Spatially resolved transcriptomics reveals genes associated with the vulnerability of middle temporal gyrus in Alzheimer’s disease

Human middle temporal gyrus (MTG) is a vulnerable brain region in early Alzheimer’s disease (AD), but little is known about the molecular mechanisms underlying this regional vulnerability. Here we utilize the 10 × Visium platform to define the spatial transcriptomic profile in both AD and control (CT) MTG. We identify unique marker genes for cortical layers and the white matter, and layer-specific differentially expressed genes (DEGs) in human AD compared to CT. Deconvolution of the Visium spots showcases the significant difference in particular cell types among cortical layers and the white matter. Gene co-expression analyses reveal eight gene modules, four of which have significantly altered co-expression patterns in the presence of AD pathology. The co-expression patterns of hub genes and enriched pathways in the presence of AD pathology indicate an important role of cell–cell-communications among microglia, oligodendrocytes, astrocytes, and neurons, which may contribute to the cellular and regional vulnerability in early AD. Using single-molecule fluorescent in situ hybridization, we validated the cell-type-specific expression of three novel DEGs (e.g., KIF5A, PAQR6, and SLC1A3) and eleven previously reported DEGs associated with AD pathology (i.e., amyloid beta plaques and intraneuronal neurofibrillary tangles or neuropil threads) at the single cell level. Our results may contribute to the understanding of the complex architecture and neuronal and glial response to AD pathology of this vulnerable brain region

Poly(ADP-ribose) polymerase inhibition: a new direction for BRCA and triple-negative breast cancer?

Inhibitors of poly(ADP-ribose) polymerase (PARP)-mediated DNA repair have shown promise in early clinical studies in the treatment of specific subgroups of breast cancer. Notably, phase II trials indicate that olaparib, an oral PARP inhibitor, has activity as a single agent in BRCA-related tumours, and that a combination of iniparib, an intravenous PARP inhibitor, and chemotherapy offers a survival advantage, compared with chemotherapy alone, in triple-negative breast cancer. Phase III data on the latter indication are expected in 2011. Intriguingly, iniparib does not increase toxicity when used as a chemo-potentiating agent, suggesting that it differs in its mechanism of action from other agents in this class. Overall, PARP inhibitors represent a potentially important new class of anti-cancer agents with two potential modes of action, as single agents causing synthetic lethality and as chemo-potentiating agents

Dual task interference during gait in patients with unilateral vestibular disorders

<p>Abstract</p> <p>Background</p> <p>Vestibular patients show slower and unsteady gait; they have also been shown to need greater cognitive resources when carrying out balance and cognitive dual tasks (DT). This study investigated DT interference during gait in a middle-aged group of subjects with dizziness and unsteadiness after unilateral vestibular neuronitis and in a healthy control group.</p> <p>Methods</p> <p>Fourteen individuals with subacute unilateral vestibular impairment after neuronitis and seventeen healthy subjects performed gait and cognitive tasks in single and DT conditions. A statistical gait analysis system was used and spatio-temporal parameters were considered. The cognitive task, consisting of backward counting by three, was tape recorded and the number of right figures was then calculated.</p> <p>Results</p> <p>Both patients and controls showed a more conservative gait during DT and between groups significant differences were not found. A significant decrease in cognitive performance during DT was found only in the vestibular group.</p> <p>Conclusions</p> <p>Results suggest that less attentional resources are available during gait in vestibular patients compared to controls, and that a priority is given in keeping up the motor task to the detriment of a decrease of the cognitive performance during DT.</p

The Impact of Voluntary Counselling and Testing Services on Sexual Behaviour Change and HIV Incidence: Observations from a Cohort Study in Rural Tanzania.

It is widely assumed that voluntary counselling and testing (VCT) services contribute to HIV prevention by motivating clients to reduce sexual risk-taking. However, findings from sub-Saharan Africa have been mixed, particularly among HIV-negative persons. We explored associations between VCT use and changes in sexual risk behaviours and HIV incidence using data from a community HIV cohort study in northwest Tanzania. Data on VCT use, sexual behaviour and HIV status were available from three HIV serological surveillance rounds undertaken in 2003-4 (Sero4), 2006-7 (Sero5) and 2010 (Sero6). We used multinomial logistic regression to assess changes in sexual risk behaviours between rounds, and Poisson regression to estimate HIV incidence. The analyses included 3,613 participants attending Sero4 and Sero5 (3,474 HIV-negative and 139 HIV-positive at earlier round) and 2,998 attending Sero5 and Sero6 (2,858 HIV-negative and 140 HIV-positive at earlier round). Among HIV-negative individuals VCT use was associated with reductions in the number of sexual partners in the last year (aRR Seros 4-5: 1.42, 95% CI 1.07-1.88; aRR Seros 5-6: 1.68, 95% CI 1.25-2.26) and in the likelihood of having a non-cohabiting partner in the last year (aRR Seros 4-5: 1.57, 95% CI 1.10-2.25; aRR Seros 5-6: 1.48, 95% CI 1.07-2.04) or a high-risk partner in the last year (aRR Seros 5-6 1.57, 95% CI 1.06-2.31). However, VCT was also associated with stopping using condoms with non-cohabiting partners between Seros 4-5 (aRR 4.88, 95% CI 1.39-17.16). There were no statistically significant associations between VCT use and changes in HIV incidence, nor changes in sexual behaviour among HIV-positive individuals, possibly due to small sample sizes. We found moderate associations between VCT use and reductions in some sexual risk behaviours among HIV-negative participants, but no impacts among HIV-positive individuals in the context of low overall VCT uptake. Furthermore, there were no significant changes in HIV incidence associated with VCT use, although declining background incidence and small sample sizes may have prevented us from detecting this. The impact of VCT services will ultimately depend upon rates of uptake, with further research required to better understand processes of behaviour change following VCT use

The role of folate receptor alpha (FRα) in the response of malignant pleural mesothelioma to pemetrexed-containing chemotherapy

BACKGROUND: The standard treatment of choice for malignant pleural mesothelioma is chemotherapy with pemetrexed and platinum, but the clinical outcome is poor. This study investigates the response to pemetrexed in a panel of eight mesothelioma cell lines and the clinical outcome for patients treated with pemetrexed in relation to folate receptor alpha (FR alpha).METHODS: Cell lines were treated with pemetrexed to determine the concentration that reduced growth to 50% (GI(50)). FR alpha expression was determined by western blotting and that of FR alpha, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT) by real-time quantitative RT-PCR. Immunohistochemistry for FR alpha was carried out on 62 paraffin-embedded samples of mesothelioma from patients who were subsequently treated with pemetrexed.RESULTS: A wide range of GI(50) values was obtained for the cell lines, H2452 cells being the most sensitive (GI(50) 22 nM) and RS5 cells having a GI(50) value greater than 10 mu M. No FR alpha protein was detected in any cell line, and there was no relationship between sensitivity and expression of folate transporters. FR alpha was detected in 39% of tumour samples, generally in a small percentage of cells. There was no correlation between the presence of FR alpha and the outcome of pemetrexed treatment, and no significant difference between histological subtypes.CONCLUSION: Response to treatment with pemetrexed does not depend on the presence of FR alpha. British Journal of Cancer (2010) 102, 553-560. doi:10.1038/sj.bjc.6605501 www.bjcancer.com Published online 5 January 2010 (C) 2010 Cancer Research U

Seroepidemiology of Bovine Viral Diarrhoea Virus (BVDV) in the Adamawa Region of Cameroon and Use of the SPOT Test to Identify Herds with PI Calves

Bovine viral diarrhoea, caused by the bovine viral diarrhoea virus (BVDV) in the Pestivirus genus of the Flaviviridae, is one of the most important diseases of cattle world wide causing poor reproductive performance in adult cattle and mucosal disease in calves. In addition it causes immunosuppression and increased susceptibility to other infections, the impact of which is uncertain, particularly in sub-Saharan Africa where animals are exposed to a much wider range and higher intensity of infections compared to Europe. There are no previous estimates of the seroprevalence of BVDV in cattle in Cameroon. This paper describes the serological screening for antibodies to BVDV and antigen of BVDV in a cattle population in the Adamawa Region of Cameroon in 2000. The estimates of herd-level and within herd seroprevalences adjusted for test imperfections were 92% and 30% respectively and 16.5% of herds were classed as having a persistently infected calf (PI) in the herd within the last year based on the “spot” test approach. There was evidence of clustering of herds with PI calves across the north and west of the Region which corresponds with the higher cattle density areas and of self-clearance of infection from herds. A multivariable model was developed for the risk of having a PI calf in the herd; proximity to antelope, owning a goat, mixing with 10 other herds at grazing and the catchment area of the veterinary centre the herd was registered at were all significant risk factors. Very little is known about BVDV in sub-Saharan Africa and these high seroprevalences suggest that there is a large problem which may be having both direct impacts on fertility and neonate mortality and morbidity and also indirect effects through immunosuppression and susceptibility to other infections. Understanding and accounting for BVDV should be an important component of epidemiological studies of other diseases in sub-Saharan Africa

Diversity among clients of female sex workers in India: comparing risk profiles and intervention impact by site of solicitation. implications for the vulnerability of less visible female sex workers.

BACKGROUND: It seems generally accepted that targeted interventions in India have been successful in raising condom use between female sex workers (FSWs) and their clients. Data from clients of FSWs have been under-utilised to analyse the risk environments and vulnerability of both partners. METHODS: The 2009 Integrated Biological and Behavioural Assessment survey sampled clients of FSWs at hotspots in Andhra Pradesh, Maharashtra and Tamil Nadu (n=5040). The risk profile of clients in terms of sexual networking and condom use are compared across usual pick-up place. We used propensity score matching (PSM) to estimate the average treatment effect on treated (ATT) of intervention messages on clients' consistent condom use with FSW. RESULTS: Clients of the more hidden sex workers who solicit from home or via phone or agents had more extensive sexual networks, reporting casual female partners as well as anal intercourse with male partners and FSW. Clients of brothel-based sex workers, who were the least educated, reported the fewest number/categories of partners, least anal sex, and lowest condom use (41%). Consistent condom use varied widely by state: 65% in Andhra Pradesh, 36% in Maharashtra and 29% in Tamil Nadu. Exposure to intervention messages on sexually transmitted infections was lowest among men frequenting brothels (58%), and highest among men soliciting less visible sex workers (70%). Exposure had significant impact on consistent condom use, including among clients of home-based sex workers (ATT 21%; p=0.001) and among men soliciting other more hidden FSW (ATT 17%; p=0.001). In Tamil Nadu no impact could be demonstrated. CONCLUSION: Commercial sex happens between two partners and both need to be, and can be, reached by intervention messages. Commercial sex is still largely unprotected and as the sex industry gets more diffuse a greater focus on reaching clients of sex workers seems important given their extensive sexual networks

Amyloid precursor protein drives down-regulation of mitochondrial oxidative phosphorylation independent of amyloid beta

Amyloid precursor protein (APP) and its extracellular domain, soluble APP alpha (sAPPα) play important physiological and neuroprotective roles. However, rare forms of familial Alzheimer’s disease are associated with mutations in APP that increase toxic amyloidogenic cleavage of APP and produce amyloid beta (Aβ) at the expense of sAPPα and other non-amyloidogenic fragments. Although mitochondrial dysfunction has become an established hallmark of neurotoxicity, the link between Aβ and mitochondrial function is unclear. In this study we investigated the effects of increased levels of neuronal APP or Aβ on mitochondrial metabolism and gene expression, in human SH-SY5Y neuroblastoma cells. Increased non-amyloidogenic processing of APP, but not Aβ, profoundly decreased respiration and enhanced glycolysis, while mitochondrial DNA (mtDNA) transcripts were decreased, without detrimental effects to cell growth. These effects cannot be ascribed to Aβ toxicity, since higher levels of endogenous Aβ in our models do not cause oxidative phosphorylation (OXPHOS) perturbations. Similarly, chemical inhibition of β-secretase decreased mitochondrial respiration, suggesting that non-amyloidogenic processing of APP may be responsible for mitochondrial changes. Our results have two important implications, the need for caution in the interpretation of mitochondrial perturbations in models where APP is overexpressed, and a potential role of sAPPα or other non-amyloid APP fragments as acute modulators of mitochondrial metabolism

Inverse Association between Methylation of Human Papillomavirus Type 16 DNA and Risk of Cervical Intraepithelial Neoplasia Grades 2 or 3

The clinical relevance of human papillomavirus type 16 (HPV16) DNA methylation has not been well documented, although its role in modulation of viral transcription is recognized.Study subjects were 211 women attending Planned Parenthood clinics in Western Washington for routine Papanicolaou screening who were HPV16 positive at the screening and/or subsequent colposcopy visit. Methylation of 11 CpG dinucleotides in the 3' end of the long control region of the HPV16 genome was examined by sequencing the cloned polymerase chain reaction products. The association between risk of CIN2/3 and degree of CpG methylation was estimated using a logistic regression model.CIN2/3 was histologically confirmed in 94 (44.5%) of 211 HPV16 positive women. The likelihood of being diagnosed as CIN2/3 increased significantly with decreasing numbers of methylated CpGs (meCpGs) in the 3' end of the long control region (P(for trend) = 0.003). After adjusting for HPV16 variants, number of HPV16-positive visits, current smoking status and lifetime number of male sex partners, the odds ratio for the association of CIN2/3 with ≥4 meCpGs was 0.31 (95% confidence interval, 0.12-0.79). The proportion of ≥4 meCpGs decreased appreciably as the severity of the cervical lesion increased (P(for trend) = 0.001). The inverse association remained similar when CIN3 was used as the clinical endpoint. Although not statistically significant, the ≥4 meCpGs-related risk reduction was more substantial among current, as compared to noncurrent, smokers.Results suggest that degree of the viral genome methylation is related to the outcome of an HPV16 cervical infection

Temperature Dependence of the Extrinsic Incubation Period of Orbiviruses in Culicoides Biting Midges

The rate at which viruses replicate and disseminate in competent arthropod vectors is limited by the temperature of their environment, and this can be an important determinant of geographical and seasonal limits to their transmission by arthropods in temperate regions.Here, we present a novel statistical methodology for estimating the relationship between temperature and the extrinsic incubation period (EIP) and apply it to both published and novel data on virus replication for three internationally important orbiviruses (African horse sickness virus (AHSV), bluetongue virus (BTV) and epizootic haemorrhagic disease virus (EHDV)) in their Culicoides vectors. Our analyses show that there can be differences in vector competence for different orbiviruses in the same vector species and for the same orbivirus in different vector species. Both the rate of virus replication (approximately 0.017-0.021 per degree-day) and the minimum temperature required for replication (11-13°C), however, were generally consistent for different orbiviruses and across different Culicoides vector species. The estimates obtained in the present study suggest that previous publications have underestimated the replication rate and threshold temperature because the statistical methods they used included an implicit assumption that all negative vectors were infected.Robust estimates of the temperature dependence of arbovirus replication are essential for building accurate models of transmission and for informing policy decisions about seasonal relaxations to movement restrictions. The methodology developed in this study provides the required robustness and is superior to methods used previously. Importantly, the methods are generic and can readily be applied to other arbovirus-vector systems, as long as the assumptions described in the text are valid