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Melanoma is the deadliest form of skin cancer and considered intrinsically resistant to chemotherapy. Nearly all melanomas harbor mutations that activate the RAS/mitogen-activated protein kinase (MAPK) pathway, which contributes to drug resistance via poorly described mechanisms. Herein we show that the RAS/MAPK pathway regulates the activity of cyclin-dependent kinase 12 (CDK12), which is a transcriptional CDK required for genomic stability. We find that melanoma cells harbor constitutively high CDK12 activity, and that its inhibition decreases the expression of long genes containing multiple exons, including many genes involved in DNA repair. Conversely, our results show that CDK12 inhibition promotes the expression of short genes with few exons, including many growth-promoting genes regulated by the AP-1 and NF-κB transcription factors. Inhibition of these pathways strongly synergize with CDK12 inhibitors to suppress melanoma growth, suggesting promising drug combinations for more effective melanoma treatment. In patients with melanoma, increased RAS/mitogen-activated protein kinase (MAPK) pathway activity is known to drive chemotherapy resistance. Here, the authors identify CDK12 as a downstream effector of the RAS/MAPK pathway and therapeutic target which mediates chemotherapy resistance through increased expression of DNA repair associated genes.

Previous studies have shown that immunological factors are involved in the pathogenesis of autism spectrum disorders (ASDs). However, this research has been conducted almost exclusively in Western contexts, and only a handful of studies on immune measures have been conducted in Asian populations, such as Chinese populations. The present study examined whether immunological abnormalities are associated with cognitive deficits and problem behaviors in Chinese children with ASD and whether these children show different immunological profiles. Thirteen typically developing (TD) children and 22 children with ASD, aged 6-17 years, participated voluntarily in the study. Executive functions and short-term memory were measured using neuropsychological tests, and behavioral measures were assessed using parent ratings. The children were also assessed on immunological measures, specifically, the levels of cytokines and chemokines in the blood serum. Children with ASD showed greater deficits in cognitive functions, as well as altered levels of immunological measures, including CCL2, CCL5, and CXCL9 levels, compared to TD children, and the cognitive functions and associated behavioral deficits of children with ASD were significantly associated with different immunological measures. The children were further sub-classified into ASD with only autistic features (ASD-only) or ASD comorbid with attention deficit hyperactivity disorder (ASD + ADHD). The comorbidity results showed that there were no differences between the two groups of ASD children in any of the cognitive or behavioral measures. However, the results pertaining to immunological measures showed that the children with ASD-only and ASD + ADHD exhibited distinct cytokine and chemokine profiles and that abnormal immunologic function was associated with cognitive functions and inattention/hyperactivity symptoms. These results support the notion that altered immune functions may play a role in the selective cognitive and behavioral symptoms of ASD.

Using deep learning model predictions requires not only understanding the model’s confidence but also its uncertainty, so we know when to trust the prediction or require support from a human. In this study, we used Monte Carlo dropout (MCDO) to characterize the uncertainty of deep learning image classification algorithms, including feature fusion models, on simulated synthetic aperture radar (SAR) images of persistent ship wakes. Comparing to a baseline, we used the distribution of predictions from dropout with simple mean value ensembling and the Kolmogorov—Smirnov (KS) test to classify in-domain and out-of-domain (OOD) test samples, created by rotating images to angles not present in the training data. Our objective was to improve the classification robustness and identify OOD images during the test time. The mean value ensembling did not improve the performance over the baseline, in that there was a –1.05% difference in the Matthews correlation coefficient (MCC) from the baseline model averaged across all SAR bands. The KS test, by contrast, saw an improvement of +12.5% difference in MCC and was able to identify the majority of OOD samples. Leveraging the full distribution of predictions improved the classification robustness and allowed labeling test images as OOD. The feature fusion models, however, did not improve the performance over the single SAR-band models, demonstrating that it is best to rely on the highest quality data source available (in our case, C-band).

During rollout of mRNA-based COVID-19 vaccines, several jurisdictions extended the interval between the first and second doses to prioritize wider population access to limited vaccine supply. This study evaluated the effects of an extended dose interval on development of antibody and cell-mediated responses following the primary dose series and a subsequent booster dose. Blood samples were collected from mRNA COVID-19 vaccine recipients at baseline and longitudinally after each dose. Samples were analyzed for SARS-CoV-2-specific antibody titers, neutralizing antibodies and memory T cell responses. An extended dose interval was associated with improved breadth of neutralizing antibody responses against both ancestral and early SARS-CoV-2 variants, but not Omicron variants. Dose interval had no impact on the development of antigen-specific memory T cell responses, the memory or T helper phenotypes of responding T cells or cytokine production. The effects of the primary dose interval on immune outcomes were no longer evident after a third dose of mRNA vaccine. An extended primary dose interval resulted in short-term benefits to humoral immunity but these were transient in the context of subsequent exposures. However, in addition to the public health benefits of wider population access to vaccines, the short-term immunological benefits of extending the dose interval may have been sustained in the absence of boosters. These findings underscore the importance of evaluating dosing intervals during the development of future vaccine candidates.

Impaired mobility is a major concern for older adults and has significant consequences. While the widely accepted belief is that improved physical function underlies the effectiveness of targeted exercise training in improving mobility and reducing falls, recent evidence suggests cognitive and neural benefits gained through exercise may also play an important role in promoting mobility. However, the underlying neural mechanisms of this relationship are currently unclear. Thus, we hypothesize that 6 months of progressive aerobic exercise training would alter frontoparietal network (FPN) connectivity during a motor task among older adults with mild subcortical ischemic vascular cognitive impairment (SIVCI)-and exercise-induced changes in FPN connectivity would correlate with changes in mobility. We focused on the FPN as it is involved in top-down attentional control as well as motor planning and motor execution. Participants were randomized either to usual-care (CON), which included monthly educational materials about VCI and healthy diet; or thrice-weekly aerobic training (AT), which was walking outdoors with progressive intensity. Functional magnetic resonance imaging was acquired at baseline and trial completion, where the participants were instructed to perform bilateral finger tapping task. At trial completion, compared with AT, CON showed significantly increased FPN connectivity strength during right finger tapping ( < 0.05). Across the participants, reduced FPN connectivity was associated with greater cardiovascular capacity ( = 0.05). In the AT group, reduced FPN connectivity was significantly associated with improved mobility performance, as measured by the Timed-Up-and-Go test ( = 0.67, = 0.02). These results suggest progressive AT may improve mobility in older adults with SIVCI via maintaining intra-network connectivity of the FPN.

The assessment of quality of life is critical in ascertaining the benefit of interventions aimed to reduce morbidity among individuals with cognitive impairment. However, the assessment of quality of life is challenging in this population due to the uncertain validity of patient responses as cognitive function declines. Hence, we examined the level of agreement between patient and proxy assessments of health related quality of life (HRQoL) and wellbeing based on the domains that comprise each of these constructs. Analysis of baseline data from 71 community-dwelling older adults with mild Vascular Cognitive Impairment (VCI) who participated in a six-month proof-of-concept single-blinded randomized trial. Level of agreement between patient and caregiver ratings of HRQoL (EQ-5D-3L) and wellbeing (ICECAP-O) were compared using raw agreement (%), intraclass correlation coefficient (ICC) and weighted Cohen's kappa statistic. Self-care (assessed via the EQ-5D-3L) demonstrated almost perfect raw agreement between the patient and caregiver ratings. Three domains (mobility, pain and anxiety) of the EQ-5D-3L demonstrated fair agreement between the patient and caregiver ratings. Two (attachment and control) of the five ICECAP-O domains demonstrated slight agreement. The ICC indicated good agreement for the EQ-5D-3L and poor agreement for the ICECAP-O. There is better patient-proxy agreement for the EQ-5D-3L compared with the ICECAP-O among individuals with mild VCI. These findings imply that the ICECAP-O may have limited clinical, research and policy related utility among individuals with mild VCI. ClinicalTrials.gov NCT01027858.

There has been much research devoted to examining the short-term effects of different interventions for improving memory functioning of older adults with memory complaints. Nevertheless, very few studies have examined the long-term effects of these interventions. Thus, the present study compared the sustained effects of a conventional memory intervention (MI) and a Chinese lifestyle intervention on improving memory functioning in older adults. Twenty-nine older adults who were aged 60 years and older and had memory complaints were recruited. Each completed 10 weekly sessions of the Mind-body Intervention (DMBI; = 11) or MI ( = 18) approximately 18 months ago. Participants' verbal and visual memory functioning and their subjective impression of the changes of their memory performance and physical and psychological health status were evaluated. Results showed significant improvements in memory in both intervention groups at the follow-up assessments when compared with baseline. In addition, older adults in both intervention groups perceived improved memory performance and physical and psychological wellness at follow-up, with the DMBI group reporting significantly greater improvements in physical health compared to the MI group. Altogether, the present study provides supportive evidence that the DMBI and MI might be two effective remedies for older adults to improve or preserve their memory functioning with relatively sustained effects.

There is growing interest in the adoption of lifestyle interventions to remediate age-related declines in memory functioning and physical and psychological health among older adults. This study aimed to investigate whether a Chinese -based lifestyle intervention, the Dejian Mind-Body Intervention (DMBI), leads to positive benefits for memory functioning in older adults. Fifty-six adults aged 60 years or older with subjective memory complaints (SMC) were randomly assigned to receive the DMBI or a control intervention (i.e., a conventional memory intervention; MI) once a week for 10 weeks; 48 of the adults completed the intervention. Participants' verbal and visual memory functioning before and after the intervention were compared. In addition, changes in the participants' subjective feelings about their memory performance and physical and psychological health after the intervention were examined. The results showed that both the DMBI and MI resulted in significant improvements in both verbal and visual memory functioning and that the extent of the improvements was correlated with participants' level of performance at baseline. In addition, compared to the MI group, the DMBI group had significantly greater improvements in subjective physical and psychological health after the intervention. In summary, the present findings support the potential of the DMBI as an alternative lifestyle intervention for improving memory functioning, subjective physical and psychological health of older adults with SMC.

To minimize the risk of cardiovascular disease (CVD), most dietary guidelines have recommended consuming 500 mg/day of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) or two servings of oily fish/week. The sum of percent EPA and DHA in red blood cell (RBC) total fatty acids-termed the omega-3 index-has been proposed as a biomarker for assessing the risk of death from CVD. The omega-3 indices of ≤4, >4 to <8 and ≥8 % have been proposed to be associated with high, intermediate and low CVD risks, respectively. In this study, we determined the EPA + DHA intake level and the omega-3 index of South Asian Canadians (SAC; n  = 308) and white Canadians (WC; n  = 341) age 20–79 years living in the National Capital Region of Canada. The mean EPA + DHA intake levels were 569 ± 571 mg/day for SAC and 684 ± 865 mg/day for WC and 46 % of SAC and 43 % of WC met the recommended EPA + DHA intake level of 500 mg/day. The mean omega-3 indices were 6.6 and 5.9 % for SAC and WC respectively. The suggested cardio-protective target level for the omega-3 index of ≥8 % was observed only in 19.8 % of SAC and in 9.4 % of WC subjects. The majority of the participants (74.4 % of SAC and 82.7 % of WC) were in the >4 to <8 % range. These results suggest that although study participants’ dietary intake of EPA + DHA is adequate, this intake was not sufficient to provide an omega-3 index that is considered cardio-protective.