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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. Optogenetic control of neural activity in the deep brain is achieved without intracranial surgery using ChRmine.

A repeating triplet-sequence ABA.sub.- 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.

Background The present study aimed to identify and critically appraise the quality of model-based economic evaluation studies in mental health prevention. Methods A systematic search was performed on MEDLINE, EMBASE, EconLit, PsycINFO, and Web of Science. Two reviewers independently screened for eligible records using predefined criteria and extracted data using a pre-piloted data extraction form. The 61-item Philips Checklist was used to critically appraise the studies. Systematic review registration number : CRD42020184519. Results Forty-nine studies were eligible to be included. Thirty studies (61.2%) were published in 2015–2021. Forty-seven studies were conducted for higher-income countries. There were mainly cost-utility analyses ( n  = 31) with the dominant primary outcome of quality-adjusted life year. The most common model was Markov ( n  = 26). Most of the studies were conducted from a societal or health care perspective ( n  = 37). Only ten models used a 50-year time horizon ( n  = 2) or lifetime horizon ( n  = 8). A wide range of mental health prevention strategies was evaluated with the dominance of selective/indicate strategy and focusing on common mental health problems (e.g., depression, suicide). The percentage of the Philip checkilst’s criteria fulfilled by included studies was 69.3% on average and ranged from 43.3 to 90%. Among three domains of the Philip checklist, criteria on the model structure were fulfilled the most (72.1% on average, ranging from 50.0% to 91.7%), followed by the data domain (69.5% on average, ranging from 28.9% to 94.0%) and the consistency domain (54.6% on average, ranging from 20.0% to 100%). The practice of identification of ‘relevant’ evidence to inform model structure and inputs was inadequately performed. The model validation practice was rarely reported. Conclusions There is an increasing number of model-based economic evaluations of mental health prevention available to decision-makers, but evidence has been limited to the higher-income countries and the short-term horizon. Despite a high level of heterogeneity in study scope and model structure among included studies, almost all mental health prevention interventions were either cost-saving or cost-effective. Future models should make efforts to conduct in the low-resource context setting, expand the time horizon, improve the evidence identification to inform model structure and inputs, and promote the practice of model validation.

As a member of the epidermal growth factor receptor (EGFR) family, ERBB3 plays an essential role in development and disease independent of inherently inactive kinase domain. Recently, ERBB3 has been found to bind to ATP and has catalytic activity in vitro. However, the biological function of ERBB3 kinase activity remains elusive in vivo. Here we have identified the physiological function of inactivated ERBB3 kinase activity by creating Erbb3‐K740M knockin mice in which ATP cannot bind to ERBB3. Unlike Erbb3 knockout mice, kinase‐inactive Erbb3K740M homozygous mice were born in Mendelian ratios and showed normal development. After dextran sulfate sodium‐induced colitis, the kinase‐inactive Erbb3 mutant mice showed normal recovery. However, the outgrowth of ileal organoids by neuregulin‐1 treatment was more attenuated in Erbb3 mutant mice than in WT mice. Moreover, in combination with the ApcMin mouse, the proportion of polyps less than 1 mm in diameter in mutant mice was higher than in control mice and an increase in the number of apoptotic cells was observed in polyps from mutant mice compared with polyps from control mice. Taken together, the ERBB3 kinase activity contributes to the outgrowth of ileal organoids and intestinal tumorigenesis, and the development of ERBB3 kinase inhibitors, including epidermal growth factor receptor family members, can be a potential way to target colorectal cancer. ERBB3 kinase activity contributes to the outgrowth of ileal organoids and intestinal tumorigenesis, and the development of ERBB3 kinase inhibitors, including epidermal growth factor receptor family members, can be a potential way to target colorectal cancer

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. Traditional systematic anti-seizure treatments alter brain-wide activity and often carry significant side effects. The authors engineered an inhibitory, acetylcholine receptor-based, chemogenetic tool to suppress targeted neurons, enabling control of chronic seizures in mice.

Neuroligins (NLGNs) are postsynaptic cell adhesion molecules that interact trans-synaptically with neurexins to mediate synapse development and function. NLGN2 is only at inhibitory synapses while NLGN3 is at both excitatory and inhibitory synapses. We found that NLGN3 function at inhibitory synapses in rat CA1 depends on the presence of NLGN2 and identified a domain in the extracellular region that accounted for this functional difference between NLGN2 and 3 specifically at inhibitory synapses. We further show that the presence of a cytoplasmic tail (c-tail) is indispensible, and identified two domains in the c-tail that are necessary for NLGN function at inhibitory synapses. These domains point to a gephyrin-dependent mechanism that is disrupted by an autism-associated mutation at R705 and a gephyrin-independent mechanism reliant on a putative phosphorylation site at S714. Our work highlights unique and separate roles for the extracellular and intracellular regions in specifying and carrying out NLGN function respectively.

ObjectiveTo estimate the direct and indirect costs of active smoking in Vietnam.MethodA prevalence-based disease-specific cost of illness approach was utilised to calculate the costs related to five smoking-related diseases: lung cancer, cancers of the upper aerodigestive tract, chronic obstructive pulmonary disease, ischaemic heart disease and stroke. Data on healthcare came from an original survey, hospital records and official government statistics. Morbidity and mortality due to smoking combined with the average per capita income were used to calculate the indirect costs of smoking by applying the human capital approach. The smoking-attributable fraction was calculated using the adjusted relative risk values from phase II of the American Cancer Society Cancer Prevention Study (CPS-II). Costs were classified as personal, governmental and health insurance costs.ResultsThe total economic cost of smoking in 2011 was estimated at 24 679.9 billion Vietnamese dong (VND), equivalent to US$1173.2 million or approximately 0.97% of the 2011 gross domestic product. The direct costs of inpatient and outpatient care reached 9896.2 billion VND (US$470.4 million) and 2567.2 billion VND (US$122.0 million), respectively. The government’s contribution to these costs was 4534.3 billion VND (US$215.5 million), which was equivalent to 5.76% of its 2011 healthcare budget. The indirect costs (productivity loss) due to morbidity and mortality were 2652.9 billion VND (US$126.1 million) and 9563.5 billion VND (US$454.6 million), respectively. These indirect costs represent about 49.5% of the total costs of smoking.ConclusionsTobacco consumption has large negative consequences on the Vietnamese economy.

This study reports for the first time on the synthesis of novel resin@P-Ag 2 O material and its application for reducing the chloride effect on COD determination of high salinity water. This engineered core–shell nanomaterial with cationic ion exchange resin core and porous Ag 2 O shell was prepared by facile ion exchange and silver oxidation method at ambient temperature without using toxic chemicals. The material was characterized by FTIR, XRD, SEM, and SEM–EDX mapping. In the chloride removal test, this material gave a high adsorption capacity of ca. 244 mgCl/gAg at the mild condition with high durability after several adsorption–desorption cycles. Moreover, resin@P-Ag 2 O was applied for removing chloride in water to improve the accuracy of the SMEWW 5220C:2012 method for COD determination of high salinity water. The result showed that the COD of a water sample with salt content after being treated by the material had a low error (≤ 10%) as compared to the sample without salt. Meanwhile, the COD of salty water measured by the dilution method had an error of around 15%. These results indicate that resin@P-Ag 2 O material has a very potential application for chloride removal and COD determination of high salinity water.

Phosphatidylinositol 4‐phosphate 5‐kinase (PIP5K) family members generate phosphatidylinositol 4,5‐bisphosphate (PIP2), a critical lipid regulator of diverse physiological processes. The PIP5K‐dependent PIP2 generation can also act upstream of the oncogenic phosphatidylinositol 3‐kinase (PI3K)/Akt pathway. Many studies have demonstrated various mechanisms of spatiotemporal regulation of PIP5K catalytic activity. However, there are few studies on regulation of PIP5K protein stability. Here, we examined potential regulation of PIP5Kα, a PIP5K isoform, via ubiquitin‐proteasome system, and its implication for breast cancer. Our results showed that the ubiquitin ligase NEDD4 (neural precursor cell expressed, developmentally down‐regulated gene 4) mediated ubiquitination and proteasomal degradation of PIP5Kα, consequently reducing plasma membrane PIP2 level. NEDD4 interacted with the C‐terminal region and ubiquitinated the N‐terminal lysine 88 in PIP5Kα. In addition, PIP5Kα gene disruption inhibited epidermal growth factor (EGF)‐induced Akt activation and caused significant proliferation defect in breast cancer cells. Notably, PIP5Kα K88R mutant that was resistant to NEDD4‐mediated ubiquitination and degradation showed more potentiating effects on Akt activation by EGF and cell proliferation than wild‐type PIP5Kα. Collectively, these results suggest that PIP5Kα is a novel degradative substrate of NEDD4 and that the PIP5Kα‐dependent PIP2 pool contributing to breast cancer cell proliferation through PI3K/Akt activation is negatively controlled by NEDD4.

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/β, 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. IL6 expression in the bone marrow is associated with reduced survival in paediatric AML. Here, the authors used RNA-seq to identify treatment resistance-associated co-occurring inflammatory signalling in leukemic cells.