Taste and smell function in Wilson's disease.

OBJECTIVE: Wilson's disease (WD) is a metabolic disorder associated with abnormal copper metabolism that results in hepatic, psychiatric, and neurologic symptoms. No investigation of taste function has been made in patients with WD, although olfactory dysfunction has been evaluated. METHODS: Quantitative taste and smell test scores of 29 WD patients were compared to those of 790 healthy controls. Taste was measured using the 53-item Waterless Empirical Taste Test (WETT®) and smell using the 40-item revised University of Pennsylvania Smell Identification Test (R-UPSIT®). Multiple linear regression analysis controlled for age and sex. RESULTS: Average WETT® scores did not differ meaningfully between WD and control subjects (respective medians & IQRs = 32 [28-42] & 34 [27-41]); linear regression coefficient = 1.19, 95% CI [-0.81, 3.19], p = 0.242). In contrast, WD was associated with significantly reduced olfactory function [respective median (IQR) R-UPSIT® scores = 35 (33-37) vs. 37 (35-38); adjusted linear regression coefficient = -1.59, 95% CI [-2.34, -0.833]; p < 0.001)]. Neither olfaction nor taste were influenced by WD symptom subtype [23 (79.3%) were hepatic-predominant; 6 (20.7%) neurologic predominant]; R-UPSIT®, p = 0.774; WETT®, p = 0.912). No effects of primary medication or years since diagnosis (R-UPSIT®, p = 0.147; WETT®, p = 0.935) were found. Weak correlations were present between R-UPSIT® and WETT® scores for both control (r=0.187, p < 0.0001) and WD (r=0.237) subjects, although the latter correlation did not reach the 0.05 α level (p = 0.084). CONCLUSION: Although WD negatively impacts smell function, taste is spared. Research is needed to understand the pathophysiologic mechanisms responsible for this divergence.

Major Depressive Disorder in an International Multisite Wilson Disease Registry.

BACKGROUND AND AIMS: Psychiatric symptoms are frequently reported in Wilson disease (WD); however, systematic assessments with validated measures are lacking. OBJECTIVE: We aim to report the prevalence and clinical correlates for major depressive disorder (MDD) as resulting from a multisite international WD registry. METHODS: All patients enrolled in the WD registry received structured psychiatric evaluations (Mini International Neuropsychiatric Interview, Patient Health Questionnaire-9, Generalized Anxiety Disorder-7 scale, Perceived Stress Scale), laboratory tests, hepatology, and neurological assessments. We present the analysis of the data collected at enrollment for the first 3 years (N = 62). RESULTS: Thirty-seven percent (23) had a lifetime history (MDD), and 6% (4) met the criteria for an active major depressive episode. Depression was self-reported in 30.51% (19) at WD diagnosis. Patients with MDD had worse mental health quality-of-life (QOL) scores (median 43 vs 53.6, P = 0.006), higher severe anxiety (13.04% vs 0), higher perceived stress (median 18 vs 9, P < 0.003), and higher levels of neuroticism (median 8 vs 5.0, P = 0.002). We found no significant difference in physical health QOL and severity of neurological or liver disease. There was no significant difference in copper parameters or liver tests in those with MDD and without. The limitations of our study consist of the small sample size, the cross-sectional report, and the lack of brain copper measurements. CONCLUSIONS: Lifetime MDD is highly prevalent in WD and associated with worse mental health QOL. We did not find a significant association among liver disease, neurological disease laboratory tests, and MDD. Screening for depression should be considered in patients with WD.

Neural network-based cooling design for high-performance processors.

Ultra-high chip power densities that are expected to surpass 1-2kW/cm2 in future high-performance systems cannot be easily handled by conventional cooling methods. Various emerging cooling methods, such as liquid cooling via microchannels, thermoelectric coolers (TECs), two-phase vapor chambers, and hybrid cooling options have been designed to efficiently remove heat from high-performance processors. However, selecting the optimal cooling solution for a given chip and determining the optimal cooling parameters for that solution to achieve high efficiency are open problems. These problems are, in fact, computationally expensive because of the massive space of possible solutions. To address this design challenge, this article introduces a deep learning-based cooling design optimization flow that rapidly and accurately converges to the optimal cooling solution as well as the optimal cooling parameters for a given chip floorplan and its power profile.

HPC Data Center Participation in Demand Response: an Adaptive Policy with QoS Assurance.

Demand response programs help stabilize the electricity grid by providing monetary stimulus to consumers if they regulate their power consumption following market requirements. Regulation service, a market that requires participants to regulate power by following a signal updated every few seconds, is particularly beneficial to HPC data centers since data centers are capable of increasing/decreasing power consumption owing to the flexibility in running workloads and the availability of power control mechanisms. While prior works have explored how data centers can provide regulation service reserves, Quality-of-Service (QoS) provisioning for the jobs running at the data centers has not been considered. In this work, we propose an Adaptive policy with QoS Assurance that enables data centers to participate in regulation service programs with assurance on job QoS. Our policy regulates data center power through job scheduling and server power capping. QoS assurance is achieved by applying a queueing-theoretic result to our job scheduling strategy. We evaluate our policy by experiments on a real cluster. Our results demonstrate that the proposed policy reduces electricity costs by 25-56% while providing QoS assurance. On the other hand, the baseline policies cannot meet QoS constraints in 9 of the 14 workload traces tested.

The Effect of Mental Health, Neurological Disease, and Liver Disease on Quality of Life in Patients With Wilson Disease.

BACKGROUND: Wilson disease (WD) is a chronic disorder of copper metabolism which may affect patient's quality of life (QOL). OBJECTIVE: Our aim was to assess the relationship between mental QOL (M-QOL) and physical QOL (P-QOL) and severity of the liver, neurological disease and mental health in patients with WD. METHODS: At enrollment into our multisite international WD registry, adults (n = 62) were administered examinations assessing QOL (Short-Form 12-Item Health Survey), cognition, and mood. Patients also underwent hepatology and neurological assessments. RESULTS: Patients had lower M-QOL than P-QOL scores, P = 0.0006. Patients with major depressive disorder (n = 22) had worse M-QOL scores, P = 0.0017 but not P-QOL. We found no association with impaired cognition (n = 37) and QOL. The P-QOL scores have a moderate negative association with neurological disease severity based on the Unified Wilson Disease Rating Scale score (total [r = -0.38, P < 0.003], part 2 [r = -0.50, P < 0.0001], and part 3 [r = -0.37, P = 0.004]). M-QOL was not associated with Unified Wilson Disease Rating Scale scores. Worse P-QOL, but not M-QOL, was found in higher cirrhosis severity indicated by Child-Pugh (r = -0.80, P = 0.002) and Model for End Stage Liver Disease scores (r = -0.64, P = 0.03). CONCLUSIONS: M-QOL was associated with depression but not cognitive impairment, neurological disease, or liver disease severity, suggesting that mental health issues may affect overall QOL independent of the degree of liver or neurological disease. P-QOL was affected by the severity of neurological and liver disease but not mental health but also contributes to overall QOL in WD. An appreciation of the range of problems that affect QOL in adults with WD will help health care providers address issues that could improve overall well-being. The Short-Form 12-Item Health Survey may provide a useful instrument for QOL surveillance in WD.

Direct Measurement of ATP7B Peptides Is Highly Effective in the Diagnosis of Wilson Disease.

BACKGROUND & AIMS: Both existing clinical criteria and genetic testing have significant limitations for the diagnosis of Wilson disease (WD), often creating ambiguities in patient identification and leading to delayed diagnosis and ineffective management. ATP7B protein concentration, indicated by direct measurement of surrogate peptides from patient dried blood spot samples, could provide primary evidence of WD. ATP7B concentrations were measured in patient samples from diverse backgrounds, diagnostic potential is determined, and results are compared with biochemical and genetic results from individual patients. METHODS: Two hundred and sixty-four samples from biorepositories at 3 international and 2 domestic academic centers and 150 normal controls were obtained after Institutional Review Board approval. Genetically or clinically confirmed WD patients with a Leipzig score >3 and obligate heterozygote (carriers) from affected family members were included. ATP7B peptide measurements were made by immunoaffinity enrichment mass spectrometry. RESULTS: Two ATP7B peptides were used to measure ATP7B protein concentration. Receiver operating characteristics curve analysis generates an area under the curve of 0.98. ATP7B peptide analysis of the sequence ATP7B 887 was found to have a sensitivity of 91.2%, specificity of 98.1%, positive predictive value of 98.0%, and a negative predictive value of 91.5%. In patients with normal ceruloplasmin concentrations (>20 mg/dL), 14 of 16 (87.5%) were ATP7B-deficient. In patients without clear genetic results, 94% were ATP7B-deficient. CONCLUSIONS: Quantification of ATP7B peptide effectively identified WD patients in 92.1% of presented cases and reduced ambiguities resulting from ceruloplasmin and genetic analysis. Clarity is brought to patients with ambiguous genetic results, significantly aiding in noninvasive diagnosis. A proposed diagnostic score and algorithm incorporating ATP7B peptide concentrations can be rapidly diagnostic and supplemental to current Leipzig scoring systems.

Transcriptional down-regulation of ccr5 in a subset of HIV+ controllers and their family members.

HIV +Elite and Viremic controllers (EC/VCs) are able to control virus infection, perhaps because of host genetic determinants. We identified 16% (21 of 131) EC/VCs with CD4 +T cells with resistance specific to R5-tropic HIV, reversed after introduction of ccr5. R5 resistance was not observed in macrophages and depended upon the method of T cell activation. CD4 +T cells of these EC/VCs had lower ccr2 and ccr5 RNA levels, reduced CCR2 and CCR5 cell-surface expression, and decreased levels of secreted chemokines. T cells had no changes in chemokine receptor mRNA half-life but instead had lower levels of active transcription of ccr2 and ccr5, despite having more accessible chromatin by ATAC-seq. Other nearby genes were also down-regulated, over a region of ~500 kb on chromosome 3p21. This same R5 resistance phenotype was observed in family members of an index VC, also associated with ccr2/ccr5 down-regulation, suggesting that the phenotype is heritable.

Differential interaction between human and murine Crm1 and lentiviral Rev proteins.

Mice have multiple obstacles to HIV replication, including a block of unspliced and partially spliced viral mRNA nuclear export. In human, Rev binds to the Rev-response element and human (h) Crm1, facilitating nuclear export of RRE-containing viral RNAs. Murine (m) Crm1 is less functional than hCrm1 in this regard. Here we demonstrated that in biochemical experiments mCrm1 failed to interact with HIV Rev whereas hCrm1 did. In genetic experiments in human cells, we observed a modest but significant differential effect between mCrm1 and hCrm1, which was also true of other lentiviral Revs tested. Triple mutant hCrm1 P411T-M412V-F414S behaved similarly to mCrm1, whereas mCrm1 with T411P-V412M-S414F regained some activity, although contribution of additional residues to its function can not be excluded. Similar results were observed in murine cells. This suggests a differential interaction between hCrm1 and mCrm1 and many lentiviral Revs, which may partially explain the HIV replicative defect in mice.

An Investigation of Unified Memory Access Performance in CUDA.

Managing memory between the CPU and GPU is a major challenge in GPU computing. A programming model, Unified Memory Access (UMA), has been recently introduced by Nvidia to simplify the complexities of memory management while claiming good overall performance. In this paper, we investigate this programming model and evaluate its performance and programming model simplifications based on our experimental results. We find that beyond on-demand data transfers to the CPU, the GPU is also able to request subsets of data it requires on demand. This feature allows UMA to outperform full data transfer methods for certain parallel applications and small data sizes. We also find, however, that for the majority of applications and memory access patterns, the performance overheads associated with UMA are significant, while the simplifications to the programming model restrict flexibility for adding future optimizations.

Isolation and characterization of mouse-human microcell hybrid cell clones permissive for infectious HIV particle release.

Mouse cells are non-permissive to human immunodeficiency virus type 1 (HIV) in that there is a pronounced post-integration block to viral replication. We have recently demonstrated that mouse-human somatic cell hybrids that contain human chromosome 2 increase both HIV Capsid (CA) production and infectious virus release. Here we report on the isolation of three mouse-human microcell hybrids (MCHs) that behave similarly, starting from a pool of 500 MCH clones. Release of virus was specific to HIV and cell revertants that no longer contained any human chromosome fragments did not release CA or infectious virus. Two of the three cell clones were identical as judged by PCR STS content and fluorescence in situ hybridization (FISH) and contained a single 2-12 human chromosome chimera. The third cell clone only contained human chromosome 12, as determined by PCR, FISH, and microarray analyses. There were no consistent differences in Gag protein and spliced/unspliced viral RNA levels between mouse cell lines. CMV promoter-driven, codon-optimized gag-pol had no effect on infectious HIV release from these mouse cells, despite allowing Gag targeting and increasing CA production. These permissive mouse-human MCHs and their corresponding non-permissive revertants may prove useful for mechanistic studies and also for identifying the responsible gene(s) or factor(s) involved in the production of HIV.

Human chromosome 2 carries a gene required for production of infectious human immunodeficiency virus type 1.

Human immunodeficiency virus type 1 (HIV) replicates only in certain primate cells. In murine cells expressing cyclin T1, a posttranscriptional block exists such that small amounts of capsid and little infectious virus are released. This block is relieved in part by fusion with human cells. Here we have tested a panel of mouse-human somatic cell hybrids for production of infectious virus. Only those containing human chromosome 2 were permissive, which correlated with capsid production. The effect was specific to HIV in that release of murine leukemia virus was minimally affected by the presence of chromosome 2. Although expression of Vpu markedly increased capsid production in the absence of chromosome 2, it did not result in a corresponding increase in infectious HIV. The presence of chromosome 2 did not have consistent effects on the amount of unspliced viral RNA, whereas the amount of cell-associated Gag p55 was increased a fewfold. These results suggest that processing of HIV Gag can be corrected by one or more genes present on human chromosome 2 to allow production of infectious HIV from murine cells.

Development of a mouse model for HIV/AIDS.

A small animal model would be very valuable for HIV/AIDS vaccine testing, investigating HIV pathophysiology, and exploring anti-HIV therapeutics. Unfortunately, HIV does not replicate in mouse cells. Provision of mouse cells with human CD4, CCR5 and cyclin T1 (cycT1) has uncovered a block to HIV assembly or release. Since mouse-human cell fusions allow viral replication, mouse cells lack at least one critical factor that permits completion of the viral life cycle. To identify this factor(s) we are employing 2 similar genetic approaches. Each cell line of a panel of monochromosomal mouse-human somatic cell hybrids was individually transduced with an HIV vector encoding both cycT1 and blasticidin resistance (HIV-CIB). Each was then transfected with vesicular stomatitis virus (VSV) G protein and measurable virus was recovered from only the hybrid-containing chromosome 2. This was verified with an M-tropic envelope and was shown to be specific to HIV. In addition, the amount of p24 release from that hybrid was substantially greater than that from the parent. A second cell line expressing chromosome 2 had a similar phenotype. CycT1 has been introduced into one chromosome 2 line to monitor the spread of HIV. In a related but separate approach, an entire collection of approximately 500 mouse-human microcell hybrids was transduced with HIV-CIB and broken down into manageable pools. Virus was similarly recovered as above from a few of the pools. Those pools were then broken down to clones and several cell clones have been identified that allow virus release. Revertants that no longer have the human chromosome are now being tested for loss of phenotype. Clones will then be tested for ability to support both HIV replication and Gag processing. Human chromosomal content of the clones of greatest interest will be determined by STS content analysis. Results from the 2 approaches are expected to be in agreement and may provide direction for an expression cloning approach.