Surface-enhanced Raman scatting microfluidic chip based on the identification competition strategy were used for rapid and simultaneous detection of liver cancer related proteins.

Biomarker testing plays a crucial role in the early detection of liver cancer. Herein, we developed a dual-signal amplification approach utilizing magnetic aggregation and a recognition competition strategy for the simultaneous detection of alpha-fetoprotein (AFP) and manganese superoxide dismutase (MnSOD) in serum. 4-MBA@AuNPs@H1 and DTNB@AuNPs@H2 were synthesized by functionalizing Raman signaling molecules and aptamer complementary chains onto the surface of gold nanoparticles (AuNPs). The detection complex Raman signal molecule@AuNPs@H-Fe3O4@cDNA was assembled by conjugating 4-MBA@AuNPs@H1 and DTNB@AuNPs@H2 with two nucleic acid aptamers (cDNA1 and cDNA2) modified with Fe3O4 through partial base complementary pairing. The target protein exhibited specific binding with the aptamer, leading to the competitive displacement of 4-MBA@AuNPs@H1 and DTNB@AuNPs@H2 from the Fe3O4 array surface, consequently resulting in a reduction of the Surface-Enhanced Raman Spectroscopy (SERS) signal. Through this approach, the limit of detection (LOD) for AFP and MnSOD in serum was achieved at remarkably low levels of 5.89 pg/mL and 6.23 pg/mL, respectively, with a reaction incubation period of only 5 min. Finally, the platform was utilized for the quantification of AFP and MnSOD in the serum of a nude mouse hepatocellular carcinoma model. The results obtained through SERS were consistent with those from enzyme-linked immunosorbent assay (ELISA), validating its accuracy. This methodology presents a novel approach for the swift and concurrent detection of proteins, holding significant clinical promise for the early diagnosis of hepatocellular carcinoma.

The cytochrome P4501A1 (CYP1A1) inhibitor bergamottin enhances host tolerance to multidrug-resistant Vibrio vulnificus infection.

PURPOSE: Vibrio vulnificus (V. Vulnificus) infection is characterized by rapid onset, aggressive progression, and challenging treatment. Bacterial resistance poses a significant challenge for clinical anti-infection treatment and is thus the subject of research. Enhancing host infection tolerance represents a novel infection prevention strategy to improve patient survival. Our team initially identified cytochrome P4501A1 (CYP1A1) as an important target owing to its negative modulation of the body's infection tolerance. This study explored the superior effects of the CYP1A1 inhibitor bergamottin compared to antibiotic combination therapy on the survival of mice infected with multidrug-resistant V. Vulnificus and the protection of their vital organs. METHODS: An increasing concentration gradient method was used to induce multidrug-resistant V. Vulnificus development. We established a lethal infection model in C57BL/6J male mice and evaluated the effect of bergamottin on mouse survival. A mild infection model was established in C57BL/6J male mice, and the serum levels of creatinine, urea nitrogen, aspartate aminotransferase, and alanine aminotransferase were determined using enzyme-linked immunosorbent assay to evaluate the effect of bergamottin on liver and kidney function. The morphological changes induced in the presence of bergamottin in mouse organs were evaluated by hematoxylin and eosin staining of liver and kidney tissues. The bacterial growth curve and organ load determination were used to evaluate whether bergamottin has a direct antibacterial effect on multidrug-resistant V. Vulnificus. Quantification of inflammatory factors in serum by enzyme-linked immunosorbent assay and the expression levels of inflammatory factors in liver and kidney tissues by real-time quantitative polymerase chain reaction were performed to evaluate the effect of bergamottin on inflammatory factor levels. Western blot analysis of IκBα, phosphorylated IκBα, p65, and phosphorylated p65 protein expression in liver and kidney tissues and in human hepatocellular carcinomas-2 and human kidney-2 cell lines was used to evaluate the effect of bergamottin on the nuclear factor kappa-B signaling pathway. One-way ANOVA and Kaplan-Meier analysis were used for statistical analysis. RESULTS: In mice infected with multidrug-resistant V. Vulnificus, bergamottin prolonged survival (p = 0.014), reduced the serum creatinine (p = 0.002), urea nitrogen (p = 0.030), aspartate aminotransferase (p = 0.029), and alanine aminotransferase (p = 0.003) levels, and protected the cellular morphology of liver and kidney tissues. Bergamottin inhibited interleukin (IL)-1ß, IL-6, and tumor necrosis factor (TNF)-α expression in serum (IL-1ß: p = 0.010, IL-6: p = 0.029, TNF-α: p = 0.025) and inhibited the protein expression of the inflammatory factors IL-1ß, IL-6, TNF-α in liver (IL-1ß: p = 0.010, IL-6: p = 0.011, TNF-α: p = 0.037) and kidney (IL-1ß: p = 0.016, IL-6: p = 0.011, TNF-α: p = 0.008) tissues. Bergamottin did not affect the proliferation of multidrug-resistant V. Vulnificus or the bacterial load in the mouse peritoneal lavage fluid (p = 0.225), liver (p = 0.186), or kidney (p = 0.637). CONCLUSION: Bergamottin enhances the tolerance of mice to multidrug-resistant V. Vulnificus infection. This study can serve as a reference and guide the development of novel clinical treatment strategies for V. Vulnificus.

Public experiences and perspectives of primary care in Canada: results from a cross-sectional survey.

BACKGROUND: Through medicare, residents in Canada are entitled to medically necessary physician services without paying out of pocket, but still many people struggle to access primary care. We conducted a survey to explore people's experience with and priorities for primary care. METHODS: We conducted an online, bilingual survey of adults in Canada in fall 2022. We distributed an anonymous link through diverse channels and a closed link to 122 053 people via a national public opinion firm. We weighted completed responses to mirror Canada's population and adjusted for sociodemographic characteristics using regression models. RESULTS: We analyzed 9279 completed surveys (5.9% response rate via closed link). More than one-fifth of respondents (21.8%) reported having no primary care clinician, and among those who did, 34.5% reported getting a same or next-day appointment for urgent issues. Of respondents, 89.4% expressed comfort seeing another team member if their doctor recommended it, but only 35.9%, 9.5%, and 12.4% reported that their practice had a nurse, social worker, or pharmacist, respectively. The primary care attribute that mattered most was having a clinician who "knows me as a person and considers all the factors that affect my health." After we adjusted for respondent characteristics, people in Quebec, the Atlantic region, and British Columbia had lower odds of reporting a primary care clinician than people in Ontario (adjusted odds ratio 0.30, 0.33, and 0.39, respectively; p < 0.001). We also observed large provincial variations in timely access, interprofessional care, and walk-in clinic use. INTERPRETATION: More than 1 in 5 respondents did not have access to primary care, with large variation by province. Reforms should strive to expand access to relationship-based, longitudinal care in a team setting.

Patient Experience With Resident Versus Staff Physicians: Results From a Cross-Sectional Patient Survey From Canadian Family Medicine Residencies.

BACKGROUND AND OBJECTIVES: We compared experiences of patients who reported usually being seen by a resident with those usually seen by a staff physician. METHODS: We analyzed responses to a patient experience survey distributed at 13 family medicine teaching practices affiliated with the University of Toronto between May and June 2020. We analyzed responses to seven questions pertaining to timely access, continuity, and patient-centeredness. We compared responses between two types of usual primary care clinicians and calculated odds ratios before and after adjustment for patient characteristics. RESULTS: We analyzed data from 6,545 unique surveys; 18.6% reported their usual clinician was a resident physician. Resident patients were more likely to be older, born outside of Canada, report a high school education or less, and report having difficulty making ends meet. Compared to patients of staff physicians, patients of resident physicians had lower odds of being able to see their preferred primary care clinician and lower odds of getting nonurgent care in a reasonable time. They also had lower odds of reporting patient-centered care, but we found no significant differences in whether the time for an urgent appointment was about right or whether accessing care after hours was easy. CONCLUSIONS: In our setting, patients who reported usually seeing resident physicians had worse continuity of care and timeliness for nonurgent care than patients who reported usually seeing staff physicians despite resident patients being older, sicker, and having a lower socioeconomic position. Postgraduate training programs need to test models to support access and continuity for resident patient panels.

Highly efficient expression of human extracellular superoxide dismutase (rhEcSOD) with ultraviolet-B-induced damage-resistance activity in transgenic silkworm cocoons.

Extracellular superoxide dismutase (EcSOD) protects tissues from oxidative stress, and thus is considered as a therapeutic agent for many diseases such as atherosclerosis, hypertension, and cancer. However, cost-effective production of bioactive recombinant human EcSOD (rhEcSOD) remains a challenge. Herein, we developed an efficient strategy for producing active rhEcSOD by transgenic silkworms. rhEcSOD was successfully synthesized as homodimers and homotetramers in the middle silk gland and spun into the cocoons with a concentration of 9.48 ± 0.21 mg/g. Purification of rhEcSOD from the cocoons could be conveniently achieved with a purity of 99.50% and a yield of 3.5 ± 0.5 mg/g. Additionally, N-glycosylation at the only site of N89 in rhEcSOD with 10 types were identified. The purified rhEcSOD gained the potent enzymatic activity of 4 162 ± 293 U/mg after Cu/Zn ions incorporation. More importantly, rhEcSOD was capable of penetrating and accumulating in the nuclei of cells to maintain cell morphology and attenuate ultraviolet B-induced cell apoptosis by eliminating reactive oxygen species and inhibiting the C-Jun N-terminal kinase signaling pathway. These results demonstrated that the transgenic silkworm could successfully produce rhEcSOD with enzymatic and biological activities for biomedical applications.

4-Mercaptopyridine-Modified Sensor for the Sensitive Electrochemical Detection of Mercury Ions.

As a highly toxic heavy metal ion, mercury ion (Hg2+) pollution has caused serious harm to the environment and human health. In this paper, 4-mercaptopyridine (4-MPY) was selected as the sensing material and decorated on the surface of a gold electrode. Trace Hg2+ could be detected by both differential pulse voltammetry (DPV) and electrochemical impedance spectroscopy (EIS) methods. The proposed sensor displayed a wide detection range from 0.01 µg/L to 500 µg/L with a low limit of detection (LOD) of 0.002 µg/L by EIS measurements. Combined with molecular simulations and electrochemical analyses, the chelating mechanism between Hg2+ and 4-MPY was explored. Through the analysis of binding energy (BE) values and stability constants, 4-MPY showed an excellent selectivity for Hg2+. In the presence of Hg2+, the coordination of Hg2+ with the pyridine nitrogen of 4-MPY was generated at the sensing region, which caused a change in the electrochemical activity of the electrode surface. Due to the strong specific binding capability, the proposed sensor featured excellent selectivity and an anti-interference capability. Furthermore, the practicality of the sensor for Hg2+ detection was validated with the samples of tap water and pond water, which demonstrated its potential application for on-site environmental detection.

Enhanced stability and tunable photoluminescence in Mn2+-doped one-dimensional hybrid lead halide perovskites for high-performance white light emitting diodes.

Organic-inorganic hybrid low-dimensional lead halides have garnered significant interest in the realm of solid-state optical materials due to their unique properties and potential applications. In this study, we report the synthesis, characterization and application of Mn2+-doped one-dimensional (1D) [AEP]PbCl5·H2O hybrid lead halide perovskites with tunable photoluminescence properties. The Mn2+ doping leads to a redshift of the dominant emission wavelength from 463 nm to 630 nm, with the optimal doping concentration resulting in an enhanced photoluminescence quantum yield (PLQY) from less than 1% to 8.96%. The structural and optical stability of these doped perovskites have been thoroughly investigated revealing excellent performance under humid and high-temperature conditions. Perovskite-PVP composite films exhibit high crystallization and bright orange-red emission under UV excitation. Furthermore, we demonstrate the successful fabrication of a white LED device using the Mn2+-doped perovskite in combination with commercial green and blue phosphors. The fabricated LED exhibits a high color rendering index (CRI) of 87.2 and stable electroluminescence performance under various operating currents and extended operation times. Our findings highlight the potential of Mn2+-doped 1D hybrid lead halide perovskites as efficient and stable phosphors for high-performance white light emitting diodes and other optoelectronic applications.

The relationship between physical activity in early pregnancy and hypertensive disorders of pregnancy: a cohort study in Chinese women.

BACKGROUND: We aimed to examine prospective associations between different intensities and different types of physical activity (PA) in early pregnancy and hypertensive disorders of pregnancy (HDP) among Chinese women. METHODS: A total of 6,820 pregnant women from the Tongji-Shuangliu Birth Cohort were included in this study. The pregnancy physical activity questionnaire (PPAQ) was used to assess PA, including household/caregiving, occupational, sports/exercise, and transportation activities in the first trimester of pregnancy. The diagnosis of HDP was collected, including gestational hypertension (GH) and preeclampsia (PE). Data were analyzed by unconditional multivariate logistic regression, and the odds ratio (OR) and 95% confidence interval (CI) were calculated. RESULTS: A total of 178 (2.6%) of the 6,820 women were diagnosed with HDP, of which 126 (1.8%) were GH and 52 (0.8%) were PE. Overall, we found no association between PA in early pregnancy and PE. A trend toward lower risk was found only among women with GH and among those with higher levels of moderate-to-vigorous intensity physical activity (MVPA) (adjusted OR 0.54, 95% CI 0.31-0.96). No association was observed between PA and HDP in early pregnancy, regardless of different intensities or types of PA. CONCLUSION: MVPA in the first trimester is an influencing factor of HDP. Encouraging pregnant women to engage in MVPA in the first trimester may help to prevent GH.

A Highly Sensitive Dual-Signal Strategy via Inner Filter Effect between Tween 20-Gold Nanoparticles and CdSe/ZnS Quantum Dots for Detecting Cu2.

A highly sensitive and accurate dual-signal strategy is developed for trace Cu2+ detection based on the inner filter effect (IFE) between Tween 20-gold nanoparticles (AuNPs) and CdSe/ZnS quantum dots (QDs). Tween 20-AuNPs are utilized as colorimetric probes and excellent fluorescent absorbers. The fluorescence of CdSe/ZnS QDs can be quenched efficiently by Tween 20-AuNPs via IFE. In the presence of D-penicillamine, D-penicillamine induces the aggregation of Tween 20-AuNPs and the fluorescent recovery of CdSe/ZnS QDs at high ionic strength. Upon addition of Cu2+, D-penicillamine tends to selectively chelate with Cu2+ and then forms the mixed-valence complexes, which consequently inhibits the aggregation of Tween 20-AuNPs and the fluorescent recovery. The dual-signal method is used to quantitatively detect trace Cu2+, with low detection limits of 0.57 µg/L and 0.36 µg/L for colorimetry and fluorescence, respectively. In addition, the proposed method using a portable spectrometer is applied to the detection of Cu2+ in water. This sensitive, accurate and miniature sensing system has potential in environmental evaluations.

A Pragmatic Randomized Controlled Trial of Financial Incentives in Case Management for Homeless Adults With Mental Illness.

OBJECTIVE: Financial incentives can facilitate behavior change and service engagement in health care settings, but research on their use with adults experiencing homelessness is limited. This study examined the effectiveness of financial incentives in improving service engagement and health outcomes among homeless adults with mental illness in Toronto. METHODS: The authors of this randomized controlled trial recruited 176 participants receiving brief multidisciplinary case management services for homeless adults with mental illness after hospital discharge. In a 1:1 randomization design, 87 participants received a financial incentive of CAN$20 for every week they remained engaged with the service for up to 6 months. The remaining 89 participants received treatment as usual. The primary outcome was service contact rates for up to 6 months of follow-up. Secondary outcomes included self-reported health status, mental health symptoms, substance use, quality of life, housing stability, acute health service use, and working alliance. Negative binomial regression models, analyses of covariance, generalized estimating equations models, and Wilcoxon rank sum tests were used to examine differences between the financial incentive and treatment-as-usual groups across outcomes of interest. RESULTS: No significant differences were found between the financial incentive and treatment-as-usual groups in service contact rates or any of the secondary outcomes examined over the 6-month period. CONCLUSIONS: In low-barrier, brief case management programs tailored to the needs of adults experiencing homelessness, financial incentives may not affect service engagement or health outcomes. Further research is needed to identify the effect of financial incentives on engagement in other services, including housing-based interventions.

Comparative Study of Chemosensory Dysfunction in COVID-19 in 2 Geographically Distinct Regions.

OBJECTIVE: To directly compare the prevalence of chemosensory dysfunction (smell and taste) in geographically distinct regions with the same questionnaires. METHODS: A cross-sectional study was performed to evaluate the self-reported symptoms among adults (older than 18 years) who underwent COVID-19 testing at an ambulatory assessment center in Canada and at a hospital in Israel between March 16, 2020, and August 19, 2020. The primary outcome was the prevalence of self-reported chemosensory dysfunction (anosmia/hypomsia and dysgeusia/ageusia). Subgroup analysis was performed to evaluate the prevalence of chemosensory deficits among the outpatients. RESULTS: We identified a total of 350 COVID-19-positive patients (138 Canadians and 212 Israelis). The overall prevalence of chemosensory dysfunction was 47.1%. There was a higher proportion of chemosensory deficits among Canadians compared to Israelis (66.7% vs 34.4%, P < .01). A subgroup analysis for outpatients (never hospitalized) still identified a higher prevalence of chemosensory dysfunction among Canadians compared to Israelis (68.2% vs 36.1%, P < 0.01). A majority of patients recovered their sense of smell after 4 weeks of symptom onset. CONCLUSION: Although the prevalence of chemosensory deficit in COVID-19 was found to be similar to previously published reports, the prevalence can vary significantly across different geographical regions. Therefore, it is important to obtain regionally specific data so that the symptom of anosmia/dysgeusia can be used as a guide for screening for the clinical diagnosis of COVID-19.

Effect of free medicine distribution on ability to make ends meet: post hoc quantitative subgroup analysis and qualitative thematic analysis.

OBJECTIVES: Out-of-pocket medication costs can contribute to financial insecurity and many Canadians have trouble affording medicines. This study aimed to determine if the effect of eliminating out-of-pocket medication costs on individual's financial security varied by gender, racialisation, income and location. DESIGN: In this post hoc subgroup analysis of the CLEAN Meds trial, a binary logistic regression model was fitted and a qualitative inductive thematic analysis of comments related to participant's ability to make ends meet was carried out. SETTING: Primary care patients in Ontario, Canada. PARTICIPANTS: Adult patients (786) who reported not being able to afford medicines during the previous 12 months. INTERVENTION: Free access to a comprehensive list of essential medicines for 24 months. PRIMARY OUTCOME MEASURE: Ability to make ends meet or afford basic necessities. RESULTS: There were no significant differences in the effect of free medicine distribution by gender (OR for male 0.82; 95% CI 0.51 to 1.33, p=0.76), age (older than 65 years OR 1.28; 95 % CI 0.62 to 2.64, p=0.73), racialisation (OR 0.85; 95 % CI 0.51 to 1.45, p=0.66), household income level (above US$30 000 per year OR 1.08; 95 % CI 0.64 to 1.80, p=0.99) or location (urban OR 0.47; 95 % CI 0.23 to 0.96, p=0.10). The main theme in the qualitative analysis was insufficient income, and there were three related themes: out-of-pocket medication expenses, cost-related non-adherence and the importance of medication coverage. In the intervention group, additional themes identified included improved health, functioning and access to basic needs. CONCLUSIONS: Providing free essential medications improved financial security across subgroups in a trial population who all had trouble affording medicines. Free access to medicines could improve health directly by improving medicine adherence and indirectly by making other necessities more accessible to people who have an insufficient income. TRIAL REGISTRATION NUMBER: NCT02744963.

Movement disorder caused by FRRS1L deficiency may be associated with morphological and functional disorders in Purkinje cells.

Ferric Chelate Reductase 1 Like (FRRS1L) protein has been identified as an auxiliary regulatory protein for the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR). FRRS1L is highly expressed in the cerebellum and other brain regions associated with the control of motor function. Loss of FRRS1L has been shown to lead to impaired synaptic transmission via AMPARs and to movement disorders. We found that deletion of the FRRS1L gene causes hyperactivity, reduced muscle strength, impaired coordination, and ataxia in mice. Deletion also impairs Purkinje cell dendritic spine formation and AMPAR expression in the cerebellum and damages the electrophysiological discharge rhythm of Purkinje cells. Cerebrospinal fluid examination and oleic acid (OA)-induced lipid accumulation monitoring in FRRS1L-knockdown SH-SY5Y cells indicated that FRRS1L deficiency could lead to aberrant metabolism of amino acids, glucose, and lipids. In summary, we found that the deletion of FRRS1L leads to impaired motor coordination and cerebellar ataxia in mice, which might be related to the reduced expression of AMPARs, metabolic deviations, and dysplastic functional defects in Purkinje cells.

Directed assembly of genetically engineered eukaryotic cells into living functional materials via ultrahigh-affinity protein interactions.

Engineered living materials (ELMs) are gaining traction among synthetic biologists, as their emergent properties and nonequilibrium thermodynamics make them markedly different from traditional materials. However, the aspiration to directly use living cells as building blocks to create higher-order structures or materials, with no need for chemical modification, remains elusive to synthetic biologists. Here, we report a strategy that enables the assembly of engineered Saccharomyces cerevisiae into self-propagating ELMs via ultrahigh-affinity protein/protein interactions. These yeast cells have been genetically engineered to display the protein pairs SpyTag/SpyCatcher or CL7/Im7 on their surfaces, which enable their assembly into multicellular structures capable of further growth and proliferation. The assembly process can be controlled precisely via optical tweezers or microfluidics. Moreover, incorporation of functional motifs such as super uranyl-binding protein and mussel foot proteins via genetic programming rendered these materials suitable for uranium extraction from seawater and bioadhesion, respectively, pointing to their potential in chemical separation and biomedical applications.

Family physician practice patterns during COVID-19 and future intentions: Cross-sectional survey in Ontario, Canada.

OBJECTIVE: To determine the extent to which family physicians closed their doors altogether or for in-person visits during the pandemic, their future practice intentions, and related factors. DESIGN: Cross-sectional survey. SETTING: Six geographic areas in Toronto, Ont, aligned with Ontario Health Team regions. PARTICIPANTS: Family doctors practising office-based, comprehensive family medicine. MAIN OUTCOME MEASURES: Practice operations in January 2021, use of virtual care, and future plans. RESULTS: Of the 1016 (85.7%) individuals who responded to the survey, 99.7% (1001 of 1004) indicated their practices were open in January 2021, with 94.8% (928 of 979) seeing patients in person and 30.8% (264 of 856) providing in-person care to patients reporting COVID-19 symptoms. Respondents estimated spending 58.2% of clinical care time on telephone visits, 5.8% on video appointments, and 7.5% on e-mail or secure messaging. Among respondents, 17.5% (77 of 439) were planning to close their existing practices in the next 5 years. There were higher proportions of physicians who worked alone in clinics among those who did not see patients in person (27.6% no vs 12.4% yes, P<.05), among those who did not see symptomatic patients (15.6% no vs 6.5% yes, P<.001), and among those who planned to close their practices in the next 5 years (28.9% yes vs 13.9% no, P<.01). CONCLUSION: Most family physicians in Toronto were open to in-person care in January 2021, but almost one-fifth were considering closing their practices in the next 5 years. Policy makers need to prepare for a growing family physician shortage and better understand factors that support recruitment and retention.

Shelter Bans Among People Experiencing Homelessness: an Exploratory Study of Predictors in Two Large Canadian Datasets.

Emergency shelters are a core component of homeless service systems that address immediate basic needs. Service bans, which refer to temporary or permanent disallowances from a program or organization, are an underresearched phenomenon that can leave people experiencing homelessness without needed supports. This exploratory study examined the factors associated with shelter bans among people experiencing homelessness using secondary data from two Canadian studies: (1) a multisite randomized controlled trial of Housing First (At Home/Chez Soi Demonstration Project) and (2) a cross-sectional survey of youth experiencing homelessness across Canada (2019 Without a Home-National Youth Homelessness Survey). The two datasets were analyzed separately using logistic regression models with similar predictors to maximize the comparability of the results. Participants who experienced homelessness at an earlier age and had recent criminal justice system involvement were more likely to have shelter bans in both datasets. Impaired impulse control, more chronic medical conditions and living in Toronto were associated with increased likelihood of shelter bans in the At Home/Chez Soi dataset, whereas more adverse childhood experiences, physical violence victimization, engagement in survival sex behaviours and longer current episodes of homelessness were significant predictors of bans in the Without A Home dataset. Overall, the findings suggest that victimization and criminalization during homelessness may increase the risk of shelter loss from bans and further exclusion. The observed regional differences also highlight the potential limits of individual-level predictors. Further research is needed on shelter ban outcomes, as well as how capacity limits and organizational policies affect banning decisions.

Deficiency of transmembrane AMPA receptor regulatory protein γ-8 leads to attention-deficit hyperactivity disorder-like behavior in mice.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder prevalent in school-age children. At present, however, its etiologies and risk factors are unknown. Transmembrane α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor regulatory protein γ-8 (TARP γ-8, also known as calcium voltage-gated channel auxiliary subunit gamma 8 (CACNG8)) is an auxiliary AMPA receptor (AMPAR) subunit. Here, we report an association between TARP γ-8 and ADHD, whereby adolescent TARP γ-8 knockout (KO) mice exhibited ADHD-like behaviors, including hyperactivity, impulsivity, anxiety, impaired cognition, and memory deficits. Human single-nucleotide polymorphism (SNP) analysis also revealed strong associations between intronic alleles in CACNG8 genes and ADHD susceptibility. In addition, synaptosomal proteomic analysis revealed dysfunction of the AMPA glutamate receptor complex in the hippocampi of TARP γ-8 KO mice. Proteomic analysis also revealed dysregulation of dopaminergic and glutamatergic transmissions in the prefrontal cortices of TARP γ-8 KO mice. Methylphenidate (MPH), which is commonly used to treat ADHD, significantly rescued the major behavioral deficits and abnormal synaptosomal proteins in TARP γ-8 KO mice. Notably, MPH significantly reversed the up-regulation of Grik2 and Slc6a3 in the prefrontal cortex. MPH also significantly improved synaptic AMPAR complex function by up-regulating other AMPAR auxiliary proteins in hippocampal synaptosomes. Taken together, our results suggest that TARP γ-8 is involved in the development of ADHD in humans. This study provides a useful alternative animal model with ADHD-like phenotypes related to TARP γ-8 deficiency, which has great potential for the development of new therapies.

Colorectal cancer-derived exosomes and modulation KRAS signaling.

Colorectal cancer (CRC) is one of the most common cancers worldwide and one of the main causes of cancer-associated mortality. At the period of diagnosis, metastases to other tissues will be present in around 30% of CRC individuals. Individuals with CRC continue to have a poor prognosis despite advances in medication. There is a growing body of literature that CRC develops as a result of the aggregation of various mutations in tumor oncogenes or suppressor genes and that diagnosing cancer in its initial phases may assist in increasing the overall lifespan of individuals with the illness. On the other hand, tumor cells may discharge exosomes in response to oncogenic mutations. By Inhibiting signaling pathways, including the Kirsten rat sarcoma virus (KRAS) mechanism, which is important in a variety of cell activities, exosomes have been shown to cause colorectal cancer in animal studies. The purpose of this review was to summarize the latest discoveries on the modulation of KRAS signaling by exosomes extracted from colorectal cancer.

Global research trends in cardiac arrest research: a visual analysis of the literature based on CiteSpace.

BACKGROUND: The high morbidity, high mortality and low survival rate of cardiac arrest (CA) cause a heavy global burden. We aimed to analyze the changes in scientific output related to CA over the past two decades. METHODS: We analyzed the scientific output related to CA from 2000 to 2020 via the Web of Science. The data were analyzed using CiteSpace software. RESULTS: In total, 28,312 articles relating to CA were identified in the Web of Science. The volume of scientific research output in the field of global CA research was mainly distributed in the Americas, Europe and Asia, covering a wide range. Of the 28,312 articles, the research content of the highly cited literature mainly focused on CA, mild hypothermia treatment, and prognosis of CA patients. CONCLUSION: Various scientific methods were applied to reveal scientific productivity, collaboration, and research hotspots in the CA research field. Cardiopulmonary resuscitation (CPR), extracorporeal membrane oxygenation (ECMO), survival and target temperature management are research hotspots. Future research on CA will continue to focus on its treatment and prognosis to improve the survival rate of CA patients.