Herpes Simplex Virus Encephalitis in Patients With Autoimmune Conditions or Exposure to Immunomodulatory Medications.

BACKGROUND AND OBJECTIVES: Among infectious etiologies of encephalitis, herpes simplex virus type 1 (HSV-1) is most common, accounting for ∼15%-40% of adult encephalitis diagnoses. We aim to investigate the association between immune status and HSV encephalitis (HSVE). Using a US Medicaid database of 75.6 million persons, we evaluated the association between HSVE and autoimmune conditions, exposure to immunosuppressive and immunomodulatory medications, and other medical comorbidities. METHODS: We used the US Medicaid Analytic eXtract data between 2007 and 2010 from the 29 most populated American states. We first examined the crude incidence of HSVE in the population. We then age and sex-matched adult cases of HSVE with a sufficient enrollment period (12 months before HSVE diagnosis) to a larger control population without HSVE. In a case-control analysis, we examined the association between HSVE and exposure to both autoimmune disease and immunosuppressive/immunomodulatory medications. Analyses were conducted with conditional logistic regression progressively adjusting for sociodemographic factors, Charlson Comorbidity Index, and non-autoimmune comorbidities. RESULTS: Incidence of HSVE was ∼3.01 per 105 person-years among adults. A total of 951 HSVE cases and 95,100 age and sex-matched controls were compared. The HSVE population had higher rates of medical comorbidities than the control population. The association of HSVE and autoimmune conditions was strong (adjusted odds ratio (OR) 2.6; 95% CI 2.2-3.2). The association of HSVE and immunomodulating medications had an OR of 2.2 (CI 1.9-2.6), also after covariate adjustment. When both exposures were included in regression models, the associations remained robust: OR 2.3 (CI 1.9-2.7) for autoimmune disease and 2.0 (CI 1.7-2.3) for immunosuppressive and immunomodulatory medications. DISCUSSION: In a large, national population, HSVE is strongly associated with preexisting autoimmune disease and exposure to immunosuppressive and immunomodulatory medications. The role of antecedent immune-related dysregulation may have been underestimated to date.

Cognitive concerns are a risk factor for mortality in people with HIV and coronavirus disease 2019.

BACKGROUND: Data supporting dementia as a risk factor for coronavirus disease 2019 (COVID-19) mortality relied on ICD-10 codes, yet nearly 40% of individuals with probable dementia lack a formal diagnosis. Dementia coding is not well established for people with HIV (PWH), and its reliance may affect risk assessment. METHODS: This retrospective cohort analysis of PWH with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) PCR positivity includes comparisons to people without HIV (PWoH), matched by age, sex, race, and zipcode. Primary exposures were dementia diagnosis, by International Classification of Diseases (ICD)-10 codes, and cognitive concerns, defined as possible cognitive impairment up to 12 months before COVID-19 diagnosis after clinical review of notes from the electronic health record. Logistic regression models assessed the effect of dementia and cognitive concerns on odds of death [odds ratio (OR); 95% CI (95% confidence interval)]; models adjusted for VACS Index 2.0. RESULTS: Sixty-four PWH were identified out of 14 129 patients with SARS-CoV-2 infection and matched to 463 PWoH. Compared with PWoH, PWH had a higher prevalence of dementia (15.6% vs. 6%, P  = 0.01) and cognitive concerns (21.9% vs. 15.8%, P  = 0.04). Death was more frequent in PWH ( P  < 0.01). Adjusted for VACS Index 2.0, dementia [2.4 (1.0-5.8), P  = 0.05] and cognitive concerns [2.4 (1.1-5.3), P  = 0.03] were associated with increased odds of death. In PWH, the association between cognitive concern and death trended towards statistical significance [3.92 (0.81-20.19), P  = 0.09]; there was no association with dementia. CONCLUSION: Cognitive status assessments are important for care in COVID-19, especially among PWH. Larger studies should validate findings and determine long-term COVID-19 consequences in PWH with preexisting cognitive deficits.

Development and Evaluation of a Natural Language Processing Annotation Tool to Facilitate Phenotyping of Cognitive Status in Electronic Health Records: Diagnostic Study.

BACKGROUND: Electronic health records (EHRs) with large sample sizes and rich information offer great potential for dementia research, but current methods of phenotyping cognitive status are not scalable. OBJECTIVE: The aim of this study was to evaluate whether natural language processing (NLP)-powered semiautomated annotation can improve the speed and interrater reliability of chart reviews for phenotyping cognitive status. METHODS: In this diagnostic study, we developed and evaluated a semiautomated NLP-powered annotation tool (NAT) to facilitate phenotyping of cognitive status. Clinical experts adjudicated the cognitive status of 627 patients at Mass General Brigham (MGB) health care, using NAT or traditional chart reviews. Patient charts contained EHR data from two data sets: (1) records from January 1, 2017, to December 31, 2018, for 100 Medicare beneficiaries from the MGB Accountable Care Organization and (2) records from 2 years prior to COVID-19 diagnosis to the date of COVID-19 diagnosis for 527 MGB patients. All EHR data from the relevant period were extracted; diagnosis codes, medications, and laboratory test values were processed and summarized; clinical notes were processed through an NLP pipeline; and a web tool was developed to present an integrated view of all data. Cognitive status was rated as cognitively normal, cognitively impaired, or undetermined. Assessment time and interrater agreement of NAT compared to manual chart reviews for cognitive status phenotyping was evaluated. RESULTS: NAT adjudication provided higher interrater agreement (Cohen κ=0.89 vs κ=0.80) and significant speed up (time difference mean 1.4, SD 1.3 minutes; P<.001; ratio median 2.2, min-max 0.4-20) over manual chart reviews. There was moderate agreement with manual chart reviews (Cohen κ=0.67). In the cases that exhibited disagreement with manual chart reviews, NAT adjudication was able to produce assessments that had broader clinical consensus due to its integrated view of highlighted relevant information and semiautomated NLP features. CONCLUSIONS: NAT adjudication improves the speed and interrater reliability for phenotyping cognitive status compared to manual chart reviews. This study underscores the potential of an NLP-based clinically adjudicated method to build large-scale dementia research cohorts from EHRs.

Dysarthria-Facial Paresis and Rostral Pontine Ischemic Stroke.

We describe an acute, postoperative dysarthria-facial paresis. While the rare stroke syndrome has been described previously, we present an under-described clinical nuance to its presentation with a particularly clear imaging correlation. A 78-year-old, right-handed man with a past medical history of aortic stenosis presented after a transcatheter aortic valve replacement. Immediately postoperatively, no neurological deficits were noted. That evening, he described his speech as "drunken." He was later noted to have a right lower facial droop in addition to the speech change. His speech exhibited labial, lingual, and (to a lesser degree) guttural dysarthria. At the patient's request due to claustrophobia, he received 2 mg of oral lorazepam prior to cranial imaging. Afterwards, he was sleepy but arousable, yet was unable to put pen to paper when asked to write. Right lower facial paresis persisted, but he now demonstrated a right pronator drift, which resolved after 14 h without other evolution to his clinical examination. Brainstem lesions above the level of the pontine facial nucleus may present with central facial paresis contralateral to the lesion. An associated dysarthria may have both labial and lingual features in the absence of tongue or pharyngeal weakness. Our review of reported cases of dysarthria in isolation, dysarthria in combination with facial paresis, and facial paresis finds that all presentations may result from cortical, subcortical, or brainstem involvement. Stroke mechanisms are most commonly thromboembolic or small-vessel-ischemic in either the anterior or posterior circulations.

ASC-dependent inflammasomes contribute to immunopathology and mortality in herpes simplex encephalitis.

Herpes simplex virus encephalitis (HSE) is the most common cause of sporadic viral encephalitis, and despite targeted antiviral therapy, outcomes remain poor. Although the innate immune system is critical for restricting herpes simplex virus type I (HSV-1) in the brain, there is evidence that prolonged neuroinflammation contributes to HSE pathogenesis. In this study, we investigated the contribution of inflammasomes to disease pathogenesis in a murine model of HSE. Inflammasomes are signaling platforms that activate the pro-inflammatory cytokines interleukin-1ß (IL-1ß) and IL-18. We found that mice deficient in the inflammasome adaptor protein, apoptosis-associated speck-like protein containing a caspase activation and recruitment domain (ASC), had significantly improved survival and lower levels of IL-1ß and IL-18 in the brain. Importantly, this difference in survival was independent of viral replication in the central nervous system (CNS). We found that microglia, the resident macrophages of the CNS, are the primary mediators of the ASC-dependent inflammasome response during infection. Using in vitro glial infections and a murine HSE model, we demonstrate that inflammasome activation contributes to the expression of chemokine (C-C motif) ligand 6 (CCL6), a leukocyte chemoattractant. The lower concentration of CCL6 in the brains of ASC-/- mice correlated with lower numbers of infiltrating macrophages during infection. Together, these data suggest that inflammasomes contribute to pathogenic inflammation in HSE and provide a mechanistic link between glial inflammasome activation and leukocyte infiltration. The contribution of inflammasomes to survival was independent of viral replication in our study, suggesting a promising new target in combating harmful inflammation in HSE.

Eastern equine encephalitis and use of IV immunoglobulin therapy and high-dose steroids.

OBJECTIVE: To determine the clinical presentation and patient outcomes after treatment with IV immunoglobulin (IVIG), high-dose steroids, or standard of care alone in Eastern equine encephalitis (EEE), a mosquito-borne viral infection with significant neurologic morbidity and mortality. METHODS: A retrospective observational study of patients admitted to 2 tertiary academic medical centers in Boston, Massachusetts, with EEE from 2005 to 2019. RESULTS: Of 17 patients (median [IQR] age, 63 [36-70] years; 10 (59%) male, and 16 (94%) White race), 17 patients had fever (100%), 15 had encephalopathy (88%), and 12 had headache (71%). Eleven of 14 patients with CSF cell count differential had a neutrophil predominance (mean = 60.6% of white blood cells) with an elevated protein level (median [IQR], 100 mg/dL [75-145]). Affected neuroanatomic regions included the basal ganglia (n = 9/17), thalamus (n = 7/17), and mesial temporal lobe (n = 7/17). A total of 11 patients (65%) received IVIG; 8 (47%) received steroids. Of the patients who received IVIG, increased time from hospital admission to IVIG administration correlated with worse long-term disability as assessed by the modified Rankin Scale (mRS) (r = 0.72, p = 0.02); steroid use was not associated with the mRS score. The mortality was 12%. CONCLUSIONS: Clinicians should suspect EEE in immunocompetent patients with early subcortical neuroimaging abnormalities and CSF neutrophilic predominance. This study suggests a lower mortality than previously reported, but a high morbidity rate in EEE. IVIG as an adjunctive to standard of care may be considered early during hospitalization.

The Innate Immune Response to Herpes Simplex Virus 1 Infection Is Dampened in the Newborn Brain and Can Be Modulated by Exogenous Interferon Beta To Improve Survival.

Newborns are particularly susceptible to severe forms of herpes simplex virus 1 (HSV-1) infection, including encephalitis and multisystemic disseminated disease. The underlying age-dependent differences in the immune response that explain this increased susceptibility relative to the adult population remain largely understudied. Using a murine model of HSV-1 infection, we found that newborn mice are largely susceptible to intracranial and intraperitoneal challenge while adult mice are highly resistant. This age-dependent difference correlated with differential basal-level expression of components of innate immune signaling pathways, which resulted in dampened interferon (IFN) signaling in the newborn brain. To explore the possibility of modulating the IFN response in the newborn brain to recapitulate the adult phenotype, we administered exogenous IFN-ß in the context of disseminated HSV-1 infection. IFN-ß treatment resulted in significantly increased survival and delayed viral neuroinvasion in the newborn. These effects were associated with changes in the type I IFN response in the brain, reduced viral replication in the periphery, and the stabilization of the blood-brain barrier (BBB). Our study reveals important age-dependent differences in the innate immune response to HSV-1 infection and suggests a contribution of the BBB and the brain parenchyma in mediating the increased susceptibility to HSV-1 infection observed in the newborn. These results could provide the basis for potential new therapeutic strategies for life-threatening HSV-1 infection in newborns.IMPORTANCE Herpes simplex virus (HSV) is a ubiquitous human pathogen affecting 50 to 80% of the population in North America and Europe. HSV infection is commonly asymptomatic in the adult population but can result in fatal encephalitis in the newborn. Current treatment with acyclovir has improved mortality in the newborn; however, severe neurologic sequelae are still a major concern following HSV encephalitis. For this reason, there is a critical need to better understand the underlying differences in the immune response between the two age groups that could be used to develop more effective treatments. In this study, we investigated differences in the innate immune response to viral infection in the brains of newborn and adult mice. We found that, similar to humans, newborn mice are more susceptible to HSV infection than the adult. Increased susceptibility was associated with dampened innate immune responses in the newborn brain that could be rescued by administering interferon beta.

Functional Coma: Two Case Reports and a Review of the Literature.

BACKGROUND: Psychiatric illness can mimic a comatose state. The most common is a conversion reaction resulting in a functional coma, which poses a unique diagnostic challenge to the clinician. Little is known about this condition, and the literature is limited by inconsistent terminology and by a lack of high-quality evidence. OBJECTIVE: To provide a conceptual definition of functional coma, describe case examples, summarize management, and increase recognition of this often underacknowledged entity. METHODS: We present two cases and provide a comprehensive review of the literature on the differential diagnosis, pathophysiology, workup, and management. RESULTS: Functional coma is defined as an involuntary coma-like state that occurs in the absence of structural or metabolic damage to the brain and that is distinct from catatonia. This term should supplant the previous phrase of "psychogenic coma." Psychiatric disorders are frequently present premorbidly, but are not required for the diagnosis. About half of the cases occur in the perioperative setting. Physical exam can provide helpful clues, including passive resistance to eye opening or avoidance of the face with arm drop. Additional work-up, including laboratory studies, brain imaging, and electroencephalography, should be obtained but are unremarkable in functional coma. Case studies suggest that the episodes last for several hours, with a range of 45 minutes to 4 days. Treatment includes supportive management and careful psychoeducation. CONCLUSIONS: Functional coma should be conceptualized as a distinct condition from catatonia and psychogenic non-epileptic seizures. Additional clinical and translation research is needed to further explore the etiology of this condition.

Leveraging a Landscape-Level Monitoring and Assessment Program for Developing Resilient Shorelines throughout the Laurentian Great Lakes.

Traditionally, ecosystem monitoring, conservation, and restoration have been conducted in a piecemeal manner at the local scale without regional landscape context. However, scientifically driven conservation and restoration decisions benefit greatly when they are based on regionally determined benchmarks and goals. Unfortunately, required data sets rarely exist for regionally important ecosystems. Because of early recognition of the extreme ecological importance of Laurentian Great Lakes coastal wetlands, and the extensive degradation that had already occurred, significant investments in coastal wetland research, protection, and restoration have been made in recent decades and continue today. Continued and refined assessment of wetland condition and trends, and the evaluation of restoration practices are all essential to ensuring the success of these investments. To provide wetland managers and decision makers throughout the Laurentian Great Lakes basin with the optimal tools and data needed to make scientifically-based decisions, our regional team of Great Lakes wetland scientists developed standardized methods and indicators used for assessing wetland condition. From a landscape perspective, at the Laurentian Great Lakes ecosystem scale, we established a stratified random-site-selection process to monitor birds, anurans, fish, macroinvertebrates, vegetation, and physicochemical conditions of coastal wetlands in the US and Canada. Monitoring of approximately 200 wetlands per year began in 2011 as the Great Lakes Coastal Wetland Monitoring Program. In this paper, we describe the development, delivery, and expected results of this ongoing international, multi-disciplinary, multi-stakeholder, landscape-scale monitoring program as a case example of successful application of landscape conservation design.

An expanded fish-based index of biotic integrity for Great Lakes coastal wetlands.

Biotic indicators are useful for assessing ecosystem health because the structure of resident communities generally reflects abiotic conditions integrated over time. We used fish data collected over 5 years for 470 Great Lakes coastal wetlands to develop multi-metric indices of biotic integrity (IBI). Sampling and IBI development were stratified by vegetation type within each wetland to account for differences in physical habitat. Metrics were evaluated against numerous indices of anthropogenic disturbance derived from water quality and surrounding land-cover variables. Separate datasets were used for IBI development and testing. IBIs were composed of 10-11 metrics for each of four vegetation types (bulrush, cattail, water lily, and submersed aquatic vegetation). Scores of all IBIs correlated well with disturbance indices using the development data, and the accuracy of our IBIs was validated using the testing data. Our fish IBIs can be used to prioritize wetland protection and restoration efforts across the Great Lakes basin. The IBIs will also be useful in monitoring programs mandated by the Agreement between Canada and the United States of America on Great Lakes Water Quality, such as for assessing Beneficial Use Impairments (BUIs) in Great Lakes Areas of Concern, and in other ecosystem management programs in Canada and the USA.

The Type I Interferon Response and Age-Dependent Susceptibility to Herpes Simplex Virus Infection.

Herpes simplex virus type 1 (HSV-1) is a highly prevalent human neurotropic pathogen. HSV-1 infection is associated with a variety of diseases ranging from benign orolabial lesions to more serious and even life-threatening conditions such as herpes simplex keratitis and herpes simplex encephalitis (HSE). HSE is a rare occurrence among healthy adult individuals, but newborns are a particularly susceptible population. Type I IFN signaling has been identified as a crucial component of the innate immune response to the control of HSV-1 infection. In this study, we review the contribution of the type I IFN response to controlling HSV-1 infection, and differences in the early host response between adults and newborns that may contribute to the increased susceptibility to infection and central nervous system disease in newborns.

Flow Separation and Turbulence in Jet Pumps for Thermoacoustic Applications.

The effect of flow separation and turbulence on the performance of a jet pump in oscillatory flows is investigated. A jet pump is a static device whose shape induces asymmetric hydrodynamic end effects when placed in an oscillatory flow. This will result in a time-averaged pressure drop which can be used to suppress acoustic streaming in closed-loop thermoacoustic devices. An experimental setup is used to measure the time-averaged pressure drop as well as the acoustic power dissipation across two different jet pump geometries in a pure oscillatory flow. The results are compared against published numerical results where flow separation was found to have a negative effect on the jet pump performance in a laminar flow. Using hot-wire anemometry the onset of flow separation is determined experimentally and the applicability of a critical Reynolds number for oscillatory pipe flows is confirmed for jet pump applications. It is found that turbulence can lead to a reduction of flow separation and hence, to an improvement in jet pump performance compared to laminar oscillatory flows.

On the performance and flow characteristics of jet pumps with multiple orifices.

The design of compact thermoacoustic devices requires compact jet pump geometries, which can be realized by employing jet pumps with multiple orifices. The oscillatory flow through the orifice(s) of a jet pump generates asymmetric hydrodynamic end effects, which result in a time-averaged pressure drop that can counteract Gedeon streaming in traveling wave thermoacoustic devices. In this study, the performance of jet pumps having 1-16 orifices is characterized experimentally in terms of the time-averaged pressure drop and acoustic power dissipation. Upon increasing the number of orifices, a significant decay in the jet pump performance is observed. Further analysis shows a relation between this performance decay and the diameter of the individual holes. Possible causes of this phenomenon are discussed. Flow visualization is used to study the differences in vortex ring interaction from adjacent jet pump orifices. The mutual orifice spacing is varied and the corresponding jet pump performance is measured. The orifice spacing is shown to have less effect on the jet pump performance compared to increasing the number of orifices.

αT-catenin in restricted brain cell types and its potential connection to autism.

BACKGROUND: Recent genetic association studies have linked the cadherin-based adherens junction protein alpha-T-catenin (αT-cat, CTNNA3) with the development of autism. Where αT-cat is expressed in the brain, and how its loss could contribute to this disorder, are entirely unknown. METHODS: We used the αT-cat knockout mouse to examine the localization of αT-cat in the brain, and we used histology and immunofluorescence analysis to examine the neurobiological consequences of its loss. RESULTS: We found that αT-cat comprises the ependymal cell junctions of the ventricles of the brain, and its loss led to compensatory upregulation of αE-cat expression. Notably, αT-cat was not detected within the choroid plexus, which relies on cell junction components common to typical epithelial cells. While αT-cat was not detected in neurons of the cerebral cortex, it was abundantly detected within neuronal structures of the molecular layer of the cerebellum. Although αT-cat loss led to no overt differences in cerebral or cerebellar structure, RNA-sequencing analysis from wild type versus knockout cerebella identified a number of disease-relevant signaling pathways associated with αT-cat loss, such as GABA-A receptor activation. CONCLUSIONS: These findings raise the possibility that the genetic associations between αT-cat and autism may be due to ependymal and cerebellar defects, and highlight the potential importance of a seemingly redundant adherens junction component to a neurological disorder.

The Type I Interferon Response Determines Differences in Choroid Plexus Susceptibility between Newborns and Adults in Herpes Simplex Virus Encephalitis.

UNLABELLED: Newborns are significantly more susceptible to severe viral encephalitis than adults, with differences in the host response to infection implicated as a major factor. However, the specific host signaling pathways responsible for differences in susceptibility and neurologic morbidity have remained unknown. In a murine model of HSV encephalitis, we demonstrated that the choroid plexus (CP) is susceptible to herpes simplex virus 1 (HSV-1) early in infection of the newborn but not the adult brain. We confirmed susceptibility of the CP to HSV infection in a human case of newborn HSV encephalitis. We investigated components of the type I interferon (IFN) response in the murine brain that might account for differences in cell susceptibility and found that newborns have a dampened interferon response and significantly lower basal levels of the alpha/beta interferon (IFN-α/ß) receptor (IFNAR) than do adults. To test the contribution of IFNAR to restricting infection from the CP, we infected IFNAR knockout (KO) adult mice, which showed restored CP susceptibility to HSV-1 infection in the adult. Furthermore, reduced IFNAR levels did not account for differences we found in the basal levels of several other innate signaling proteins in the wild-type newborn and the adult, including protein kinase R (PKR), that suggested specific regulation of innate immunity in the developing brain. Viral targeting of the CP, a region of the brain that plays a critical role in neurodevelopment, provides a link between newborn susceptibility to HSV and long-term neurologic morbidity among survivors of newborn HSV encephalitis. IMPORTANCE: Compared to adults, newborns are significantly more susceptible to severe disease following HSV infection. Over half of newborn HSV infections result in disseminated disease or encephalitis, with long-term neurologic morbidity in 2/3 of encephalitis survivors. We investigated differences in host cell susceptibility between newborns and adults that contribute to severe central nervous system disease in the newborn. We found that, unlike the adult brain, the newborn choroid plexus (CP) was susceptible early in HSV-1 infection. We demonstrated that IFN-α/ß receptor levels are lower in the newborn brain than in the adult brain and that deletion of this receptor restores susceptibility of the CP in the adult brain. The CP serves as a barrier between the blood and the cerebrospinal fluid and plays a role in proper neurodevelopment. Susceptibility of the newborn choroid plexus to HSV-1 has important implications in viral spread to the brain and, also, in the neurologic morbidity following HSV encephalitis.

Characterization and reduction of flow separation in jet pumps for laminar oscillatory flows.

A computational fluid dynamics model is used to predict the oscillatory flow through tapered cylindrical tube sections (jet pumps). The asymmetric shape of jet pumps results in a time-averaged pressure drop that can be used to suppress Gedeon streaming in closed-loop thermoacoustic devices. However, previous work has shown that flow separation in the diverging flow direction counteracts the time-averaged pressure drop. In this work, the characteristics of flow separation in jet pumps are identified and coupled with the observed jet pump performance. Furthermore, it is shown that the onset of flow separation can be shifted to larger displacement amplitudes by designs that have a smoother transition between the small opening and the tapered surface of the jet pump. These design alterations also reduce the duration of separated flow, resulting in more effective and robust jet pumps. To make the proposed jet pump designs more compact without reducing their performance, the minimum big opening radius that can be implemented before the local minor losses have an influence on the jet pump performance is investigated. To validate the numerical results, they are compared with experimental results for one of the proposed jet pump designs.

HSV targeting of the host phosphatase PP1α is required for disseminated disease in the neonate and contributes to pathogenesis in the brain.

Newborns are significantly more susceptible to severe disease after infection with herpes simplex virus (HSV) compared with adults, with differences in the host response implicated as a major factor. To understand host response differences between these age groups, we investigated the shutoff of protein synthesis by the host and the retargeting of host phosphatase PP1α by the HSV-1 protein γ34.5 for reversal of translational arrest. In a murine newborn model of viral dissemination, infection with the HSV-1 mutant for PP1α binding resulted in complete absence of disease. PP1α-binding mutant HSV-1 replicated in visceral organs early after inoculation, demonstrating that HSV-1 replication requires PP1α-targeting only later in infection. Newborn mice deficient in type I IFN signaling partially rescued the virulence of the PP1α-binding mutant virus, suggesting an IFN-independent role for eIF2α kinases during infection. When we investigated the contribution of PP1α targeting to pathogenesis in the brain, we found that the inability of HSV-1 to bind PP1α increased survival time in both newborn and adult mice. Unlike disseminated disease, type I IFN signaling in the brain was required to attenuate disease following PP1α-mutant virus infection. Furthermore, pharmacologic inhibition of eIF2α dephosphorylation reduced HSV-1 replication in a brain slice culture model of encephalitis. Our findings reveal age-dependent differences in γ34.5 function and tissue-specific reliance on the type I IFN response for protection from HSV disease. These results define an important role for γ34.5 in neonatal infections in contrast to other studies indicating that the autophagy-inhibiting function of γ34.5 is dispensable for pathogenesis in the newborn brain.

Jet pumps for thermoacoustic applications: Design guidelines based on a numerical parameter study.

The oscillatory flow through tapered cylindrical tube sections (jet pumps) is characterized by a numerical parameter study. The shape of a jet pump results in asymmetric hydrodynamic end effects which cause a time-averaged pressure drop to occur under oscillatory flow conditions. Hence, jet pumps are used as streaming suppressors in closed-loop thermoacoustic devices. A two-dimensional axisymmetric computational fluid dynamics model is used to calculate the performance of a large number of conical jet pump geometries in terms of time-averaged pressure drop and acoustic power dissipation. The investigated geometrical parameters include the jet pump length, taper angle, waist diameter, and waist curvature. In correspondence with previous work, four flow regimes are observed which characterize the jet pump performance and dimensionless parameters are introduced to scale the performance of the various jet pump geometries. The simulation results are compared to an existing quasi-steady theory and it is shown that this theory is only applicable in a small operation region. Based on the scaling parameters, an optimum operation region is defined and design guidelines are proposed which can be directly used for future jet pump design.