Optogenetic and chemogenetic actuators are critical for deconstructing the neural correlates of behavior. However, these tools have several limitations, including invasive modes of stimulation or ...slow on/off kinetics. We have overcome these disadvantages by synthesizing a single-component, magnetically sensitive actuator, "Magneto," comprising the cation channel TRPV4 fused to the paramagnetic protein ferritin. We validated noninvasive magnetic control over neuronal activity by demonstrating remote stimulation of cells using in vitro calcium imaging assays, electrophysiological recordings in brain slices, in vivo electrophysiological recordings in the brains of freely moving mice, and behavioral outputs in zebrafish and mice. As proof of concept, we used Magneto to delineate a causal role of striatal dopamine receptor 1 neurons in mediating reward behavior in mice. Together our results present Magneto as an actuator capable of remotely controlling circuits associated with complex animal behaviors.
Mild traumatic brain injury (mTBI), also referred to as concussion, remains a controversial diagnosis because the brain often appears quite normal on conventional computed tomography (CT) and ...magnetic resonance imaging (MRI) scans. Such conventional tools, however, do not adequately depict brain injury in mTBI because they are not sensitive to detecting diffuse axonal injuries (DAI), also described as traumatic axonal injuries (TAI), the major brain injuries in mTBI. Furthermore, for the 15 to 30 % of those diagnosed with mTBI on the basis of cognitive and clinical symptoms, i.e., the “miserable minority,” the cognitive and physical symptoms do not resolve following the first 3 months post-injury. Instead, they persist, and in some cases lead to long-term disability. The explanation given for these chronic symptoms, i.e., postconcussive syndrome, particularly in cases where there is no discernible radiological evidence for brain injury, has led some to posit a psychogenic origin. Such attributions are made all the easier since both posttraumatic stress disorder (PTSD) and depression are frequently co-morbid with mTBI. The challenge is thus to use neuroimaging tools that are sensitive to DAI/TAI, such as diffusion tensor imaging (DTI), in order to detect brain injuries in mTBI. Of note here, recent advances in neuroimaging techniques, such as DTI, make it possible to characterize better extant brain abnormalities in mTBI. These advances may lead to the development of biomarkers of injury, as well as to staging of reorganization and reversal of white matter changes following injury, and to the ability to track and to characterize changes in brain injury over time. Such tools will likely be used in future research to evaluate treatment efficacy, given their enhanced sensitivity to alterations in the brain. In this article we review the incidence of mTBI and the importance of characterizing this patient population using
objective radiological measures
. Evidence is presented for detecting brain abnormalities in mTBI based on studies that use advanced neuroimaging techniques. Taken together, these findings suggest that more sensitive neuroimaging tools improve the detection of brain abnormalities (i.e., diagnosis) in mTBI. These tools will likely also provide important information relevant to outcome (prognosis), as well as play an important role in longitudinal studies that are needed to understand the dynamic nature of brain injury in mTBI. Additionally, summary tables of MRI and DTI findings are included. We believe that the enhanced sensitivity of newer and more advanced neuroimaging techniques for identifying areas of brain damage in mTBI will be important for documenting the biological basis of postconcussive symptoms, which are likely associated with subtle brain alterations, alterations that have heretofore gone undetected due to the lack of sensitivity of earlier neuroimaging techniques. Nonetheless, it is noteworthy to point out that detecting brain abnormalities in mTBI does not mean that other disorders of a more psychogenic origin are not co-morbid with mTBI and equally important to treat. They arguably are. The controversy of psychogenic versus physiogenic, however, is not productive because the psychogenic view does not carefully consider the limitations of conventional neuroimaging techniques in detecting subtle brain injuries in mTBI, and the physiogenic view does not carefully consider the fact that PTSD and depression, and other co-morbid conditions, may be present in those suffering from mTBI. Finally, we end with a discussion of future directions in research that will lead to the improved care of patients diagnosed with mTBI.
Dopamine (DA) neurotransmission controls behaviors important for survival, including voluntary movement, reward processing, and detection of salient events, such as food or mate availability. ...Dopaminergic tone also influences circadian physiology and behavior. Although the evolutionary significance of this input is appreciated, its precise neurophysiological architecture remains unknown. Here, we identify a novel, direct connection between the DA neurons of the ventral tegmental area (VTA) and the suprachiasmatic nucleus (SCN). We demonstrate that D1 dopamine receptor (Drd1) signaling within the SCN is necessary for properly timed resynchronization of activity rhythms to phase-shifted light:dark cycles and that elevation of DA tone through selective activation of VTA DA neurons accelerates photoentrainment. Our findings demonstrate a previously unappreciated role for direct DA input to the master circadian clock and highlight the importance of an evolutionarily significant relationship between the circadian system and the neuromodulatory circuits that govern motivational behaviors.
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•Absence of D1 dopamine receptor (Drd1) reduces circadian entrainment rate•Restoration of Drd1 in the suprachiasmatic nucleus (SCN) restores entrainment rate•Midbrain dopamine neurons innervate the SCN•Midbrain dopamine neuron stimulation accelerates circadian entrainment
Grippo et al. demonstrate a direct functional connection from the midbrain dopamine neurons to the central circadian clock. This D1 dopamine-receptor-dependent connection regulates the rate of entrainment, highlighting the critical role for dopamine signaling in the modulation of central circadian rhythms.
The widespread availability of energy-dense, rewarding foods is correlated with the increased incidence of obesity across the globe. Overeating during mealtimes and unscheduled snacking disrupts ...timed metabolic processes, which further contribute to weight gain. The neuronal mechanism by which the consumption of energy-dense food restructures the timing of feeding is poorly understood. Here, we demonstrate that dopaminergic signaling within the suprachiasmatic nucleus (SCN), the central circadian pacemaker, disrupts the timing of feeding, resulting in overconsumption of food. D1 dopamine receptor (Drd1)-null mice are resistant to diet-induced obesity, metabolic disease, and circadian disruption associated with energy-dense diets. Conversely, genetic rescue of Drd1 expression within the SCN restores diet-induced overconsumption, weight gain, and obesogenic symptoms. Access to rewarding food increases SCN dopamine turnover, and elevated Drd1-signaling decreases SCN neuronal activity, which we posit disinhibits downstream orexigenic responses. These findings define a connection between the reward and circadian pathways in the regulation of pathological calorie consumption.
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•Diet-induced obesity (DIO) requires dopamine (DA)-Drd1 signaling•DA-Drd1 signaling in the central circadian clock (SCN) instigates DIO•SCN DA-Drd1 signaling disinhibits hedonic food consumption in between meals•Diet drives dysbiosis and peripheral circadian desynchrony independent of Drd1
Palatable diets rich in fat and sugar incentivize overeating, which leads to obesity. Grippo and Tang et al. discover a unique role for dopamine signaling in the central circadian clock that promotes overconsumption outside of mealtimes.
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The anticancer properties of selenium (Se) and curcumin nanoparticles in solo formulations as well as in combination with other therapeutic agents have been proved time and again. ...Exploiting this facet of the two, we clubbed their tumoricidal characteristics and designed curcumin loaded Se nanoparticles (Se-CurNPs) to achieve an enhanced therapeutic effect. We evaluated their therapeutic effects on different cancer cell lines and Ehrlich’s ascites carcinoma mouse model. In vitro results showed that Se-CurNPs were most effective on colorectal carcinoma cells (HCT116) compared to the other cancer cell lines used and possessed pleiotropic anticancer effects. The therapeutic effect on HCT116 was primarily attributed to an elevated level of autophagy and apoptosis as evident from significant up-regulation of autophagy associated (LC3B-II) and pro-apoptotic (Bax) proteins, down-regulation of anti-apoptotic (Bcl-2) protein and Cytochrome c (cyt c) release from mitochondria along with reduced NFκB signaling and EMT based machineries marked by downregulation of inflammation (NFκB, phospho-NFκB) and epithelial-mesenchymal transition (CD44, N-cadherin) associated proteins. In vivo studies on Ehrlich’s ascites carcinoma (EAC) mice model indicated that Se-CurNPs significantly reduced the tumor load and enhanced the mean survival time (days) of tumor-bearing EAC mice.
Purpose: Dry eye syndrome (DES) is a global issue occurring due to tear deficiency or excessive tear evaporation. It is associated with a variety of symptoms causing ocular discomfort. The purpose of ...the study was to evaluate causative factors, treatment modalities, quality of life, and preservatives used in eye drops. Methods: This prospective, follow-up study was conducted in the ophthalmology outpatient department of a tertiary care teaching hospital. Patients older than 18 years of age of either sex diagnosed with DES and willing to give written informed consent were included. The patients were subjected to the Ocular surface disease index Questionnaire (OSDI Questionnaire) twice; at the time of the first visit and at 15 days follow-up. Results: A male preponderance was observed with a 1.86:1 male-to-female ratio. The mean age of the study population was 29.15 ± 10.07 years. The most common presenting complaints were symptoms related to dryness of the eyes followed by refractive error. Exposure to TV/computer screen for more than 6 hours is the most common causative factor. There was a statistically significant improvement in overall quality of life (QoL) in patients of DES on treatment. However, no significant difference was seen in the improvement of quality of life in comparison with different preservatives used in prescribed eye drops for the treatment of DES. Conclusion: DES can adversely affect the quality of life of patients. Prompt treatment of this condition can significantly improve the patient's QoL. Physicians should be encouraged to perform quality of life evaluations for patients with DES to guide them in treatment with more individual-specific treatment options.
Segregation of household waste at the source is an effective and sustainable strategy for management of municipal waste. However, household segregation levels remain insufficient as waste management ...approaches are mostly top down and lack local support. The realisation and recognition of effective, improved and adequate waste management may be one of the vital drivers for attaining environmental protection and improved health and well-being. The presence of a local level motivator may promote household waste segregation and ultimately pro-environmental behaviour. The present cluster randomized control trial aims to understand if volunteer based information on waste segregation (I-MISS) can effectively promote increased waste segregation practices at the household level when compared with existing routine waste segregation information in an urban Indian setting.
This paper describes the protocol of an 18 month two-group parallel,cluster randomised controlled trialin the urban setting of Ujjain, Madhya Pradesh, India. Randomization will be conducted at ward level, which is the last administrative unit of the municipality. The study will recruit 425 households in intervention and control groups. Assessments will be performed at baseline (0 months), midline (6 months), end line (12 months) and post intervention (18 months). The primary outcome will be the comparison of change in proportion of households practicing waste segregation and change in proportion of mis-sorted waste across the study period between the intervention and control groups as assessed by pick analysis. Intention to treat analysis will be conducted. Written informed consent will be obtained from all participants.
The present study is designed to study whether an external motivator, a volunteer selected from the participating community and empowered with adequate training, could disseminate waste segregation information to their community, thus promoting household waste segregation and ultimately pro-environmental behaviour. The study envisages that the volunteers could link waste management service providers and the community, give a local perspective to waste management, and help to change community habits through information, constant communication and feedback.
The study is registered prospectively with Indian Council of Medical Research- Clinical Trial Registry of India ( CTRI/2020/03/024278 ).
One giant plagioclase basalt GPB) flow from the northeast corner of the DVP, about 70 km south of Sagar, is reported for the first time. This GPB flow, over 40 m in thickness, is exposed ...approximately for 15 sq. km area and overlies a fine-grained, non-porphyritic basalt at 40 m depth in a borehole. Plagioclase phenocrysts, 4–5 cm in length, and occasionally larger, range in composition from bytownite-labradorite (An
80–60
). Clinopyroxene phenocrysts though present, are rare. Major and trace element chemistry of the GPB and the non-porphyritic basalt below is presented and discussed in comparison to the well-known GPBs from Western Ghats as also those reported later from Jhabua and Jabalpur districts in Madhya Pradesh. Among other differences, MgO content of the Sagar GPB (6.13%) seems to be the highest of all the GPBs reported from DVP so far.
Oral Sub-Mucous Fibrosis (OSMF) is a premalignant condition that alters fibro elasticity of oral submucosa and predominantly confined to Southeast Asian region. Variability in clinical course is ...intriguing, a fraction of betel nut users develops OSMF (0.1-11%), while a majority show no signs and symptoms despite prolonged use; severe forms are associated with very short history of tobacco use. This inconsistency in disease association is indicative of genetic association, but specific role of genes in its susceptibility remains largely unidentified. The objective was to assess and compare HLA-DRB1, -DQB1, -DPB1 allele phenotype frequencies in OSMF patients and healthy controls.
Patients aged 18-55 years were recruited and tobacco history was recorded followed by collection of blood sample for DNA extraction and quality check. HLA class II genotyping was performed using Next Generation Sequencing protocol for 154 samples with 119 OSMF patients and 35 controls. Data was analysed using sequencing software. Study was approved by Institute Ethics committee of AIIMS New Delhi and study duration was 18 months.
Mean age of patients was 42.23±11.98 years with mild (36.7%), moderate (36.7%) and severe (26.7%) OSMF patients. -DPB1*04 was observed as the most frequent allele (71.43%) followed by HLA-DQB1 *03 allele in 46.5% of the samples. HLA-DQB1 *04 was the least frequent allele present in 1.73% of the samples.
Insights into potential predisposing or protective HLA allele help better characterize inter individual variations in immune responses in severity and progression of OSMF and develop potential genetic biomarker for screening and prognosis & reduce malignant transformation rate in OSMF.
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