective HDAC6 inhibitor tubastatin A (TubA) alleviated high blood pressure and vasoconstriction induced by AngII. Cotreatment of the aorta and human aortic endothelial cells with TubA recovered AngII-mediated decreased H2S levels. AngII treatment upregulated HDAC6 mRNA and protein expression, but conversely downregulated CSEγ protein. Notably, potent HDAC6 inhibitors and HDAC6 siRNA as well as a proteasomal inhibitor increased CSEγ protein levels and blocked the downregulatory effect of AngII on CSEγ. In contrast, other HDAC isoforms-specific inhibitors and siRNAs did not show such blocking effects. Transfected CSEγ protein levels were also reciprocally regulated by AngII and TubA, and were reduced by wild-type, but not by deacetylase-deficient, HDAC6. Moreover, TubA significantly increased both protein stability and K73 acetylation level of CSEγ. Consistent with these results, AngII induced CSEγ ubiquitination and degradation, which was inhibited by TubA. Our results indicate that AngII promoted HDAC6-dependent deacetylation of CSEγ at K73 residue, leading to its ubiquitin-mediated proteolysis, which underlies AngII-induced hypertension. Overall, this study suggests that upregulation of CSEγ and H2S through HDAC6 inhibition may be considered as a valid strategy for preventing the progression of hypertension.

Resolving the Micro-Macro Disconnect to Address Core Features of Seizure Networks.

Current drug treatments for epilepsy attempt to broadly restrict excitability to mask a symptom, seizures, with little regard for the heterogeneous mechanisms that underlie disease manifestation across individuals. Here, we discuss the need for a more complete view of epilepsy, outlining how key features at the cellular and microcircuit level can significantly impact disease mechanisms that are not captured by the most common methodology to study epilepsy, electroencephalography (EEG). We highlight how major advances in neuroscience tool development now enable multi-scale investigation of fundamental questions to resolve the currently controversial understanding of seizure networks. These findings will provide essential insight into what has emerged as a disconnect between the different levels of investigation and identify new targets and treatment options.