Learning and memory and the underlying cellular correlate, long-term synaptic plasticity, involve regulation by posttranslational modifications (PTMs). Here we demonstrate that conjugation with the ...small ubiquitin-like modifier (SUMO) is a novel PTM required for normal synaptic and cognitive functioning. Acute inhibition of SUMOylation impairs long-term potentiation (LTP) and hippocampal-dependent learning. Since Alzheimer's disease (AD) prominently features both synaptic and PTM dysregulation, we investigated SUMOylation under pathology induced by amyloid-β (Aβ), a primary neurotoxic molecule implicated in AD. We observed that SUMOylation is dysregulated in both human AD brain tissue and the Tg2576 transgenic AD mouse model. While neuronal activation normally induced upregulation of SUMOylation, this effect was impaired by Aβ42 oligomers. However, supplementing SUMOylation via transduction of its conjugating enzyme, Ubc9, rescued Aβ-induced deficits in LTP and hippocampal-dependent learning and memory. Our data establish SUMO as a novel regulator of LTP and hippocampal-dependent cognition and additionally implicate SUMOylation impairments in AD pathogenesis.
This article proposes StiMote, an untethered, free-floating and individually addressable stimulator mote designed for visual cortex stimulation, aimed at vision restoration. The system is optically ...powered by a custom photovoltaic (PV) layer. In addition, the photodiode (PD) layer captures the light modulation and forwards it to the optical receiver (ORX) including a tranimpedance amplifier. Translated instructions can assign a unique slot, up to 1024 available, to each mote within the time-division multiple access (TDMA) framework. In this work, we propose an automatic charge balance (CB) technique that monitors the injected charge to balance in bi-phasic switched-capacitor stimulation (SCS). The chip was confirmed fully functional when operated completely wirelessly using harvested light. Measurement results revealed a power consumption of 4.48 <inline-formula> <tex-math notation="LaTeX">\mu </tex-math></inline-formula> W with a 7.5-kb/s optical downlink data rate, corresponding to continuous updates at 2.5 Hz of 1024 motes to their individual 3-b stimulation intensity levels. The dc-dc converter, responsible for providing high voltage for stimulation, demonstrated 4.3-V output voltage when unloaded, with a maximum efficiency of 67.4%. The proposed CB circuit exhibited linear controllability of stimulation charge up to 16 nC, with a charge imbalance of less than 0.2 nC. Furthermore, in vitro testing confirmed the absence of chemical reactions at electrodes, and in vivo experiments conducted on live rats verified the effectiveness of the stimulation through StiMote.
The purpose of this study was to evaluate the characteristics of patients with congenital heart disease (CHD) who developed necrotizing enterocolitis (NEC).
A retrospective review of neonates with ...CHD at a tertiary care center between January 2006 and January 2016 was performed. Diagnosis of NEC was based on modified Bell's criteria. Patients were grouped by Risk Adjustment for Congenital Heart Surgery (RACHS-1) or by ductal-dependent (DD) lesions that require a patent ductus arteriosus to supply pulmonary or systemic circulation.
Of 1811 neonates with CHD, 3.4% (n=61) developed NEC. Eighteen (30%) of these required surgical management. The rate of NEC among DD patients was 5% (n=33/653), compared to 2.4% (n=28/1158) in the non-DD group (p=0.003). RACHS-1 score>2 had a higher rate of NEC 6.2% (41/658) compared to RACHS-1≤2 cases, 1.7% (20/1153) (p=0.005). DD patients and complex patients with RACHS-1>2 were more likely to develop NEC after cardiac surgery. Hypoplastic left heart syndrome patients had a rate of 9% (n=16/185). Surgical NEC was more prevalent in the non-DD group. Mortality was similar among groups.
CHD patients with ductal-dependent lesions or complex cases (RACHS-1 score>2) have higher rates of NEC than non-ductal-dependent patients or RACHS-1 score of 2 or less. Mortality is similar regardless of ductal dependence, but surgical NEC was more prevalent in non-DD patients.
Level IIb.
Exome sequencing of 343 families, each with a single child on the autism spectrum and at least one unaffected sibling, reveal de novo small indels and point substitutions, which come mostly from the ...paternal line in an age-dependent manner. We do not see significantly greater numbers of de novo missense mutations in affected versus unaffected children, but gene-disrupting mutations (nonsense, splice site, and frame shifts) are twice as frequent, 59 to 28. Based on this differential and the number of recurrent and total targets of gene disruption found in our and similar studies, we estimate between 350 and 400 autism susceptibility genes. Many of the disrupted genes in these studies are associated with the fragile X protein, FMRP, reinforcing links between autism and synaptic plasticity. We find FMRP-associated genes are under greater purifying selection than the remainder of genes and suggest they are especially dosage-sensitive targets of cognitive disorders.
► De novo mutations derive mainly from the paternal line in an age-dependent manner ► Mutations disrupting genes are twice as frequent in affected as unaffected siblings ► Many disrupted genes are associated with the fragile X protein, FMRP ► FMRP-associated genes are under unexpectedly strong purifying selection
Iossifov et al. use exome sequencing of 343 autistic families to identify de novo gene mutations associated with autism. Many of the mutated genes are associated with the fragile X protein FMRP, indicating new links between autism and synaptic plasticity.
mutations define a subset of metastatic breast cancers with a unique mechanism of oncogenic addiction to HER2 signaling. We explored activity of the irreversible pan-HER kinase inhibitor neratinib, ...alone or with fulvestrant, in 81 patients with
-mutant metastatic breast cancer. Overall response rate was similar with or without estrogen receptor (ER) blockade. By comparison, progression-free survival and duration of response appeared longer in ER
patients receiving combination therapy, although the study was not designed for direct comparison. Preexistent concurrent activating
or
alterations were associated with poor treatment outcome. Similarly, acquisition of multiple
-activating events, as well as gatekeeper alterations, were observed at disease progression in a high proportion of patients deriving clinical benefit from neratinib. Collectively, these data define
mutations as a therapeutic target in breast cancer and suggest that coexistence of additional HER signaling alterations may promote both
and acquired resistance to neratinib. SIGNIFICANCE:
mutations define a targetable breast cancer subset, although sensitivity to irreversible HER kinase inhibition appears to be modified by the presence of concurrent activating genomic events in the pathway. These findings have implications for potential future combinatorial approaches and broader therapeutic development for this genomically defined subset of breast cancer.
.
Using electrophoretic karyotyping, RAPD fingerprinting and phylogenetic analysis of ribosomal RNA gene sequences, twenty-six
Vanderwaltozyma
strains were studied. Out of 19 strains isolated in ...mountainous areas of Taiwan, eighteen strains were isolated from soil and one strain was isolated from the fruiting body of mushroom, six were identified as
V. polyspora
and three as
V. verrucispora.
Based on the results of a multigene sequence analysis (D1/D2, ITS and mitochondrial COX II gene) and DNA–DNA reassociation, three new ascosporic members of the genus
Vanderwaltozyma
are formally described:
V. huisunica
sp. nov. (GA1S06
T
= CBS 12250
T
= BCRC 23260
T
),
V. meishanica
sp. nov. (EN4S02
T
= CBS 12249
T
= BCRC 23255
T
) and
V. molinica
sp. nov. (GJ8S05
T
= CBS 12251
T
= BCRC 23264
T
), and the holotypes of these novel species are assigned as BCRC 23260
T
, BCRC 23255
T
and BCRC 23264
T
, respectively.
Impairments of the visual system are implicated in psychotic disorders. However, studies exploring visual cortex (VC) morphology in this population are limited. Using data from the ...Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium, we examined VC structure in psychosis probands and their first-degree relatives (RELs), sex differences in VC measures, and their relationships with cognitive and peripheral inflammatory markers.
Cortical thickness, surface area, and volume of the primary (Brodmann area 17/V1) and secondary (Brodmann area 18/V2) visual areas and the middle temporal (V5/MT) region were quantified using FreeSurfer version 6.0 in psychosis probands (n = 530), first-degree RELs (n = 544), and healthy control subjects (n = 323). Familiality estimates were determined for probands and RELs. General cognition, response inhibition, and emotion recognition functions were assessed. Systemic inflammation was measured in a subset of participants.
Psychosis probands demonstrated significant area, thickness, and volume reductions in V1, V2, and MT, and their first-degree RELs demonstrated area and volume reductions in MT compared with control subjects. There was a higher degree of familiality for VC area than thickness. Area and volume reductions in V1 and V2 were sex dependent, affecting only female probands in a regionally specific manner. Reductions in some VC regions were correlated with poor general cognition, worse response inhibition, and increased C-reactive protein levels.
The visual cortex is a site of significant pathology in psychotic disorders, with distinct patterns of area and thickness changes, sex-specific and regional effects, potential contributions to cognitive impairments, and association with C-reactive protein levels.
Cardiovascular disease (CVD) is responsible for 31% of all deaths worldwide. Among CVD risk factors are age, race, increased systolic blood pressure (BP), and dyslipidemia. Both BP and blood lipids ...levels change with age, with a dose‐dependent relationship between the cumulative exposure to hyperlipidemia and the risk of CVD. We performed an exome sequence association study using longitudinal data with up to 7805 European Americans (EAs) and 3171 African Americans (AAs) from the Atherosclerosis Risk in Communities (ARIC) study. We assessed associations of common (minor allele frequency > 5%) nonsynonymous and splice‐site variants and gene‐based sets of rare variants with levels and with longitudinal change of seven CVD risk factor phenotypes (BP traits: systolic BP, diastolic BP, pulse pressure; lipids traits: triglycerides, total cholesterol, high‐density lipoprotein cholesterol HDL‐C, low‐density lipoprotein cholesterol LDL‐C). Furthermore, we investigated the relationship of the identified variants and genes with select CVD endpoints. We identified two novel genes: DCLK3 associated with the change of HDL‐C levels in AAs and RAB7L1 associated with the change of LDL‐C levels in EAs. RAB7L1 is further associated with an increased risk of heart failure in ARIC EAs. Investigation of the contribution of genetic factors to the longitudinal change of CVD risk factor phenotypes promotes our understanding of the etiology of CVD outcomes, stressing the importance of incorporating the longitudinal structure of the cohort data in future analyses.
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