Explore the vast range of titles available.

DNA methylation is capable of modulating coordinate expression of large numbers of genes across many different pathways, and may therefore warrant investigation for their potential role between genes and disease phenotype. In a rare set of monozygotic twins discordant for Alzheimer's disease (AD), significantly reduced levels of DNA methylation were observed in temporal neocortex neuronal nuclei of the AD twin. These findings are consistent with the hypothesis that epigenetic mechanisms may mediate at the molecular level the effects of life events on AD risk, and provide, for the first time, a potential explanation for AD discordance despite genetic similarities.

Background Neurofibrillary tangles (NFT), a cardinal neuropathological feature of Alzheimer's disease (AD) that is highly correlated with synaptic loss and dementia severity, appear to be partly attributable to increased phosphorylation of the microtubule stabilizing protein tau at certain AD-related residues. Identifying the kinases involved in the pathologic phosphorylation of tau may provide targets at which to aim new AD-modifying treatments. Results We report results from a screen of 572 kinases in the human genome for effects on tau hyperphosphorylation using a loss of function, high-throughput RNAi approach. We confirm effects of three kinases from this screen, the eukaryotic translation initiation factor 2 α kinase 2 (EIF2AK2), the dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A), and the A-kinase anchor protein 13 (AKAP13) on tau phosphorylation at the 12E8 epitope (serine 262/serine 356). We provide evidence that EIF2AK2 effects may result from effects on tau protein expression, whereas DYRK1A and AKAP13 are likely more specifically involved in tau phosphorylation pathways. Conclusions These findings identify novel kinases that phosphorylate tau protein and provide a valuable reference data set describing the kinases involved in phosphorylating tau at an AD-relevant epitope.

Alzheimer's disease (AD) is associated with regional reductions in fluorodeoxyglucose positron emission tomography (FDG PET) measurements of the cerebral metabolic rate for glucose, which may begin long before the onset of histopathological or clinical features, especially in carriers of a common AD susceptibility gene. Molecular evaluation of cells from metabolically affected brain regions could provide new information about the pathogenesis of AD and new targets at which to aim disease-slowing and prevention therapies. Data from a genome-wide transcriptomic study were used to compare the expression of 80 metabolically relevant nuclear genes from laser-capture microdissected non-tangle-bearing neurons from autopsy brains of AD cases and normal controls in posterior cingulate cortex, which is metabolically affected in the earliest stages; other brain regions metabolically affected in PET studies of AD or normal aging; and visual cortex, which is relatively spared. Compared with controls, AD cases had significantly lower expression of 70% of the nuclear genes encoding subunits of the mitochondrial electron transport chain in posterior cingulate cortex, 65% of those in the middle temporal gyrus, 61% of those in hippocampal CA1, 23% of those in entorhinal cortex, 16% of those in visual cortex, and 5% of those in the superior frontal gyrus. Western blots confirmed underexpression of those complex I-V subunits assessed at the protein level. Cerebral metabolic rate for glucose abnormalities in FDG PET studies of AD may be associated with reduced neuronal expression of nuclear genes encoding subunits of the mitochondrial electron transport chain.

Transcription of DNA is essential for cell maintenance and survival; inappropriate localization of proteins that are involved in transcription would be catastrophic. In Alzheimer's disease brains, and in vitro studies, we have found qualitative and quantitative deficits in transport into the nucleus of DNA methyltransferase 1 (DNMT1) and RNA polymerase II (RNA pol II), accompanied by their abnormal sequestration in the cytoplasm. RAN (RAs-related Nuclear protein) knockdown, by siRNA and oligomeric Aβ42 treatment in neurons, replicate human data which indicate that transport disruption in AD may be mechanistically linked to reduced expression of RAN, a pivotal molecule in nucleocytoplasmic transport. In vitro studies also indicate a significant role for oligomeric Aβ42 in the observed phenomena. We propose a model in which reduced transcription regulators in the nucleus and their increased presence in the cytoplasm may lead to many of the cellular manifestations of Alzheimer's disease.

Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17) is caused by mutations in the gene encoding the microtubule-associated protein, tau. Some FTDP-17 mutations affect exon 10 splicing. To correct aberrant exon 10 splicing while retaining endogenous transcriptional control, we evaluated the feasibility of using spliceosome-mediated RNA trans-splicing (SMaRT) to reprogram tau mRNA. We designed a pre-trans-splicing molecule containing human tau exons 10 to 13 and a binding domain complementary to the 3' end of tau intron 9. A minigene comprising tau exons 9, 10, and 11 and minimal flanking intronic sequences was used as a target. RT-PCR analysis of SH-SY5Y cells or COS cells cotransfected with a minigene and a pre-trans-splicing molecule using primers to opposite sides of the predicted splice junction generated products containing exons 9 to 13. Sequencing of the chimeric products showed that an exact exon 9-exon 10 junction had been created, thus demonstrating that tau RNA can be reprogrammed by trans-splicing. Furthermore, by using the same paradigm with a minigene containing full-length intronic sequences, we show that cis-splicing exclusion of exon 10 can be by-passed by trans-splicing and that conversion of exon 10- tau RNA into exon $10^+$ tau RNA could be achieved with $\\approx 34\\%$ efficiency. Our results demonstrate that an alternatively spliced exon can be replaced by trans-splicing and open the way to novel therapeutic applications of SMaRT for tauopathies and other disorders linked to aberrant alternative splicing.

Abstract Context Leptin is an adipokine that signals energy sufficiency. In rodents, leptin deficiency decreases energy expenditure (EE), which is corrected following leptin replacement. In humans, data are mixed regarding leptin-mediated effects on EE. Objective To determine the effects of metreleptin on EE in patients with lipodystrophy. Design, setting, and patients Nonrandomized crossover study of 25 patients with lipodystrophy (National Institutes of Health, 2013-2018). Intervention The initiation cohort consisted of 17 patients without prior exposure to metreleptin, studied before and after 14 days of metreleptin. The withdrawal cohort consisted of 8 previously metreleptin-treated patients, studied before and after 14 days of metreleptin withdrawal. Main outcomes 24-h total energy expenditure (TEE), resting energy expenditure (REE), autonomic nervous system activity [heart rate variability (HrV)], plasma-free triiodothyronine (T3), free thyroxine (T4), epinephrine, norepinephrine, and dopamine. Results In the initiation cohort, TEE and REE decreased by 5.0% (121 ± 152 kcal/day; P = 0.006) and 5.9% (120 ± 175 kcal/day; P = 0.02). Free T3 increased by 19.4% (40 ± 49 pg/dL; P = 0.01). No changes in catecholamines or HrV were observed. In the withdrawal cohort, free T3 decreased by 8.0% (P = 0.04), free T4 decreased by 11.9% (P = 0.002), and norepinephrine decreased by 34.2% (P = 0.03), but no changes in EE, epinephrine, dopamine, or HrV were observed. Conclusions Metreleptin initiation decreased EE in patients with lipodystrophy, but no changes were observed after metreleptin withdrawal. Thyroid hormone was higher on metreleptin in both initiation and withdrawal cohorts. Decreased EE after metreleptin in lipodystrophy may result from reductions in energy-requiring metabolic processes that counteract increases in EE via adipose tissue-specific neuroendocrine and adrenergic signaling.

Short interpregnancy intervals (conception occurring <18 months after delivery or pregnancy loss) are associated with increased risk of adverse outcomes such as preterm delivery, low birth weight, and invasive placental pathologies. To reduce unintended short-interval pregnancy (SIP) among people desiring contraception, our health network in 2019 began offering immediate postpartum long-acting reversible contraception (LARC), using copper and hormonal intrauterine devices (IUDs) and etonogestrel implants. This study evaluated the impact of the initiative on the incidence of SIP at our institution. We conducted a retrospective cohort study of patients on government insurance who delivered between July 1, 2019, and March 31, 2020. The exposure of interest was LARC placement in the immediate postpartum period. The outcome of interest was confirmed pregnancy within 18 months of delivery. Exclusion criteria were immediate postpartum sterilization, cesarean or peripartum hysterectomy, or fetal demise. SIP rates were compared between those opting for LARC immediately after delivery (pp LARC group) and those who declined (no pp LARC group). A logistic regression model controlled for potential confounders. Of the 1,126 patients who met the inclusion criteria, there were 140 in the pp LARC group (68 etonogestrel implant, 54 levonorgestrel IUD, and 18 copper IUD) and 986 in the no pp LARC group. The pp LARC group experienced a lower proportion of SIP (7.9% versus 23.8%, P < 0.001). In adjusted analysis, immediate postpartum LARC reduced the rate of SIP (adjusted risk ratio (ARR): 0.28, 95% confidence interval (CI): 0.14-0.55, P < 0.001). Providing LARC shortly after delivery shows promise for patient uptake and prevention of SIP among individuals wishing for contraception. Expanded studies are warranted.

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , historically termed Pick's disease 10 . Most FTDP-17 cases show neuronal and/or glial inclusions that stain positively with antibodies raised against the microtubule-associated protein Tau, although the Tau pathology varies considerably in both its quantity (or severity) and characteristics 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 12 . Previous studies have mapped the FTDP-17 locus to a 2-centimorgan region on chromosome 17q21.11; the tau gene also lies within this region. We have now sequenced tau in FTDP-17 families and identified three missense mutations (G272V, P301L and R406W) and three mutations in the 5′ splice site of exon 10. The splice-site mutations all destabilize a potential stem–loop structure which is probably involved in regulating the alternative splicing of exon10 ( ref. 13 ). This causes more frequent usage of the 5′ splice site and an increased proportion of tau transcripts that include exon 10. The increase in exon 10 + messenger RNA will increase the proportion of Tau containing four microtubule-binding repeats, which is consistent with the neuropathology described in several families with FTDP-17 ( refs 12 , 14 ).

Leptin is an adipokine that signals energy sufficiency. In rodents, leptin deficiency is associated with decreased body temperature and energy expenditure (EE), which is reversed with leptin replacement. Leptin’s role in EE in humans is unclear; however, one study of 10% weight-reduced healthy subjects suggested that leptin replacement to pre-weight loss levels restored the decline in EE, thyroid hormone, and catecholamines associated with weight loss. Patients with lipodystrophy (LD) are characterized by deficiency of adipose tissue and can serve as models to study effects of leptin deficiency and replacement in humans. We hypothesized that treatment with recombinant leptin (metreleptin) in patients with LD would increase EE, thyroid hormone, and catecholamines. We conducted a non-randomized crossover study of 25 patients with LD who were hospitalized for 19 days on an iso-caloric diet. The initiation cohort consisted of 17 patients with no prior exposure to metreleptin, who were first studied for 5 days without metreleptin (period 1), then were treated with metreleptin for 14 days (period 2). The withdrawal cohort consisted of 8 previously metreleptin-treated patients who were continued on metreleptin for the first 5 days of the study (period 1), then were taken off metreleptin for 14 days (period 2). At the end of each period, we measured 24-hour EE (TEE) and resting EE (REE) using indirect calorimetry and free T3, T4, epinephrine, norepinephrine and dopamine after an 8–12 hour fast. In the leptin initiation cohort, TEE and REE decreased from 2402±383 kcal/day and 1805±332 kcal/day to 2272±396 kcal/day (p=0.003) and 1688±318 kcal/day (p=0.03), respectively. Free T3 increased from median (IQR) 248 (200, 270) pg/mL to 295 (259, 315) (p=0.006). No changes in catecholamines were observed in the initiation cohort. In the withdrawal cohort, free T3 decreased from 295 (267, 331) pg/mL to 265 (237, 323) (p=0.008), free T4 decreased from 1.2 ±0.2 ng/dL to 1.0±0.2 (p=0.002), and norepinephrine decreased from 191±70 pg/mL to 112±47 (p=0.03) after metreleptin withdrawal. No changes in EE, epinephrine or dopamine were observed in the withdrawal cohort. Contrary to previous studies in rodents and healthy humans, we found that introduction of metreleptin reduced EE in patients with LD. Consistent with rodent and prior human data, patients with LD had increased thyroid hormone on metreleptin, which would be expected to increase EE. The discrepancy in EE compared to other models may be due to metreleptin-induced correction of severe metabolic derangements in LD, including reduction in energy-requiring processes such as de novo lipogenesis and gluconeogenesis. These changes may offset increases in leptin-induced mediators of increased EE, such as thyroid hormone.

The high-profile lethal violence that has occurred in multiple schools around the country has brought school safety to the forefront of educational concerns. These high-profile cases are rare, but when they do occur, they create serious concern for parents, teachers, students, administrators, and communities about school safety. Accountability has become a buzzword in today’s educational setting. When students do not feel safe at school, their academic success suffers. This study was designed to encompass a variety of research methods, using a mixed-methods research study to examine the relationship between students’ perception of safety in the schools and how it affects their academic success. There have been multiple studies on high-profile school shootings, but there has not been enough research on everyday issues that students face, such as bullying, discipline issues, or simply reacting to being a student. Research has shown that students who feel unsafe or threatened at school have a harder time academically and have a high probability of dropping out of school. There have been many studies on the effects of unsafe learning environments. This research was designed to address what makes students feel unsafe at school and to address areas to help students overcome these issues. Students, teachers, and administrators were interviewed, and they completed a survey designed to analyze issues of safety impacting academic performance. Student data, including discipline records, attendance, demographics, and grade point averages, were analyzed. The quantitative data were examined and compared to see if there were significant differences between students with discipline problems and academic success, and if demographics play a role in the feelings of being unsafe. Analysis of data from previous research has shown that students who feel safe at school do better academically. Students who feel unsafe at school have lower grades, no grade improvement, or an increase in disciplinary action.