Intrinsic apoptosis is principally governed by the BCL-2 family of proteins, but some non-BCL-2 proteins are also critical to control this process. To identify novel apoptosis regulators, we performed a genome-wide CRISPR-Cas9 library screen, and it identified the mitochondrial E3 ubiquitin ligase MARCHF5/MITOL/RNF153 as an important regulator of BAK apoptotic function. Deleting MARCHF5 in diverse cell lines dependent on BAK conferred profound resistance to BH3-mimetic drugs.
View Article and Find Full Text PDFIntrinsic apoptosis is critical to prevent tumor formation and is engaged by many anti-cancer agents to eliminate tumor cells. BAX and BAK, the two essential mediators of apoptosis, are thought to be regulated through similar mechanisms and act redundantly to drive apoptotic cell death. From an unbiased genome-wide CRISPR/Cas9 screen, we identified VDAC2 (voltage-dependent anion channel 2) as important for BAX, but not BAK, to function.
View Article and Find Full Text PDFBAK and BAX are the essential effectors of apoptosis because without them a cell is resistant to most apoptotic stimuli. BAK and BAX undergo conformation changes to homooligomerize then permeabilize the mitochondrial outer membrane during apoptosis. How BCL-2 homology 3 (BH3)-only proteins bind to activate BAK and BAX is unclear.
View Article and Find Full Text PDFDuring apoptosis, Bak permeabilizes mitochondria after undergoing major conformational changes, including poorly defined N-terminal changes. Here, we characterize those changes using 11 antibodies that were epitope mapped using peptide arrays and mutagenesis. After Bak activation by Bid, epitopes throughout the α1 helix are exposed indicating complete dissociation of α1 from α2 in the core and from α6-α8 in the latch.
View Article and Find Full Text PDFObjective: To characterize clinical features, neuroimaging, and outcomes of herpes simplex encephalitis (HSE) in immunocompromised individuals.
Methods: We performed a retrospective case control review of patients diagnosed with HSE. Adult patients were dichotomized into immunocompromised (n = 14) and immunocompetent groups (n = 15).
Survival in people infected with HIV has improved because of an increasingly powerful array of antiretroviral treatments, but neurological symptoms due to comorbid conditions, including infection with hepatitis C virus, malnutrition, and the effects of accelerated cardiovascular disease and ageing, are increasingly salient. A therapeutic gap seems to exist between the salutary effects of antiretroviral regimens and the normalisation of neurological function in HIV-associated neurocognitive disorders. Despite the advances in antiretroviral therapy, CNS opportunistic infections remain a serious burden worldwide.
View Article and Find Full Text PDFObjective: To investigate the role of skin biopsy in nitrofurantoin peripheral neuropathy.
Design: We describe the clinical features and skin biopsies of 2 cases of non-length-dependent small-fiber neuropathy/ganglionopathy attributable to nitrofurantoin.
Setting: Clinical evaluation and skin biopsies were performed at a tertiary teaching hospital in Baltimore, Maryland.
There has been speculation that chronic HIV infection is a condition of accelerated aging that may lead to early onset of disease in multiple organ systems. The neuromuscular disorders of HIV, in particular distal symmetric polyneuropathy and myopathies, are also seen in the general population among older patients. As the HIV-infected population ages, there may be deleterious synergistic effects of age and chronic HIV infection on the brain, peripheral nerve, and muscle.
View Article and Find Full Text PDFMore than 25 loci have been linked to type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse, but identification of the underlying genes remains challenging. We describe here the positional cloning of a T1D susceptibility locus, Idd11, located on mouse chromosome 4. Sequence analysis of a series of congenic NOD mouse strains over a critical 6.
View Article and Find Full Text PDFFulminant forms of Guillain-Barré syndrome (GBS) present as acute onset tetraparesis and areflexia with absent brainstem reflexes, simulating brain death. Head trauma as an antecedent to fulminant GBS has been infrequently reported, and recognizing an association between GBS and head trauma may be crucial for patient management. Consequently, we report a patient with fulminant GBS with mixed demyelinating and axonal features preceded by a closed head injury, and discuss the possible pathophysiological mechanisms.
View Article and Find Full Text PDFAutoimmune lymphocytic infiltration of the salivary glands, termed sialadenitis, is a pathologic feature of Sjögren's syndrome (SjS) that is also prominent in nonobese diabetic (NOD) mice. Genetic factors regulate sialadenitis, and a previous (NOD x NZW)F2 study detected linkage to murine chromosome (Chr) 7. The locus, subsequently annotated as Ssial3, maps to the distal end of Chr7 and overlaps a region associated with type 1 diabetes susceptibility in NOD mice.
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