Mapping the Neural Substrates of Behavior.

Assigning behavioral functions to neural structures has long been a central goal in neuroscience and is a necessary first step toward a circuit-level understanding of how the brain generates behavior. Here, we map the neural substrates of locomotion and social behaviors for Drosophila melanogaster using automated machine-vision and machine-learning techniques. From videos of 400,000 flies, we quantified the behavioral effects of activating 2,204 genetically targeted populations of neurons. We combined a novel quantification of anatomy with our behavioral analysis to create brain-behavior correlation maps, which are shared as browsable web pages and interactive software. Based on these maps, we generated hypotheses of regions of the brain causally related to sensory processing, locomotor control, courtship, aggression, and sleep. Our maps directly specify genetic tools to target these regions, which we used to identify a small population of neurons with a role in the control of walking.

Motor neurons generate pose-targeted movements via proprioceptive sculpting.

Motor neurons are the final common pathway1 through which the brain controls movement of the body, forming the basic elements from which all movement is composed. Yet how a single motor neuron contributes to control during natural movement remains unclear. Here we anatomically and functionally characterize the individual roles of the motor neurons that control head movement in the fly, Drosophila melanogaster. Counterintuitively, we find that activity in a single motor neuron rotates the head in different directions, depending on the starting posture of the head, such that the head converges towards a pose determined by the identity of the stimulated motor neuron. A feedback model predicts that this convergent behaviour results from motor neuron drive interacting with proprioceptive feedback. We identify and genetically2 suppress a single class of proprioceptive neuron3 that changes the motor neuron-induced convergence as predicted by the feedback model. These data suggest a framework for how the brain controls movements: instead of directly generating movement in a given direction by activating a fixed set of motor neurons, the brain controls movements by adding bias to a continuing proprioceptive-motor loop.

A comprehensive measure of Golgi sphingolipid flux using NBD C6-ceramide: evaluation of sphingolipid inhibitors.

Measurements of sphingolipid metabolism are most accurately performed by LC-MS. However, this technique is expensive, not widely accessible, and without the use of specific probes, it does not provide insight into metabolic flux through the pathway. Employing the fluorescent ceramide analogue NBD-C6-ceramide as a tracer in intact cells, we developed a comprehensive HPLC-based method that simultaneously measures the main nodes of ceramide metabolism in the Golgi. Hence, by quantifying the conversion of NBD-C6-ceramide to NBD-C6-sphingomyelin, NBD-C6-hexosylceramides, and NBD-C6-ceramide-1-phosphate (NBD-C1P), the activities of Golgi resident enzymes sphingomyelin synthase 1, glucosylceramide synthase, and ceramide kinase (CERK) could be measured simultaneously. Importantly, the detection of NBD-C1P allowed us to quantify CERK activity in cells, a usually difficult task. By applying this method, we evaluated the specificity of commonly used sphingolipid inhibitors and discovered that 1-phenyl-2-decanoylamino-3-morpholino-1-propanol, which targets glucosylceramide synthase, and fenretinide (4HPR), an inhibitor for dihydroceramide desaturase, also suppress CERK activity. This study demonstrates the benefit of an expanded analysis of ceramide metabolism in the Golgi, and it provides a qualitative and easy-to-implement method.

Benefits of Prokinetics, Gastroparesis Diet, or Neuromodulators Alone or in Combination for Symptoms of Gastroparesis.

BACKGROUND & AIMS: Prokinetics have limited effectiveness for treating symptoms of gastroparesis. Thus, alternative or adjunct therapies, such as gastroparesis diets or neuromodulators, are often prescribed. Their therapeutic benefits alone or in combination remain unclear. METHODS: One hundred and twenty-nine patients with symptoms of gastroparesis underwent wireless motility capsule gastric emptying time and gastric emptying scintigraphy. Based on test results, changes in therapy were recommended. Changes in Gastroparesis Cardinal Symptom Index (GCSI) and individual symptom scores over 6 months were related to recommendations for prokinetics, gastroparesis diet, or neuromodulators given as solo new therapies or in dual combinations. Multivariate analyses were performed to adjust for gastric emptying and other variables. RESULTS: In the whole group regardless of therapy, GCSI scores decreased by 0.53 points (interquartile range, -1.25 to 0.05; P < .0001) over 6 months. GCSI did not decrease for prokinetics as solo new therapy (P = .95). Conversely, neuromodulators as solo therapy decreased GCSI scores (P = .04) and all individual symptoms except nausea/vomiting (P = .86). Prokinetics combined with gastroparesis diets or neuromodulators improved GCSI scores (P ≤ .04) and most individual symptoms. Adjusting for gastric emptying time on multivariate analyses showed greater GCSI decreases for nondelayed emptying for neuromodulators as solo new therapy (P = .01). Gastric emptying scintigraphy, gender, diabetes, and functional dyspepsia did not influence responses to any treatment. CONCLUSIONS: Initiating prokinetics as solo new therapy had little benefit for patients with symptoms of gastroparesis. Neuromodulators as the only new therapy decreased symptoms other than nausea and vomiting, especially with nondelayed gastric emptying. Adding gastroparesis diets or neuromodulators to prokinetics offered relief, suggesting that combination therapies may be more useful in managing these patients. (ClinicalTrials.gov NCT02022826.).

Percutaneous electrical nerve field stimulation for adolescents with irritable bowel syndrome: Cost-benefit and cost-minimization analysis.

Abdominal pain drives significant cost for adolescents with irritable bowel syndrome (IBS). We performed an economic analysis to estimate cost-savings for patients' families and healthcare insurance, and health outcomes, based on abdominal pain improvement with percutaneous electrical nerve field stimulation (PENFS) with IB-Stim® (Neuraxis). We constructed a Markov model with a 1-year time horizon comparing outcomes and costs with PENFS versus usual care without PENFS. Clinical outcomes were derived from a sham-controlled double-blind trial of PENFS for adolescents with IBS. Costs/work-productivity impact for parents were derived from appropriate observational cohorts. PENFS was associated with 18 added healthy days over 1 year of follow-up, increased annual parental wages of $5,802 due to fewer missed work days to care for the child, and $4744 in cost-savings to insurance. Percutaneous electrical field nerve stimulation for adolescents with IBS appears to yield significant cost-savings to patients' families and insurance.

Development and validation of cognitive ageing risk score (CARS) for early detection of subtle cognitive deficits in older people.

BACKGROUND: Early cognitive deficits commonly seen in older people have not been well defined and managed in primary care. The objectives are (1) to develop and validate a new risk score to estimate the risk of dementia in Chinese older population; and (2) to evaluate the use of risk score in conjunction with cognitive screening in detecting early cognitive deficits in community older people. METHODS: A development cohort of 306 cognitive healthy older adults aged 60 or above were followed for 6 years. A CARS was constructed using the estimated coefficients of risk factors associated with dementia at follow up. Validation was carried out in another five-year cohort of 383 older adults. The usefulness of CARS in detecting early cognitive deficits was evaluated. RESULTS: Risk factors include older age, male gender, low level of education, poorly controlled diabetes, prolonged sleep latency, fewer mind body or light exercise, loneliness, and being apolipoprotein e4 carriers. A cutoff of CARS at -1.3 had a sensitivity of 83.9% and a specificity of 75.4% to predict dementia. The area under curve was 82.5% in the development cohort. Early cognitive deficits were characterized by impaired retention (p <.001, 95% CI 0.2-0.9) and attention (p =.012, 95% CI 0.1-0.8). CONCLUSION: The CARS can be used as a standard risk assessment of dementia or in conjunction with a computerized cognitive screening to evaluate a full cognitive profile for detecting early cognitive deficits. The result put forward the integration of risk algorithm into smart healthcare system to provide personalized lifestyle interventions.

Upregulation of acid sensing ion channels is associated with esophageal hypersensitivity in GERD.

Proton pump inhibitors (PPIs) are the mainstay of therapy for gastroesophageal reflux disease (GERD) but up to 60% of patients have inadequate response to therapy. Acid sensing ion channels (ASICs) play important roles in nociception. This study aimed to investigate whether the increased expression of ASICs results in neuronal hyperexcitability in GERD. Esophageal biopsies were taken from GERD patients and healthy subjects to compare expression of ASIC1 and 3. Next, gene and protein expression of ASIC1 and 3 from esophageal mucosa and dorsal root ganglia (DRG) neurons were measured by qPCR, Western-blot and immunofluorescence in rodent models of reflux esophagitis (RE), non-erosive reflux disease (NERD), and sham operated groups. Excitability of DRG neurons in the GERD and sham groups were also tested by whole-cell patch-clamp recordings. We demonstrated that ASIC1 and 3 expression were significantly increased in patients with RE compared with healthy controls. This correlated positively with symptom severity of heartburn and regurgitation (p < .001). Next, ASIC1 and 3 gene and protein expression in rodent models of RE and NERD were similarly increased in esophageal mucosa as well as T3-T5 DRG neurons compared with sham operation. DRG neurons from RE animals showed hyperexcitability compared with sham group. However, intrathecal injection of ASIC specific inhibitors, PcTx1 and APTEx-2, as well as silencing ASIC1 and 3 genes with specific siRNAs prevented visceral hypersensitivity. Overall, upregulation of ASIC1 and 3 may lead to visceral hypersensitivity in RE and NERD and may be a potential therapeutic target for PPI non-responsive patients.

Dementia literacy in an ageing world.

AIMS: This discursive article aims to capture and explore the most pertinent nursing aspects of dementia literacy (DL). BACKGROUND: Older people constitute a rapidly increasing proportion of the global population, experiencing higher risk of developing chronic disease, including dementia. It is important that older adults receive and understand reliable health-related information, as age-related changes may affect the level of health literacy in an older person. It has been suggested that older adults may have poorer health literacy than younger adults, associated with poorer health outcomes. Health literacy, how people receive, interpret and act on health information, play a significant role in dementia-related disorders, both as a possible predicter of onset of dementia and as a potential modifier of cognitive decline. Dementia literacy constitutes one aspect of health literacy in relation to nursing care, related to knowledge of dementia-related disorders and approaches towards older people with dementia. DESIGN: This discursive article explores the importance of DL for the nursing profession, including dementia-related assessment, education and interventions. METHOD: This article is informed by analysis of relevant descriptive and empirical literature and policy documents related to DL, an increasingly important aspect of dementia-related nursing care. Valid assessment tools that can accurately assess aspects an individuals' DL are examined; these have the potential to help nurses detect dementia-related symptoms. With early detection and prevention of dementia, older people may have better chance of benefiting from evolving treatment options. CONCLUSION: Greater attention needs to be given to the issue of DL in older people, especially in terms of nursing assessment and care. Globally, increased DL-related education is urgently required to improve knowledge of this concept; this includes public awareness initiatives to better understanding this chronic condition. IMPLICATION NURSING PRACTICE: Enhancing DL has the potential to empower older people to have greater access to healthcare services and to make more informed decisions about their health care. PATIENT OR PUBLIC CONTRIBUTION: No patient or public contribution, as this is a discursive article.

Baseline Predictors of Longitudinal Changes in Symptom Severity and Quality of Life in Patients With Suspected Gastroparesis.

BACKGROUND & AIMS: Whether gastric emptying tests predict longitudinal outcomes in patients with symptoms of gastroparesis is unclear. We aimed to determine whether baseline gastric emptying tests and gut motility parameters could impact longitudinal symptom(s) and quality of life (QOL) in a prospective, observational cohort study of patients with symptoms of gastroparesis. METHODS: One hundred fifty patients with gastroparesis symptoms underwent simultaneous scintigraphy (GES) and wireless motility capsule (WMC) measurement of gastric emptying and other motility parameters. Patient Assessment of Upper Gastrointestinal Symptoms and Quality of Life were administered at baseline, and 3 and 6 months after testing. Multivariable generalized linear marginal models were fit to determine which baseline parameters predict longitudinal changes in symptoms and QOL. RESULTS: Overall upper GI symptoms and QOL scores were moderate in severity at baseline and significantly improved over 6 months. Clinical variables, including female gender, harder stools by Bristol stool form score, and presence of functional dyspepsia (FD) by Rome III criteria, were predictive of more severe upper GI symptoms. Even after controlling for these clinical factors, delayed gastric emptying by GES or WMC was associated with worse symptom severity and QOL scores. Low gastric and elevated small bowel contractile parameters by WMC were also independently associated with more severe upper GI symptoms and worse QOL scores. CONCLUSIONS: Baseline features, including demographic and clinical variables, delayed gastric emptying and abnormal gastrointestinal contractility, were independent predictors of more severe longitudinal symptoms and worse quality of life outcomes. These factors may help to risk stratify patients and guide treatment decisions. ClinicalTrials.gov no: NCT02022826.

Is sleep quality a potential predictor of neurocognitive disorders? A 6-year follow-up study in Chinese older adults.

OBJECTIVE: To investigate the longitudinal association of sleep quality with incidence of neurocognitive disorders in 6 years. METHODS: This was a 6-year follow-up study of community-living older adults who scored a Clinical Dementia Rating (CDR) of 0 at baseline. Sleep quality was assessed by the self-rated Pittsburgh Sleep Quality Index (PSQI) questionnaire, where higher scores indicated poorer sleep quality, and a cutoff score of 5 or above was suggestive of sleep disorder. The study outcome was incident neurocognitive disorders in 6 years, as identified by a CDR of 0.5 or above. Poisson regression analysis was conducted to test if baseline sleep quality was independently associated with risk of incident neurocognitive disorders in 6 years. RESULTS: Of the 290 participants in this study, 166 (57.2%) developed neurocognitive disorders in 6 years. They had poorer sleep quality (mean [SD] total PSQI score: 6.2 [3.8] vs. 4.9 [3.2], p = 0.001) and higher prevalence of sleep disorder (100 [60.2%] vs. 56 [45.2%], p = 0.01) at baseline than those who remained free of neurocognitive disorder. After controlling for age, gender, education, and physical and psychiatric morbidities, the risk ratios (RRs) for incident neurocognitive disorders were 1.05 (95% confidence interval (CI) = 1.00-1.11, p < 0.05) for PSQI total score and 1.50 (95% CI = 1.05-2.14, p = 0.03) for sleep disorder at baseline. CONCLUSIONS: Sleep quality might predict the development of neurocognitive disorders. From a clinical perspective, enquiry of sleep quality and screening for sleep disorder should be promoted as part of the neurocognitive disorder risk assessment in older adults.

Sublethal doxorubicin promotes migration and invasion of breast cancer cells: role of Src Family non-receptor tyrosine kinases.

BACKGROUND: Doxorubicin (Dox) is a widely used chemotherapy, but its effectiveness is limited by dose-dependent side effects. Although lower Dox doses reduce this risk, studies have reported higher recurrence of local disease with no improvement in survival rate in patients receiving low doses of Dox. To effectively mitigate this, a better understanding of the adverse effects of suboptimal Dox doses is needed. METHODS: Effects of sublethal dose of Dox on phenotypic changes were assessed with light and confocal microscopy. Migratory and invasive behavior were assessed by wound healing and transwell migration assays. MTT and LDH release assays were used to analyze cell growth and cytotoxicity. Flow cytometry was employed to detect cell surface markers of cancer stem cell population. Expression and activity of matrix metalloproteinases were probed with qRT-PCR and zymogen assay. To identify pathways affected by sublethal dose of Dox, exploratory RNAseq was performed and results were verified by qRT-PCR in multiple cell lines (MCF7, ZR75-1 and U-2OS). Regulation of Src Family kinases (SFK) by key players in DNA damage response was assessed by siRNA knockdown along with western blot and qRT-PCR. Dasatinib and siRNA for Fyn and Yes was employed to inhibit SFKs and verify their role in increased migration and invasion in MCF7 cells treated with sublethal doses of Dox. RESULTS: The results show that sublethal Dox treatment leads to increased migration and invasion in otherwise non-invasive MCF7 breast cancer cells. Mechanistically, these effects were independent of the epithelial mesenchymal transition, were not due to increased cancer stem cell population, and were not observed with other chemotherapies. Instead, sublethal Dox induces expression of multiple SFK-including Fyn, Yes, and Src-partly in a p53 and ATR-dependent manner. These effects were validated in multiple cell lines. Functionally, inhibiting SFKs with Dasatinib and specific downregulation of Fyn suppressed Dox-induced migration and invasion of MCF7 cells. CONCLUSIONS: Overall, this study demonstrates that sublethal doses of Dox activate a pro-invasive, pro-migration program in cancer cells. Furthermore, by identifying SFKs as key mediators of these effects, our results define a potential therapeutic strategy to mitigate local invasion through co-treatment with Dasatinib.

How the North American Consensus Protocol Affects the Performance of Glucose Breath Testing for Bacterial Overgrowth Versus a Traditional Method.

INTRODUCTION: The North American Consensus guidelines for glucose breath testing (GBT) for small intestinal bacterial overgrowth (SIBO) incorporated changes in glucose dosing and diagnostic cutoffs. We compared GBT positivity based on hydrogen and methane excretion and quantified symptoms during performance of the North American vs older modified Rome Consensus protocols. METHODS: GBT was performed using the North American protocol (75 g glucose, cutoffs >20 parts per million [ppm] hydrogen increase after glucose and >10 ppm methane anytime) in 3,102 patients vs modified Rome protocol (50 g glucose, >12 ppm hydrogen and methane increases after glucose) in 3,193 patients with suspected SIBO. RESULTS: Positive GBT were more common with the North American vs modified Rome protocol (39.5% vs 29.7%, P < 0.001). Overall percentages with GBT positivity using methane criteria were greater and hydrogen criteria lower with the North American protocol (P < 0.001). Peak methane levels were higher for the North American protocol (P < 0.001). Times to peak hydrogen and methane production were not different between protocols. With the North American protocol, gastrointestinal and extraintestinal symptoms were more prevalent after glucose with both positive and negative GBT (P < 0.04) and greater numbers of symptoms (P < 0.001) were reported. DISCUSSION: GBT performed using the North American Consensus protocol was more often positive for SIBO vs the modified Rome protocol because of more prevalent positive methane excretion. Symptoms during testing were greater with the North American protocol. Implications of these observations on determining breath test positivity and antibiotic decisions for SIBO await future prospective testing.

The Bidirectional Relationship between Vision and Cognition: A Systematic Review and Meta-analysis.

TOPIC: Visual impairment (VI) and cognitive impairment (CIM) are prevalent age-related conditions that impose substantial burden on the society. Findings on the hypothesized bidirectional association of VI and CIM remains equivocal. Hence, we conducted a systematic review and meta-analysis to examine this bidirectional relationship. CLINICAL RELEVANCE: Sixty percent risk of CIM has not been well elucidated in the literature. A bidirectional relationship between VI and CIM may support the development of strategies for early detection and management of risk factors for both conditions in older people. METHODS: PubMed, Embase, and Cochrane Central registers were searched systematically for observational studies, published from inception until April 6, 2020, in adults 40 years of age or older reporting objectively measured VI and CIM assessment using clinically validated cognitive screening tests or diagnostic evaluation. Meta-analyses on cross-sectional and longitudinal associations between VI and CIM outcomes (any CIM assessed using screening tests and clinically diagnosed dementia) were examined. Random effect models were used to generate pooled odds ratios (ORs) and 95% confidence intervals (CIs). We also examined study quality, publication bias, and heterogeneity. RESULTS: Forty studies were included (n = 47 913 570). Meta-analyses confirmed that persons with VI were more likely to have CIM, with significantly higher odds of: (1) any CIM (cross-sectional: OR, 2.38 [95% CI, 1.84-3.07]; longitudinal: OR, 1.66 [95% CI, 1.46-1.89]) and (2) clinically diagnosed dementia (cross-sectional: OR, 2.43 [95% CI, 1.48-4.01]; longitudinal: OR, 2.09 [95% CI, 1.37-3.21]) compared with persons without VI. Significant heterogeneity was explained partially by differences in age, sex, and follow-up duration. Also, some evidence suggested that individuals with CIM, relative to cognitively intact persons, were more likely to have VI, with most articles (8/9 [89%]) reporting significantly positive associations; however, meta-analyses on this association could not be conducted because of insufficient data. DISCUSSION: Overall, our work suggests that VI is a risk factor of CIM, although further work is needed to confirm the association of CIM as a risk factor for VI. Strategies for early detection and management of both conditions in older people may minimize individual clinical and public health consequences.

Noncanonical role for the binding protein in substrate uptake by the MetNI methionine ATP Binding Cassette (ABC) transporter.

The Escherichia coli methionine ABC transporter MetNI exhibits both high-affinity transport toward l-methionine and broad specificity toward methionine derivatives, including d-methionine. In this work, we characterize the transport of d-methionine derivatives by the MetNI transporter. Unexpectedly, the N229A substrate-binding deficient variant of the cognate binding protein MetQ was found to support high MetNI transport activity toward d-selenomethionine. We determined the crystal structure at 2.95 Šresolution of the ATPγS-bound MetNIQ complex in the outward-facing conformation with the N229A apo MetQ variant. This structure revealed conformational changes in MetQ providing substrate access through the binding protein to the transmembrane translocation pathway. MetQ likely mediates uptake of methionine derivatives through two mechanisms: in the methionine-bound form delivering substrate from the periplasm to the transporter (the canonical mechanism) and in the apo form by facilitating ligand binding when complexed to the transporter (the noncanonical mechanism). This dual role for substrate-binding proteins is proposed to provide a kinetic strategy for ABC transporters to transport both high- and low-affinity substrates present in a physiological concentration range.

Higher psychogeriatric admissions in COVID-19 than in severe acute respiratory syndrome.

OBJECTIVES: To examine whether psychogeriatric admissions increased after COVID-19, independent of seasonal variation; whether the increase was comparable with that seen in severe acute respiratory syndrome (SARS); and which factors were associated with such increase. METHODS: All psychiatric admissions aged 65 or older in the 3 months before and after COVID-19 (from November 2019 to April 2020), in the previous 2 years (from November 2017 to April 2018 and from November 2018 to April 2019), and in the year of SARS (from November 2002 to April 2003) in a major gazette inpatient psychiatric unit in Hong Kong, which serves a catchment population of 1.4 million, were anonymously reviewed. The number of psychogeriatric admissions between different timeframes was compared, and factors that might explain the increase in admissions following COVID-19 were examined. RESULTS: Psychogeriatric admissions increased by 21.4% following the COVID-19 outbreak. This increase was not explained by seasonal variation and was greater and lasted longer than that in SARS. A rising trend in admissions for older adults living in residential care homes was observed. The increase in admissions was associated with fewer outpatient attendance, fewer home visits by nurses, and more older adults with dementia requiring inpatient care. CONCLUSIONS: Our findings highlight the impact of COVID-19 on older adults' mental health, greater demand for inpatient psychogeriatric services in COVID-19 than in SARS, and the importance of maintaining support for community-living older adults, in particular those with dementia, and their caregivers in reducing the needs for inpatient psychiatric treatment during the pandemic. Clinicaltrials.gov # ChiCTR2000033317.

Cognitive training interventions and depression in mild cognitive impairment and dementia: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Depression is common in people with cognitive impairment but the effect of cognitive training in the reduction of depression is still uncertain. AIMS: The purpose of this paper is to evaluate the effect of cognitive training interventions in the reduction of depression rating scale score in people with cognitive impairment. METHODS: Literature searches were conducted via OVID databases. Randomized controlled trials (RCTs) evaluated the effect of cognitive training interventions for the reduction of depression rating scale score in people with mild cognitive impairment (MCI) or dementia were included. Mean difference (MD) with 95% confidence interval (CI) was used to combine the results of Geriatric Depression Scale (GDS). Standardized mean difference (SMD) was used to combine the results of different depression rating scales. Subgroup analyses were conducted according to the types of cognitive training and severity of cognitive impairment, i.e. MCI and dementia. RESULTS: A total of 2551 people with MCI or dementia were extracted from 36 RCTs. The baseline mean score of GDS-15 was 4.83. Participants received cognitive training interventions had a significant decrease in depression rating scale score than the control group (MD of GDS-15 = -1.30, 95% CI = -2.14--0.47; and SMD of eight depression scales was -0.54 (95% CI = -0.77--0.31). In subgroup analyses, the effect size of computerized cognitive training and cognitive stimulation therapy were medium-to-large and statistically significant in the reduction of depression rating scale score. CONCLUSIONS: Cognitive training interventions show to be a potential treatment to ameliorate depression in people with cognitive impairment.

Tackling challenges in care of Alzheimer's disease and other dementias amid the COVID-19 pandemic, now and in the future.

We have provided an overview on the profound impact of COVID-19 upon older people with Alzheimer's disease and other dementias and the challenges encountered in our management of dementia in different health-care settings, including hospital, out-patient, care homes, and the community during the COVID-19 pandemic. We have also proposed a conceptual framework and practical suggestions for health-care providers in tackling these challenges, which can also apply to the care of older people in general, with or without other neurological diseases, such as stroke or parkinsonism. We believe this review will provide strategic directions and set standards for health-care leaders in dementia, including governmental bodies around the world in coordinating emergency response plans for protecting and caring for older people with dementia amid the COIVD-19 outbreak, which is likely to continue at varying severity in different regions around the world in the medium term.

On code sharing and model documentation of published individual and agent-based models.

Being able to replicate research results is the hallmark of science. Replication of research findings using computational models should, in principle, be possible. In this manuscript, we assess code sharing and model documentation practices of 7500 publications about individual-based and agent-based models. The code availability increased over the years, up to 18% in 2018. Model documentation does not include all the elements that could improve the transparency of the models, such as mathematical equations, flow charts, and pseudocode. We find that articles with equations and flow charts being cited more among other model papers, probably because the model documentation is more transparent. The practices of code sharing improve slowly over time, partly due to the emergence of more public repositories and archives, and code availability requirements by journals and sponsors. However, a significant change in norms and habits need to happen before computational modeling becomes a reproducible science.

Altered R-spondin 1/CART neurocircuit in the hypothalamus contributes to hyperphagia in diabetes.

Hyperphagia is common in diabetes and may worsen hyperglycemia and diabetic complications. The responsible mechanisms are not well understood. The hypothalamus is a key center for the control of appetite and energy homeostasis. The ventromedial nucleus (VMH) and arcuate nucleus (ARC) are two critical nuclei involved in these processes. We have reported that R-spondin 1 (Rspo1) and its receptor leucin-rich repeat and G protein-coupled receptor 4 (LGR4) in the VMH and ARC suppressed appetite, but the downstream neuronal pathways are unclear. Here we show that neurons containing cocaine and amphetamine-regulated transcript (CART) in ARC express both LGR4 and insulin receptor; intracerebroventricular injection of Rspo1 induced c-Fos expression in CART neurons of ARC; and silencing CART in ARC attenuated the anorexigenic actions of Rspo1. In diabetic and obese fa/fa rats, Rspo1 mRNA in VMH and CART mRNA in ARC were reduced; this was accompanied by increased food consumption. Insulin treatment restored Rspo1 and CART gene expressions and normalized eating behavior. Chronic intracerebroventricular injection of Rspo1 inhibited food intake and normalized diabetic hyperphagia; intracerebroventricular injection of Rspo1 or insulin increased CART mRNA in ARC. In the CART neuron cell line, Rspo1 and insulin potentiated each other on pERK and ß-catenin, and in rats, they acted synergistically to inhibit food intake. Silencing Rspo1 in VMH reduced CART expression in ARC and attenuated the inhibitory effect of insulin on food intake. In conclusion, our data indicated that CART works downstream of Rspo1 and Rspo1 mediated the action of insulin centrally. The altered Rspo1/CART neurocircuit in the hypothalamus contributes to hyperphagia in diabetes. NEW & NOTEWORTHY This study reports that cocaine and amphetamine-regulated transcript (CART) neurons in the arcuate nucleus (ARC) of hypothalamus acted downstream of R-spondin 1 (Rspo1) to inhibit food intake. The Rspo1 mRNA level in ventromedial nucleus (VMH) and CART mRNA level in ARC were reduced in type 1 diabetic rat and obese fa/fa rat. Rspo1 and insulin acted synergistically on phospho-ERK and ß-catenin signal pathways and in suppressing food intake. The current results proposed that altered Rspo1/CART neurocircuit in the hypothalamus contributes to hyperphagia in diabetes.