Association of Vitamin D Levels with Risk of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of Prospective Studies.

Background: Emerging evidence suggests the potential relationship between vitamin D deficiency and risk of cognitive impairment or dementia. To what extent the excess risk of dementia conferred by vitamin D deficiency is less clear. Objective: We summarized the current evidence from several aspects and further quantified these associations. Methods: We collected relevant prospective cohort studies by searching PubMed, Embase and Cochrane up to July 2023. The pooled relative risks (RR) were evaluated by random-effects models. Dose-response analyses were conducted by the method of two-stage generalized least squares regression. Results: Of 9,267 identified literatures, 23 were eligible for inclusion in the meta-analyses, among which 9 and 4 literatures were included in the dose-response analyses for the risk of dementia and Alzheimer's disease (AD). Vitamin D deficiency exhibited a 1.42 times risk for dementia (95% confidence interval (CI) = 1.21-1.65) and a 1.57-fold excess risk for AD (95% CI = 1.15-2.14). And vitamin D deficiency was associated with 34% elevated risk with cognitive impairment (95% CI = 1.19-1.52). Additionally, vitamin D was non-linearly related to the risk of dementia (pnonlinearity = 0.0000) and AD (pnonlinearity = 0.0042). The approximate 77.5-100 nmol/L 25-hydroxyvitamin D [25(OH)D] was optimal for reducing dementia risk. And the AD risk seemed to be decreased when the 25(OH)D level >40.1 nmol/L. Conclusions: Vitamin D deficiency was a risk factor for dementia, AD, and cognitive impairment. The nonlinear relationships may further provide the optimum dose of 25(OH)D for dementia prevention.

Instant and short-term effects of acupuncture for depression and anxiety in unstable angina pectoris patients with percutaneous coronary interventions.

Aim: Patients with unstable angina pectoris (UAP) usually present anxiety or depression during percutaneous coronary intervention (PCI). This study sought to investigate the instant and short-term effects of acupuncture for anxiety and depression in UAP patients with PCI. Methods: A total of 210 UAP patients who underwent PCI were recruited and randomly assigned (1:1:1) to acupuncture, placebo, or control groups. Enzyme-linked immunosorbent assay was used to detect the levels of fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), interleukin-6 (IL-6), high-sensitivity C-reactive protein (Hs-CRP), advanced oxidation protein products (AoPPs), and oxidized low-density lipoprotein (OX-LDL). Serial questionnaires with the Hamilton Anxiety (HAMA) scale and the Pittsburgh Sleep Quality Index were evaluated, and heart rate variability indicators were obtained. Results: Primary end-point: low frequency/high frequency (HF) was lower in the electroacupuncture group (p = 0.014), while standard deviation of normal-to-normal intervals, average standard deviation of normal-to-normal intervals, percentage of successive intervals that differ more than 50 ms, and HF were increased with acupuncture (p = 0.018, p = 0.043, p = 0.016, and p = 0.002, respectively). Secondary end-point: significant improvements in anxiety levels (HAMA) were observed in the three groups (p < 0.001). The fasting insulin and HOMA-IR levels were similar between the control group and the acupuncture group (p = 0.285 and p = 0.165, respectively). The levels of IL-6 and AoPPs differed among the three groups (p = 0.021 and p < 0.001, respectively). However, no significant differences were found in fasting plasma glucose, fasting c-peptide, Hs-CRP, and OX-LDL levels among the three groups (p = 0.585, p = 0.611, p = 0.902, and p = 0.756, respectively). Conclusions: In this study, short-term acupuncture may potentially relieve clinical symptoms before PCI treatment. Clinical Trial Registration: ClinicalTrials.gov, identifier (NCT03789344).

Senktide blocks aberrant RTN3 interactome to retard memory decline and tau pathology in social isolated Alzheimer's disease mice.

Sporadic or late-onset Alzheimer's disease (LOAD) accounts for more than 95% of Alzheimer's disease (AD) cases without any family history. Although genome-wide association studies have identified associated risk genes and loci for LOAD, numerous studies suggest that many adverse environmental factors, such as social isolation, are associated with an increased risk of dementia. However, the underlying mechanisms of social isolation in AD progression remain elusive. In the current study, we found that 7 days of social isolation could trigger pattern separation impairments and presynaptic abnormalities of the mossy fibre-CA3 circuit in AD mice. We also revealed that social isolation disrupted histone acetylation and resulted in the downregulation of 2 dentate gyrus (DG)-enriched miRNAs, which simultaneously target reticulon 3 (RTN3), an endoplasmic reticulum protein that aggregates in presynaptic regions to disturb the formation of functional mossy fibre boutons (MFBs) by recruiting multiple mitochondrial and vesicle-related proteins. Interestingly, the aggregation of RTN3 also recruits the PP2A B subunits to suppress PP2A activity and induce tau hyperphosphorylation, which, in turn, further elevates RTN3 and forms a vicious cycle. Finally, using an artificial intelligence-assisted molecular docking approach, we determined that senktide, a selective agonist of neurokinin3 receptors (NK3R), could reduce the binding of RTN3 with its partners. Moreover, application of senktide in vivo effectively restored DG circuit disorders in socially isolated AD mice. Taken together, our findings not only demonstrate the epigenetic regulatory mechanism underlying mossy fibre synaptic disorders orchestrated by social isolation and tau pathology but also reveal a novel potential therapeutic strategy for AD.

Free Water MR Imaging of White Matter Microstructural Changes is a Sensitive Marker of Amyloid Positivity in Alzheimer's Disease.

BACKGROUND: Extracellular free water (FW) resulting from white matter degeneration limits the sensitivity of diffusion tensor imaging (DTI) in predicting Alzheimer's disease (AD). PURPOSE: To evaluate the sensitivity of FW-DTI in detecting white matter microstructural changes in AD. To validate the effectiveness of FW-DTI indices to predict amyloid-beta (Aß) positivity in mild cognitive impairment (MCI) subtypes. STUDY TYPE: Retrospective. POPULATION: Thirty-eight Aß-negative cognitively healthy (CH) controls (68.74 ± 8.28 years old, 55% female), 15 Aß-negative MCI patients (MCI-n) (68.87 ± 8.83 years old, 60% female), 29 Aß-positive MCI patients (MCI-p) (73.03 ± 7.05 years old, 52% female), and 29 Aß-positive AD patients (72.93 ± 9.11 years old, 55% female). FIELD STRENGTH/SEQUENCE: 3.0T; DTI, T1 -weighted, T2 -weighted, T2 star-weighted angiography, and Aß PET (18 F-florbetaben or 11 C-PIB). ASSESSMENT: FW-corrected and standard diffusion indices were analyzed using trace-based spatial statistics. Area under the curve (AUC) in distinguishing MCI subtypes were compared using support vector machine (SVM). STATISTICAL TESTS: Chi-squared test, one-way analysis of covariance, general linear regression analyses, nonparametric permutation tests, partial Pearson's correlation, receiver operating characteristic curve analysis, and linear SVM. A P value <0.05 was considered statistically significant. RESULTS: Compared with CH/MCI-n/MCI-p, AD showed significant change in tissue compartment indices of FW-DTI. No difference was found in the FW index among pair-wise group comparisons (the minimum FWE-corrected P = 0.114). There was a significant association between FW-DTI indices and memory and visuospatial function. The SVM classifier with tissue radial diffusivity as an input feature had the best classification performance of MCI subtypes (AUC = 0.91), and the classifying accuracy of FW-DTI was all over 89.89%. DATA CONCLUSION: FW-DTI indices prove to be potential biomarkers of AD. The classification of MCI subtypes based on SVM and FW-DTI indices has good accuracy and could help early diagnosis. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

Rapidly developed, optimized, and applied wastewater surveillance system for real-time monitoring of low-incidence, high-impact MPOX outbreak.

Recent MPOX viral resurgences have mobilized public health agencies around the world. Recognizing the significant risk of MPOX outbreaks, large-scale human testing, and immunization campaigns have been initiated by local, national, and global public health authorities. Recently, traditional clinical surveillance campaigns for MPOX have been complemented with wastewater surveillance (WWS), building on the effectiveness of existing wastewater programs that were built to monitor SARS-CoV-2 and recently expanded to include influenza and respiratory syncytial virus surveillance in wastewaters. In the present study, we demonstrate and further support the finding that MPOX viral fragments agglomerate in the wastewater solids fraction. Furthermore, this study demonstrates that the current, most commonly used MPOX assays are equally effective at detecting low titers of MPOX viral signal in wastewaters. Finally, MPOX WWS is shown to be more effective at passively tracking outbreaks and/or resurgences of the disease than clinical testing alone in smaller communities with low human clinical case counts of MPOX.

Tau pathology epigenetically remodels the neuron-glial cross-talk in Alzheimer's disease.

The neuron-glia cross-talk is critical to brain homeostasis and is particularly affected by neurodegenerative diseases. How neurons manipulate the neuron-astrocyte interaction under pathological conditions, such as hyperphosphorylated tau, a pathological hallmark in Alzheimer's disease (AD), remains elusive. In this study, we identified excessively elevated neuronal expression of adenosine receptor 1 (Adora1 or A1R) in 3×Tg mice, MAPT P301L (rTg4510) mice, patients with AD, and patient-derived neurons. The up-regulation of A1R was found to be tau pathology dependent and posttranscriptionally regulated by Mef2c via miR-133a-3p. Rebuilding the miR-133a-3p/A1R signal effectively rescued synaptic and memory impairments in AD mice. Furthermore, neuronal A1R promoted the release of lipocalin 2 (Lcn2) and resulted in astrocyte activation. Last, silencing neuronal Lcn2 in AD mice ameliorated astrocyte activation and restored synaptic plasticity and learning/memory. Our findings reveal that the tau pathology remodels neuron-glial cross-talk and promotes neurodegenerative progression. Approaches targeting A1R and modulating this signaling pathway might be a potential therapeutic strategy for AD.

Free-space dissemination of time and frequency with 10-19 instability over 113 km.

Networks of optical clocks find applications in precise navigation1,2, in efforts to redefine the fundamental unit of the 'second'3-6 and in gravitational tests7. As the frequency instability for state-of-the-art optical clocks has reached the 10-19 level8,9, the vision of a global-scale optical network that achieves comparable performances requires the dissemination of time and frequency over a long-distance free-space link with a similar instability of 10-19. However, previous attempts at free-space dissemination of time and frequency at high precision did not extend beyond dozens of kilometres10,11. Here we report time-frequency dissemination with an offset of 6.3 × 10-20 ± 3.4 × 10-19 and an instability of less than 4 × 10-19 at 10,000 s through a free-space link of 113 km. Key technologies essential to this achievement include the deployment of high-power frequency combs, high-stability and high-efficiency optical transceiver systems and efficient linear optical sampling. We observe that the stability we have reached is retained for channel losses up to 89 dB. The technique we report can not only be directly used in ground-based applications, but could also lay the groundwork for future satellite time-frequency dissemination.

Understanding the dynamic relation between wastewater SARS-CoV-2 signal and clinical metrics throughout the pandemic.

Wastewater surveillance (WWS) of SARS-CoV-2 was proven to be a reliable and complementary tool for population-wide monitoring of COVID-19 disease incidence but was not as rigorously explored as an indicator for disease burden throughout the pandemic. Prior to global mass immunization campaigns and during the spread of the wildtype COVID-19 and the Alpha variant of concern (VOC), viral measurement of SARS-CoV-2 in wastewater was a leading indicator for both COVID-19 incidence and disease burden in communities. As the two-dose vaccination rates escalated during the spread of the Delta VOC in Jul. 2021 through Dec. 2021, relations weakened between wastewater signal and community COVID-19 disease incidence and maintained a strong relationship with clinical metrics indicative of disease burden (new hospital admissions, ICU admissions, and deaths). Further, with the onset of the vaccine-resistant Omicron BA.1 VOC in Dec. 2021 through Mar. 2022, wastewater again became a strong indicator of both disease incidence and burden during a period of limited natural immunization (no recent infection), vaccine escape, and waned vaccine effectiveness. Lastly, with the populations regaining enhanced natural and vaccination immunization shortly prior to the onset of the Omicron BA.2 VOC in mid-Mar 2022, wastewater is shown to be a strong indicator for both disease incidence and burden. Hospitalization-to-wastewater ratio is further shown to be a good indicator of VOC virulence when widespread clinical testing is limited. In the future, WWS is expected to show moderate indication of incidence and strong indication of disease burden in the community during future potential seasonal vaccination campaigns.

Wastewater to clinical case (WC) ratio of COVID-19 identifies insufficient clinical testing, onset of new variants of concern and population immunity in urban communities.

Clinical testing has been the cornerstone of public health monitoring and infection control efforts in communities throughout the COVID-19 pandemic. With the anticipated reduction of clinical testing as the disease moves into an endemic state, SARS-CoV-2 wastewater surveillance (WWS) will have greater value as an important diagnostic tool. An in-depth analysis and understanding of the metrics derived from WWS is required to interpret and utilize WWS-acquired data effectively (McClary-Gutierrez et al., 2021; O'Keeffe, 2021). In this study, the SARS-CoV-2 wastewater signal to clinical cases (WC) ratio was investigated across seven cities in Canada over periods ranging from 8 to 21 months. This work demonstrates that significant increases in the WC ratio occurred when clinical testing eligibility was modified to appointment-only testing, identifying a period of insufficient clinical testing (resulting in a reduction to testing access and a reduction in the number of daily tests) in these communities, despite increases in the wastewater signal. Furthermore, the WC ratio decreased significantly in 6 of the 7 studied locations, serving as a potential signal of the emergence of the Alpha variant of concern (VOC) in a relatively non-immunized community (40-60 % allelic proportion), while a more muted decrease in the WC ratio signaled the emergence of the Delta VOC in a relatively well-immunized community (40-60 % allelic proportion). Finally, a significant decrease in the WC ratio signaled the emergence of the Omicron VOC, likely because of the variant's greater effectiveness at evading immunity, leading to a significant number of new reported clinical cases, even when community immunity was high. The WC ratio, used as an additional monitoring metric, could complement clinical case counts and wastewater signals as individual metrics in its potential ability to identify important epidemiological occurrences, adding value to WWS as a diagnostic technology during the COVID-19 pandemic and likely for future pandemics.

Municipal and neighbourhood level wastewater surveillance and subtyping of an influenza virus outbreak.

Recurrent influenza epidemics and pandemic potential are significant risks to global health. Public health authorities use clinical surveillance to locate and monitor influenza and influenza-like cases and outbreaks to mitigate hospitalizations and deaths. Currently, global integration of clinical surveillance is the only reliable method for reporting influenza types and subtypes to warn of emergent pandemic strains. The utility of wastewater surveillance (WWS) during the COVID-19 pandemic as a less resource intensive replacement or complement for clinical surveillance has been predicated on analyzing viral fragments in wastewater. We show here that influenza virus targets are stable in wastewater and partitions favorably to the solids fraction. By quantifying, typing, and subtyping the virus in municipal wastewater and primary sludge during a community outbreak, we forecasted a citywide flu outbreak with a 17-day lead time and provided population-level viral subtyping in near real-time to show the feasibility of influenza virus WWS at the municipal and neighbourhood levels in near real time using minimal resources and infrastructure.

Prevalence of SARS-CoV-2 infection among obstetric patients in Ottawa, Canada: a descriptive study.

BACKGROUND: There is limited information on the prevalence of SARS-CoV-2 infection in obstetric settings in Canada, beyond the first wave of the COVID-19 pandemic (February to June 2020). We sought to describe the prevalence of SARS-CoV-2 infection in pregnant people admitted to triage units at a tertiary care hospital in Ottawa, Canada. METHODS: We conducted a descriptive study of pregnant people admitted to obstetric triage assessment units at The Ottawa Hospital between Oct. 19 and Nov. 27, 2020 (second local wave of the COVID-19 pandemic). Participants underwent SARS-CoV-2 polymerase chain reaction (PCR) (via naso- or oropharyngeal swabs) and serology testing upon admission. We excluded individuals younger than 18 years, those who did not speak English or French, those who enrolled in conflicting studies, those admitted for pregnancy termination and those triaged between 11:31 pm and 7:29 am. Swab and serology samples were analyzed using digital droplet PCR and enzyme-linked immunosorbent assays, respectively. We defined SARS-CoV-2 seropositivity as a positive result for immunoglobulin (Ig) G, either alone or in combination with IgM or IgA. RESULTS: Of the 632 eligible patients, 363 (57.4%) consented to participation and 362 collectively provided 284 swab and 352 blood samples eligible for analysis. Common reasons for declining participation included feeling overwhelmed or anxious, being worried about repercussions of testing, pain or discomfort with testing or disinterest in research. Participants were mostly multiparous (53.9%) and in their third trimester upon admission (88.4%). In all, 18 (4.9%) participants had evidence of SARS-CoV-2 exposure; 2 (0.7%) of 284 were positive for SARS-CoV-2 by PCR and 16 (4.5%) of 352 were positive for IgG antibodies to SARS-CoV-2. INTERPRETATION: During the second local wave of the COVID-19 pandemic, the prevalence of active SARS-CoV-2 infection among obstetric patients in Ottawa was 0.7% and seroprevalence was 4.5%. Our low participation rate highlights the need for improvements in patient education and public health messaging on the benefits of SARS-CoV-2 testing programs.

Early MRI imaging and follow-up study in cerebral amyloid angiopathy.

AIM: To study the imaging features of leukoaraiosis (LA) and hemorrhage in cerebral amyloid angiopathy (CAA) patients. METHODS: The earliest MRI images of probable CAA patients and non-CAA patients were collected. The characteristics of LA in the two groups were analyzed. Cerebral micro bleeding (CMB), superficial siderosis (SS), and intracranial hemorrhage (ICH) were recorded in the follow-up study. The space relationship between CMB or SS and ICH was assessed. RESULTS: We found that 10/21 (47.6%) patients had occipital prominent LA and 14/21 (66.7%) patients had subcortical punctate LA before the ICH, which was higher than that of the ones in the control group (p = 0.015 and 0.038, respectively). The recurrence rate of ICH was 100% (3/3) in patients with diffuse SS and 36.4% (4/11) in patients without. The recurrence rate of ICH was 60% (3/5) in patients with multiple-lobe CMBs and 44.4% (4/9) in those without. The location of the ICH and CMB was inconsistent. ICH occurred in the ipsilateral cerebral hemisphere of SS in three patients with diffuse SS. CONCLUSION: LA, diffuse SS, and multiple-lobe CMBs are important imaging characteristics of CAA, which may help make early diagnosis and predict the recurrence of ICH.

mTORC1 promotes TOP mRNA translation through site-specific phosphorylation of LARP1.

LARP1 is a key repressor of TOP mRNA translation. It binds the m7Gppp cap moiety and the adjacent 5'TOP motif of TOP mRNAs, thus impeding the assembly of the eIF4F complex on these transcripts. mTORC1 controls TOP mRNA translation via LARP1, but the details of the mechanism are unclear. Herein we elucidate the mechanism by which mTORC1 controls LARP1's translation repression activity. We demonstrate that mTORC1 phosphorylates LARP1 in vitro and in vivo, activities that are efficiently inhibited by rapamycin and torin1. We uncover 26 rapamycin-sensitive phospho-serine and -threonine residues on LARP1 that are distributed in 7 clusters. Our data show that phosphorylation of a cluster of residues located proximally to the m7Gppp cap-binding DM15 region is particularly sensitive to rapamycin and regulates both the RNA-binding and the translation inhibitory activities of LARP1. Our results unravel a new model of translation control in which the La module (LaMod) and DM15 region of LARP1, both of which can directly interact with TOP mRNA, are differentially regulated: the LaMod remains constitutively bound to PABP (irrespective of the activation status of mTORC1), while the C-terminal DM15 'pendular hook' engages the TOP mRNA 5'-end to repress translation, but only in conditions of mTORC1 inhibition.

Quantitative analysis of SARS-CoV-2 RNA from wastewater solids in communities with low COVID-19 incidence and prevalence.

In the absence of an effective vaccine to prevent COVID-19 it is important to be able to track community infections to inform public health interventions aimed at reducing the spread and therefore reduce pressures on health-care, improve health outcomes and reduce economic uncertainty. Wastewater surveillance has rapidly emerged as a potential tool to effectively monitor community infections through measuring trends of RNA signal in wastewater systems. In this study SARS-CoV-2 viral RNA N1 and N2 gene regions are quantified in solids collected from influent post grit solids (PGS) and primary clarified sludge (PCS) in two water resource recovery facilities (WRRF) serving Canada's national capital region, i.e., the City of Ottawa, ON (pop. ≈ 1.1M) and the City of Gatineau, QC (pop. ≈ 280K). PCS samples show signal inhibition using RT-ddPCR compared to RT-qPCR, with PGS samples showing similar quantifiable concentrations of RNA using both assays. RT-qPCR shows higher frequency of detection of N1 and N2 gene regions in PCS (92.7, 90.6%, n = 6) as compared to PGS samples (79.2, 82.3%, n = 5). Sampling of PCS may therefore be an effective approach for SARS-CoV-2 viral quantification, especially during periods of declining and low COVID-19 incidence in the community. The pepper mild mottle virus (PMMoV) is determined to have a less variable RNA signal in PCS over a three month period for two WRRFs, regardless of environmental conditions, compared to Bacteroides 16S rRNA or human 18S rRNA, making PMMoV a potentially useful biomarker for normalization of SARS-CoV-2 signal. PMMoV-normalized PCS RNA signal from WRRFs of two cities correlated with the regional public health epidemiological metrics, identifying PCS normalized to a fecal indicator (PMMoV) as a potentially effective tool for monitoring trends during decreasing and low-incidence of infection of SARS-Cov-2 in communities.

4E-BP-Dependent Translational Control of Irf8 Mediates Adipose Tissue Macrophage Inflammatory Response.

Deregulation of mRNA translation engenders many human disorders, including obesity, neurodegenerative diseases, and cancer, and is associated with pathogen infections. The role of eIF4E-dependent translational control in macrophage inflammatory responses in vivo is largely unexplored. In this study, we investigated the involvement of the translation inhibitors eIF4E-binding proteins (4E-BPs) in the regulation of macrophage inflammatory responses in vitro and in vivo. We show that the lack of 4E-BPs exacerbates inflammatory polarization of bone marrow-derived macrophages and that 4E-BP-null adipose tissue macrophages display enhanced inflammatory gene expression following exposure to a high-fat diet (HFD). The exaggerated inflammatory response in HFD-fed 4E-BP-null mice coincides with significantly higher weight gain, higher Irf8 mRNA translation, and increased expression of IRF8 in adipose tissue compared with wild-type mice. Thus, 4E-BP-dependent translational control limits, in part, the proinflammatory response during HFD. These data underscore the activity of the 4E-BP-IRF8 axis as a paramount regulatory mechanism of proinflammatory responses in adipose tissue macrophages.

Induction of an Alternative mRNA 5' Leader Enhances Translation of the Ciliopathy Gene Inpp5e and Resistance to Oncolytic Virus Infection.

Residual cell-intrinsic innate immunity in cancer cells hampers infection with oncolytic viruses. Translational control of mRNA is an important feature of innate immunity, yet the identity of translationally regulated mRNAs functioning in host defense remains ill-defined. We report the translatomes of resistant murine "4T1" breast cancer cells infected with three of the most clinically advanced oncolytic viruses: herpes simplex virus 1, reovirus, and vaccinia virus. Common among all three infections are translationally de-repressed mRNAs, including Inpp5e, encoding an inositol 5-phosphatase that modifies lipid second messenger signaling. We find that viral infection induces the expression of an Inpp5e mRNA variant that lacks repressive upstream open reading frames (uORFs) within its 5' leader and is efficiently translated. Furthermore, we show that INPP5E contributes to antiviral immunity by altering virus attachment. These findings uncover a role for translational control through alternative 5' leader expression and assign an antiviral function to the ciliopathy gene Inpp5e.

Partial improvement in performance of patients with severe Alzheimer's disease at an early stage of fornix deep brain stimulation.

Deep brain stimulation is a therapy for Alzheimer's disease (AD) that has previously been used for mainly mild to moderate cases. This study provides the first evidence of early alterations in performance induced by stimulation targeted at the fornix in severe AD patients. The performance of the five cases enrolled in this study was scored with specialized assessments including the Mini-Mental State Examination and Clinical Dementia Rating, both before and at an early stage after deep brain stimulation. The burden of caregivers was also evaluated using the Zarit Caregiver Burden Interview. As a whole, the cognitive performance of patients remained stable or improved to varying degrees, and caregiver burden was decreased. Individually, an improved mental state or social performance was observed in three patients, and one of these three patients showed remarkable improvement in long-term memory. The conditions of another patient deteriorated because of inappropriate antipsychotic medications that were administered by his caregivers. Taken together, deep brain stimulation was capable of improving some cognitive aspects in patients with severe AD, and of ameliorating their emotional and social performance, at least at an early stage. However, long-term effects induced by deep brain stimulation in patients with severe AD need to be further validated. More research should focus on clarifying the mechanism of deep brain stimulation. This study was registered with ClinicalTrials.gov (NCT03115814) on April 14, 2017.

Active-site mTOR inhibitors augment HSV1-dICP0 infection in cancer cells via dysregulated eIF4E/4E-BP axis.

Herpes Simplex Virus 1 (HSV1) is amongst the most clinically advanced oncolytic virus platforms. However, efficient and sustained viral replication within tumours is limiting. Rapamycin can stimulate HSV1 replication in cancer cells, but active-site dual mTORC1 and mTORC2 (mammalian target of rapamycin complex 1 and 2) inhibitors (asTORi) were shown to suppress the virus in normal cells. Surprisingly, using the infected cell protein 0 (ICP0)-deleted HSV1 (HSV1-dICP0), we found that asTORi markedly augment infection in cancer cells and a mouse mammary cancer xenograft. Mechanistically, asTORi repressed mRNA translation in normal cells, resulting in defective antiviral response but also inhibition of HSV1-dICP0 replication. asTORi also reduced antiviral response in cancer cells, however in contrast to normal cells, transformed cells and cells transduced to elevate the expression of eukaryotic initiation factor 4E (eIF4E) or to silence the repressors eIF4E binding proteins (4E-BPs), selectively maintained HSV1-dICP0 protein synthesis during asTORi treatment, ultimately supporting increased viral replication. Our data show that altered eIF4E/4E-BPs expression can act to promote HSV1-dICP0 infection under prolonged mTOR inhibition. Thus, pharmacoviral combination of asTORi and HSV1 can target cancer cells displaying dysregulated eIF4E/4E-BPs axis.

Satellite-to-ground quantum key distribution.

Quantum key distribution (QKD) uses individual light quanta in quantum superposition states to guarantee unconditional communication security between distant parties. However, the distance over which QKD is achievable has been limited to a few hundred kilometres, owing to the channel loss that occurs when using optical fibres or terrestrial free space that exponentially reduces the photon transmission rate. Satellite-based QKD has the potential to help to establish a global-scale quantum network, owing to the negligible photon loss and decoherence experienced in empty space. Here we report the development and launch of a low-Earth-orbit satellite for implementing decoy-state QKD-a form of QKD that uses weak coherent pulses at high channel loss and is secure because photon-number-splitting eavesdropping can be detected. We achieve a kilohertz key rate from the satellite to the ground over a distance of up to 1,200 kilometres. This key rate is around 20 orders of magnitudes greater than that expected using an optical fibre of the same length. The establishment of a reliable and efficient space-to-ground link for quantum-state transmission paves the way to global-scale quantum networks.