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PURPOSE: Overlapping clinical features of cutaneous leishmaniasis (CL) with ulcers caused by fungi and mycobacteria necessitate confirmatory diagnostic testing. We evaluated a handheld battery-operated device for detection of CL and common fungal and mycobacterial causes of ulcers. METHODS: We validated Palm PCR™ for detection of common ulcerative skin pathogens using ATCC(®) reference and clinical strains of Leishmania, mycobacteria, and fungi in the lab and field. Amplified products were Sanger sequenced. Performance characteristics were calculated using conventional PCR as a reference standard. RESULTS: Palm PCR™ detected 100% of ATCC(®) strains of Leishmania, fungi, and mycobacteria, with sensitivity and specificity of 90% and 91.7%, respectively. In the field, the sensitivity for detection of Leishmania in patients with suspected CL was 100%. In 61% of CL patients, co-colonization with genera such as Malassezia, Aspergillus, Candida, and Cladosporium was detected. In 50% of CL patients with an inflammatory (secondarily infected) phenotype, detected fungal species had known associations with human cutaneous disease. CONCLUSIONS: Palm PCR™ performs comparably to conventional PCR for detection of Leishmania, fungi, and mycobacteria. This work has implications for the diagnostic approach to tropical ulcers, and has the potential to improve field detection of ulcerative pathogens in resource constrained areas

Summary Nonconvulsive epileptiform activity and microglial alterations have been detected in people with Alzheimer’s disease (AD) and related mouse models. However, the relationship between these abnormalities remains to be elucidated. We suppressed epileptiform activity by treatment with the antiepileptic drug levetiracetam or by genetic ablation of tau and found that these interventions reversed or prevented aberrant microglial gene expression in brain tissues of aged human amyloid precursor protein transgenic mice, which simulate several key aspects of AD. The most robustly modulated genes included multiple factors previously implicated in AD pathogenesis, including TREM2, the hypofunction of which increases disease risk. Genetic reduction of TREM2 exacerbated epileptiform activity after mice were injected with kainate. We conclude that AD-related epileptiform activity markedly changes the molecular profile of microglia, inducing both maladaptive and adaptive alterations in their activities. Increased expression of TREM2 seems to support microglial activities that counteract this type of network dysfunction., Graphical abstract, Highlights • Epileptiform activity and microglial mRNA changes in aged hAPP mice • Antiepileptic drug treatment and tau ablation reduce both abnormalities • TREM2 reduction exacerbates epileptiform activity after excitotoxin challenge • Neural network and microglial dysfunctions could form a vicious circle in AD, Das et al. show that suppressing nonconvulsive epileptiform activity in an Alzheimer’s disease related mouse model reduces aberrant expression of microglial genes, including overexpression of TREM2, a strong Alzheimer risk gene in humans. Reducing TREM2 in mice exacerbated excitotoxin-induced epileptiform activity. Thus, TREM2 may help microglia curtail neural network dysfunction.

The penis is the primary site of HIV acquisition in heterosexual men. Elevated penile inflammatory cytokines increase sexual acquisition risk, and topically applied cytokines enhance foreskin HIV susceptibility in an explant model. However, the impact of penile-vaginal sex on these immune parameters is undefined. Heterosexual couples were recruited to the Sex, Couples and Science (SECS) Study, with the collection of penile swabs, semen, cervico-vaginal secretions, and blood after a period of abstinence, and repeated sampling up to 72 hours after either condomless (n=30) or condom-protected (n=8) penile-vaginal sex. Soluble immune parameters were quantified by multiplex immunoassay. Co-primary immune endpoints were penile levels of IL-8 and MIG, cytokines previously linked to penile HIV acquisition. One hour after sex there were dramatic increases in penile IL-8 and MIG levels, regardless of condom use, with a gradual return to baseline by 72 hours; similar patterns were observed for other chemoattractant chemokines. Penile cytokine changes were similar in circumcised and uncircumcised men, and repeated measures ANOVA and ANCOVA models demonstrated that the degree of change after condomless sex was explained by cytokine levels in their partners’ cervico-vaginal secretions. This may have important implications for the biology of penile HIV acquisition.Author summaryIn heterosexual men, the penis is the primary site of Human Immunodeficiency Virus (HIV) acquisition. Levels of inflammatory cytokines in the coronal sulcus are associated with an increased HIV risk, and we hypothesized that these may be altered after insertive penile sex. Therefore, we designed the Sex, Couples and Science Study (SECS study) to define the impact of penile-vaginal sex on the penile immune correlates of HIV susceptibility. We found that multiple coronal sulcus cytokines increased dramatically and rapidly after sex, regardless of condom use, with a return to baseline levels by 72 hours. The changes observed after condomless sex were strongly predicted by cytokine concentrations in the vaginal secretions of the female partner, and were similar in circumcised and uncircumcised men. We believe that these findings have important implications for understanding the immunopathogenesis of penile HIV acquisition; in addition, they have important implications for the design of clinical studies of penile HIV acquisition and prevention.

Overlapping clinical features of cutaneous leishmaniasis (CL) with ulcers caused by fungi and mycobacteria necessitate confirmatory diagnostic testing. We evaluated a handheld battery-operated device for detection of CL and common fungal and mycobacterial causes of ulcers.We validated Palm PCR™ for detection of common ulcerative skin pathogens using ATCCPalm PCR™ detected 100% of ATCCPalm PCR™ performs comparably to conventional PCR for detection of Leishmania, fungi, and mycobacteria. This work has implications for the diagnostic approach to tropical ulcers, and has the potential to improve field detection of ulcerative pathogens in resource constrained areas.

Diverse gene products contribute to the pathogenesis of Alzheimer’s disease (AD). Experimental models have helped elucidate their mechanisms and impact on brain functions. Human amyloid precursor protein (hAPP) transgenic mice from line J20 (hAPP-J20 mice) are widely used to simulate key aspects of AD. However, they also carry an insertional mutation in noncoding sequence of one Zbtb20 allele, a gene involved in neural development. We demonstrate that heterozygous hAPP-J20 mice have reduced Zbtb20 expression in some AD-relevant brain regions, but not others, and that Zbtb20 levels are higher in hAPP-J20 mice than heterozygous Zbtb20 knockout (Zbtb20+/–) mice. Whereas hAPP-J20 mice have premature mortality, severe deficits in learning and memory, other behavioral alterations, and prominent nonconvulsive epileptiform activity, Zbtb20+/– mice do not. Thus, the insertional mutation in hAPP-J20 mice does not ablate the affected Zbtb20 allele and is unlikely to account for the AD-like phenotype of this model. Significance Statement Genetically modified mice can help unravel complex disorders such as Alzheimer’s disease (AD) by revealing effects of pathogenic drivers on neural networks and behaviors. Inadvertent genome modifications can occur during the generation of such models but their consequences are rarely explored in depth, even though they could confound the interpretation of phenotypes and therapeutic interventions. hAPP-J20 mice simulate multiple aspects of AD but also carry an insertional mutation in one Zbtb20 allele. Our study differentiates specific from nonspecific Zbtb20 antibodies and provides evidence that the functional AD-like alterations of hAPP-J20 mice are not caused by hypofunction of Zbtb20. We further demonstrate in Zbtb20+/– mice that neural development and brain functions are well preserved when Zbtb20 levels are reduced in half.

Several lines of evidence implicate the protein tau in the pathogenesis of multiple brain disorders, including Alzheimer’s disease, other neurodegenerative conditions, autism, and epilepsy. Tau is abundant in neurons and interacts with microtubules, but its main functions in the brain remain to be defined. These functions may involve the regulation of signaling pathways relevant to diverse biological processes. Informative disease models have revealed a plethora of abnormal tau species and mechanisms that might contribute to neuronal dysfunction and loss, but the relative importance of their respective contributions is uncertain. This knowledge gap poses major obstacles to the development of truly impactful therapeutic strategies. The current expansion and intensification of efforts to translate mechanistic insights into tau-related therapeutics should address this issue and could deliver better treatments for a host of devastating conditions.

Continuous process improvement is an important issue for industry processes. In order to achieve this prominent objective, recent years have witnessed considerable interest in the prospects for process enhancement to be realized by integrated usc of statistical process control (SPC) and engineering process control (EPC). Most of the studies assumed that the assignable causes or disturbances could be identified and removed right away as long as an out-of-control signal is triggered by employing the SPC mechanism of the integrated system. However, for a practical consideration, it is not straightforward to identify, isolate, remove, and correct the causes of disturbance. This study aims to develop techniques which effectively integrate SPC and EPC so that the system is able to distinguish two well-known classes of disturbances - step change and linear - from one another. The use and the potential advantages of the proposed techniques are illustrated through simulation studies.

The sales promotion data resulting from multiple marketing strategies are usually autocorrelated. Consequently, the characteristics of those data sets can be analyzed using time-series and/or intervention analysis. Traditional time-series intervention analysis focuses on the effects of single or few interventions, and forecasts may be obtained as long as the future interventions can be assured. This study is different from traditional approaches, and considers the cases in which multiple interventions and the uncertainty of future interventions exist in the system. In addition, this study utilizes a set of real sales promotion data to demonstrate the effectiveness of the proposed approach.