The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is expansion of the intronic hexanucleotide repeat (GGGGCC)n in C9orf72. Here, we investigate the formation of nucleic acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of ALS/FTD. We observe significant aggregation of the hexanucleotide sequence (GGGGCC)n, which we associate to the formation of multimolecular G-quadruplexes (mG4s) by using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions leads to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validate the biological relevance of our findings by detecting an increased prevalence of G4-structures in C9orf72 mutant human motor neurons when compared to healthy motor neurons by staining with a G4-selective fluorescent probe, revealing signal in putative condensates. Our findings strongly suggest that RNA G-rich repetitive sequences can form protein-free condensates sustained by multimolecular G-quadruplexes, highlighting their potential relevance as therapeutic targets for C9orf72 mutation-related ALS/FTD

Evidence for solar cycles in a late Holocene speleothem record from Dongge Cave, China

The association between solar activity and Asian monsoon (AM) remains unclear. Here we evaluate the possible connection between them based on a precisely-dated, high-resolution speleothem oxygen isotope record from Dongge Cave, southwest China during the past 4.2 thousand years (ka). Without being adjusted chronologically to the solar signal, our record shows a distinct peak-to-peak correlation with cosmogenic nuclide 14C, total solar irradiance (TSI) and sunspot number (SN) at multi-decadal to centennial timescales. Further cross-wavelet analyses between our calcite δ18O and atmospheric 14C show statistically strong coherence at three typical periodicities of ~80, 200 and 340 years, suggesting important roles of solar activities in modulating AM changes at those timescales. Our result has further indicated a better correlation between our calcite δ18O record and atmospheric 14C than between our record and TSI. This better correlation may imply that the Sun–monsoon connection is dominated most likely by cosmic rays and oceanic circulation (both associated to atmospheric 14C), instead of the direct solar heating (TSI)

Text messaging: an innovative method of data collection in medical research

BACKGROUND: The ubiquitous use of mobile phones in sending and receiving text messages has become a norm for young people. Undeniably, text messaging has become a new and important communication medium not only in the social realm but in education as well. The aim of this study is to evaluate the effectiveness of using text messaging as a means to collect data for a medical research project.A cross sectional study was carried out during a double blind, randomized controlled trial to assess the efficacy and safety of a probiotic in the management of Irritable Bowel Syndrome (IBS). The study aim was to assess the response rate of weekly symptom reports via Short Message Service (SMS). The subjects were undergraduates in a private medical university in Malaysia. They were identified through a previous university wide study as suffering from IBS based on Rome III criteria. The subjects were randomly assigned to either the treatment arm receiving a daily probiotic, or the placebo arm. They were required to score their symptoms using eight-item-questionnaires at baseline, and thereafter weekly, for a total of 8 weeks. All subjects were given the choice to communicate their symptom scores by text messaging via mobile phones or by email. SMS text messages were sent to remind trial subjects to attend face-to-face visits and to complete a paper based 34-item-questionnaires on IBS quality of life assessment at baseline and at end of 8 weeks. FINDINGS: The response rate of weekly symptom scores via Short Message Service (SMS) from a total of 38 subjects was 100%. Through the study, 342 reports were submitted: 33.3% of these were received on the due date without reminder, 60.0% one day after the deadline, after a single reminder, 6.1% 2-3 days after the deadline, after 2-3 reminders and 0.6% 5 days after the deadline, after SMS, phone reminder and face-to-face encounter. All SMS symptom reports, whether on time or late, were complete. With the help of SMS reminder, all trial subjects completed the paper based IBS quality of life assessment at baseline and at end of study. CONCLUSIONS: This study found using text messaging via mobile phone an excellent instrument for collecting weekly symptom reports in response to trial medication, reminding trial subjects to attend face to face visits and completing more complex paper based evaluation. The 100% response rate of weekly symptom reports was facilitated by using simple number codes for SMS submission

Methamphetamine Inhibits the Glucose Uptake by Human Neurons and Astrocytes: Stabilization by Acetyl-L-Carnitine

Methamphetamine (METH), an addictive psycho-stimulant drug exerts euphoric effects on users and abusers. It is also known to cause cognitive impairment and neurotoxicity. Here, we hypothesized that METH exposure impairs the glucose uptake and metabolism in human neurons and astrocytes. Deprivation of glucose is expected to cause neurotoxicity and neuronal degeneration due to depletion of energy. We found that METH exposure inhibited the glucose uptake by neurons and astrocytes, in which neurons were more sensitive to METH than astrocytes in primary culture. Adaptability of these cells to fatty acid oxidation as an alternative source of energy during glucose limitation appeared to regulate this differential sensitivity. Decrease in neuronal glucose uptake by METH was associated with reduction of glucose transporter protein-3 (GLUT3). Surprisingly, METH exposure showed biphasic effects on astrocytic glucose uptake, in which 20 µM increased the uptake while 200 µM inhibited glucose uptake. Dual effects of METH on glucose uptake were paralleled to changes in the expression of astrocytic glucose transporter protein-1 (GLUT1). The adaptive nature of astrocyte to mitochondrial β-oxidation of fatty acid appeared to contribute the survival of astrocytes during METH-induced glucose deprivation. This differential adaptive nature of neurons and astrocytes also governed the differential sensitivity to the toxicity of METH in these brain cells. The effect of acetyl-L-carnitine for enhanced production of ATP from fatty oxidation in glucose-free culture condition validated the adaptive nature of neurons and astrocytes. These findings suggest that deprivation of glucose-derived energy may contribute to neurotoxicity of METH abusers

Functional and prognostic effects when emphysema complicates idiopathic pulmonary fibrosis

This study aimed to investigate whether the combination of fibrosis and emphysema has a greater effect than the sum of its parts on functional indices and outcome in idiopathic pulmonary fibrosis (IPF), using visual and computer-based (CALIPER) computed tomography (CT) analysis.Consecutive patients (n=272) with a multidisciplinary IPF diagnosis had the extent of interstitial lung disease (ILD) scored visually and by CALIPER. Visually scored emphysema was subcategorised as isolated or mixed with fibrotic lung. The CT scores were evaluated against functional indices forced vital capacity (FVC), diffusing capacity of the lungs for carbon monoxide (DLCO), transfer coefficient of the lung for carbon monoxide (KCO), composite physiologic index (CPI)) and mortality.The presence and extent of emphysema had no impact on survival. Results were maintained following correction for age, gender, smoking status and baseline severity using DLCO, and combined visual emphysema and ILD extent. Visual emphysema quantitation indicated that relative preservation of lung volumes (FVC) resulted from tractionally dilated airways within fibrotic lung, ventilating areas of admixed emphysema (p<0.0001), with no independent effect on FVC from isolated emphysema. Conversely, only isolated emphysema (p<0.0001) reduced gas transfer (DLCO).There is no prognostic impact of emphysema in IPF, beyond that explained by the additive extents of both fibrosis and emphysema. With respect to the location of pulmonary fibrosis, emphysema distribution determines the functional effects of emphysema

C. albicans Colonization of Human Mucosal Surfaces

Background: Candida albicans is a low level commensal organism in normal human populations with the continuous potential to expand and cause a spectrum of clinical conditions. Methodology/Principal Findings: Using ex vivo human organ cultures and populations of primary human cells, we have developed several related experimental systems to examine early-stage interactions between C. albicans and mucosal surfaces. Experiments have been conducted both with exogenously added C. albicans and with overtly normal human mucosal surfaces supporting pre-existing infections with natural isolates of Candida. Under different culture conditions, we have demonstrated the formation of C. albicans colonies on human target cells and filament formation, equivalent to tissue invasion. Conclusions/Significance: These organ culture systems provide a valuable new resource to examine the molecular and cellular basis for Candida colonization of human mucosal surfaces

A population-based cross-sectional study of age-specific risk factors for high risk human papillomavirus prevalence in rural Nigeria

<p>Abstract</p> <p>Background</p> <p>Cervical cancer, caused by persistent infection with carcinogenic human papillomavirus (HR-HPV), is particularly prevalent in Sub-Saharan Africa and is associated with a high mortality rate. Some studies in West Africa, including our own, have found unusually high HR-HPV across all ages with a slight peak in older women. This increased prevalence at older ages may complicate screen-and-treat programs, which are implemented in regions where HPV prevalence declines with age and typically target women between 30-49 years. A better understanding of the determinants of high HR-HPV prevalence at older ages is needed. The goal of this study is to explore risk factors for HR-HPV prevalence by age among women in our population-based study in Irun, a rural town in southwestern Nigeria.</p> <p>Methods</p> <p>1,420 women were administered a clinic-based questionnaire regarding sexual and reproductive behavior, marital status (including co-wives), and malaria exposure. Logistic regression compared questionnaire responses and PCR positivity for a set of 13 carcinogenic HR-HPV types. Results were stratified by age (15-29, 30-45, 46-55, and 56+ years).</p> <p>Results</p> <p>Birth control use and age at first pregnancy were associated with HR-HPV (<it>p-value </it>= 0.03 and 0.05, respectively). Early age at sexual debut and multiple sex partners were risks for HR-HPV, but did not reach significance (<it>p-value </it>= 0.1 and 0.07, respectively). Neither self-reported malaria nor presence of co-wives in the household was associated with HR-HPV (<it>p-value </it>= 0.85 and 0.24, respectively). In age sub-categories, early age at sexual debut was a significant risk factor for HR-HPV among women 35-45 years (<it>p-value = 0.02</it>). Early age at first pregnancy remained a significant risk factor for women aged 56+ years (<it>p-value </it>= 0.04). Greater than 2 sex partners and use of birth control were associated (though not significantly) with HR-HPV in women aged 30-45 (<it>p-value </it>= 0.08, respectively).</p> <p>Conclusions</p> <p>In this high-risk region with elevated HR-HPV prevalence at older ages, we confirmed previously described, behavioral determinants of HR-HPV. There was no association with self-reported malaria or co-wives, which we had hypothesized might correlate with HR-HPV at older ages.</p

An assessment of factors contributing to treatment adherence and knowledge of TB transmission among patients on TB treatment

BACKGROUND: The treatment guidelines for tuberculosis treatment under Directly Observed Treatment, Short-course (DOTS) have been a common strategy for TB treatment in Zambia. The study was carried out in Ndola, Zambia, to investigate factors contributing to treatment non-adherence and knowledge of TB transmission among patients on TB treatment, in order to design a community-based intervention, that would promote compliance. METHODS: A household-based survey was conducted in six randomly selected catchment areas of Ndola, where 400 out of 736 patients receiving TB treatment within the six months period, were recruited through the District's Health Management Board (DHMB) clinics. All patients were interviewed using a pre-tested structured questionnaire, consisting of i. Socio-demographic characteristics ii. Socio-economic factors iii. Knowledge about TB transmission and prevention iv. Patterns in health seeking behaviour and v. TB treatment practices at household level. RESULTS: Most male TB patient respondents tended to be older and more educated than the female TB patient respondents. Overall, 29.8% of the patients stopped taking their medication. There were 39.1% of the females and 33.9% of the males, who reported that TB patients stopped taking their medication within the first 2 months of commencing treatment. Age, marital status and educational levels were not significantly associated with compliance. The major factors leading to non-compliance included patients beginning to feel better (45.1% and 38.6%), lack of knowledge on the benefits of completing a course (25.7%), running out of drugs at home (25.4%) and TB drugs too strong (20.1% and 20.2%). There was a significant difference [OR = 1.66, 95% CI 1.23, 2.26] in TB knowledge, with more males than females reporting sharing of cups as a means for TB transmission, after adjusting for age, marital status and educational levels. Significantly [p = 0.016] more patients who had resided in the study for less than two years (59%) were more likely to report mother to child transmission of TB, compared to 41.2% of those who had been in the area for more than 2 years. CONCLUSION: This study established that 29.8% of TB patients failed to comply with TB drug taking regimen once they started feeling better

Pulmonary hypertension in interstitial lung disease: Limitations of echocardiography compared to cardiac catheterization

BACKGROUND AND OBJECTIVE: In interstitial lung disease (ILD), pulmonary hypertension (PH) is a major adverse prognostic determinant. Transthoracic echocardiography (TTE) is the most widely used tool when screening for PH, although discordance between TTE and right heart catheter (RHC) measured pulmonary haemodynamics is increasingly recognized. We evaluated the predictive utility of the updated European Society of Cardiology/European Respiratory Society (ESC/ERS) TTE screening recommendations against RHC testing in a large, well-characterized ILD cohort. METHODS: Two hundred and sixty-five consecutive patients with ILD and suspected PH underwent comprehensive assessment, including RHC, between 2006 and 2012. ESC/ERS recommended tricuspid regurgitation (TR) velocity thresholds for assigning high (>3.4 m/s), intermediate (2.9-3.4 m/s) and low (3.4 m/s, and excluded PH in 60% of ILD subjects with a TR velocity <2.8 m/s. Thus, the ESC/ERS guidelines misclassified 40% of subjects as 'low probability' of PH, when PH was confirmed on subsequent RHC. Evaluating alternative TR velocity thresholds for assigning a low probability of PH did not significantly improve the ability of TR velocity to exclude a diagnosis of PH. CONCLUSION: In patients with ILD and suspected PH, currently recommended ESC/ERS TR velocity screening thresholds were associated with a high positive predictive value (86%) for confirming PH, but were of limited value in excluding PH, with 40% of patients misclassified as low probability when PH was confirmed at subsequent RHC