Predicting future community-level ocular Chlamydia trachomatis infection prevalence using serological,clinical, molecular,and geospatial data

Trachoma is an infectious disease characterized by repeated exposures to Chlamydia trachomatis (Ct) that may ultimately lead to blindness. Efficient identification of communities with high infection burden could help target more intensive control efforts. We hypothesized that IgG seroprevalence in combination with geospatial layers, machine learning, and model-based geostatistics would be able to accurately predict future community-level ocular Ct infections detected by PCR. We used measurements from 40 communities in the hyperendemic Amhara region of Ethiopia to assess this hypothesis. Median Ct infection prevalence among children 0–5 years old increased from 6% at enrollment, in the context of recent mass drug administration (MDA), to 29% by month 36, following three years without MDA. At baseline, correlation between seroprevalence and Ct infection was stronger among children 0–5 years old (ρ = 0.77) than children 6–9 years old (ρ = 0.48), and stronger than the correlation between active trachoma and Ct infection (0-5y ρ = 0.56; 6-9y ρ = 0.40). Seroprevalence was the strongest concurrent predictor of infection prevalence at month 36 among children 0–5 years old (cross-validated R² = 0.75, 95% CI: 0.58–0.85), though predictive performance declined substantially with increasing temporal lag between predictor and outcome measurements. Geospatial variables, a spatial Gaussian process, and stacked ensemble machine learning did not meaningfully improve predictions. Serological markers among children 0–5 years old may be an objective tool for identifying communities with high levels of ocular Ct infections, but accurate, future prediction in the context of changing transmission remains an open challenge.     

模拟计算平行样对流域生物信息流估算的影响

流域生物信息流是流域生态学研究中的重要内容,是流域生态系统中的物质输移和能量输移过程的信息标记,是用eDNA技术调查评估河流水体中物种组成空间特征的基础。估算流域生物信息流是流域生态系统过程研究和eDNA技术调查评估河流水体中物种组成空间特征的关键。在有限的调查采样中,平行样的数量如何影响流域生物信息流的估算,尚待解答。基于随机抽样调查的基本原理,提出假设--采样数量不影响流域生物信息流估算结果的准确度,但会影响其精密度,然后通过问题简化转化和模拟计算,对该假设进行了检验。模拟计算结果显示,随着样点生物信息检出度(平行样数量)的增大,流域生物信息流估算结果会从偏小逐渐靠近流域生物信息流实际值,同时其99.9%置信区间也逐渐集中于流域生物信息流实际值。即样点生物信息检出度(平行样数量)对流域生物信息流估算的准确度和精密度均有影响。在实际调查研究过程中,建议先在所研究区域对平行样数量和样点生物信息检出度的关系进行预评估,然后基于流域生物信息流估算可信度目标在正式实施方案中经济有效地设置平行样,基于多平行样调查结果估算流域生物信息流,再根据各样点生物信息检出状况对流域生物信息流估算结果进行后验评估。     

N-Benzyl-indolo carboxylic acids: Design and synthesis of potent and selective adipocyte fatty-acid binding protein (A-FABP) inhibitors

Small molecule inhibitors of adipocyte fatty-acid binding protein (A-FABP) have gained renewed interest following the recent publication of pharmacologically beneficial effects of such inhibitors. Despite the potential utility of selective A-FABP inhibitors within the fields of metabolic disease, inflammation and atherosclerosis, there are few examples of useful A-FABP inhibitors in the public domain. Herein, we describe the optimization of N-benzyl-tetrahydrocarbazole derivatives through the use of co-crystal structure guided medicinal chemistry efforts. This led to the identification of a potent and selective class of A-FABP inhibitors as illustrated by N-benzyl-hexahydrocyclohepta[b]indole 30.     

Reprogramming of HUVECs into Induced Pluripotent Stem Cells (HiPSCs), Generation and Characterization of HiPSC-Derived Neurons and Astrocytes

Neurodegenerative diseases are characterized by chronic and progressive structural or functional loss of neurons. Limitations related to the animal models of these human diseases have impeded the development of effective drugs. This emphasizes the need to establish disease models using human-derived cells. The discovery of induced pluripotent stem cell (iPSC) technology has provided novel opportunities in disease modeling, drug development, screening, and the potential for “patient-matched” cellular therapies in neurodegenerative diseases. In this study, with the objective of establishing reliable tools to study neurodegenerative diseases, we reprogrammed human umbilical vein endothelial cells (HUVECs) into iPSCs (HiPSCs). Using a novel and direct approach, HiPSCs were differentiated into cells of central nervous system (CNS) lineage, including neuronal, astrocyte and glial cells, with high efficiency. HiPSCs expressed embryonic genes such as nanog, sox2 and Oct-3/4, and formed embryoid bodies that expressed markers of the 3 germ layers. Expression of endothelial-specific genes was not detected in HiPSCs at RNA or protein levels. HiPSC-derived neurons possess similar morphology but significantly longer neurites compared to primary human fetal neurons. These stem cell-derived neurons are susceptible to inflammatory cell-mediated neuronal injury. HiPSC-derived neurons express various amino acids that are important for normal function in the CNS. They have functional receptors for a variety of neurotransmitters such as glutamate and acetylcholine. HiPSC-derived astrocytes respond to ATP and acetylcholine by elevating cytosolic Ca²⁺ concentrations. In summary, this study presents a novel technique to generate differentiated and functional HiPSC-derived neurons and astrocytes. These cells are appropriate tools for studying the development of the nervous system, the pathophysiology of various neurodegenerative diseases and the development of potential drugs for their treatments.     

HLA-linked and unlinked determinants of multiple sclerosis

Genetic methods, especially segregation and linkage analysis and supplementary tests on identity by descent and phenotype distributions, help to clarify the etiology of multiple sclerosis (MS). They reveal two determinants, one tightly linked to DR2 haplotypes in the HLA system, the other unlinked, which interact to simulate loose linkage.     

Genetic evaluation of Ethiopian Boran cattle and their crosses with Holstein Friesian in central Ethiopia: milk production traits

Breed additive and non-additive effects, and genetic parameters of lactation milk yield (LYD), 305-day milk yield (305YD), lactation length (LL), milk yield per day of lactation (DM) and lifetime milk yield (LTYD) were estimated in Ethiopian Boran cattle and their crosses with Holstein in central Ethiopia. The data analyzed included 2360 lactation records spread over 15 years. Ethiopian Boran cattle were consistently inferior (P < 0.01) to the Ethiopian Boran-Holstein crosses for the dairy traits studied. When the crosses were compared, LYD, 305YD and DM were higher (P < 0.01) for 75% and 87.5% crosses compared to 50% and 62.5% ones. However, the 50% crosses had higher (P < 0.01) LTYD than the other genetic groups. The individual additive genetic breed differences for milk production traits were all significant (P < 0.01). The estimates, in favor of Holstein, were 2055 ± 192 kg for LYD, 1776 ± 142 kg for 305YD, 108 ± 24 days for LL, 5.9 ± 0.5 kg for DM and 3353 ± 1294 kg for LTYD. Crossbreeding of the Holstein with the Ethiopian Boran resulted in desirable and significant (P < 0.01) individual heterosis for all milk production traits. The heterosis estimates were, 529 ± 98, 427 ± 72 kg, 44 ± 12 days 1.47 ± 0.23 kg and 3337 ± 681 kg, for LYD, 305YD, LL, DM and LTYD, respectively. The maternal heterotic effects were non-significant (P > 0.05) for all traits. Heritabilities of LYD, 305YD, LL, DM and LTYD for Ethiopian Boran were 0.20 ± 0.03, 0.18 ± 0.03, 0.26 ± 0.03, 0.13 ± 0.03 and 0.02 ± 0.04, respectively. The corresponding estimates for crosses were 0.10 ± 0.002, 0.11 ± 0.003, 0.63 ± 0.02, 0.45 ± 1.05 and 0.24 ± 0.11, respectively. Selection within each of the genetic groups and crossbreeding should substantially improve the milk production potential of the Ethiopian Boran breed under such production system.     

Use of a Cholera Rapid Diagnostic Test during a Mass Vaccination Campaign in Response to an Epidemic in Guinea, 2012

Background

During the 2012 cholera outbreak in the Republic of Guinea, the Ministry of Health, supported by Médecins Sans Frontières - Operational Center Geneva, used the oral cholera vaccine Shanchol as a part of the emergency response. The rapid diagnostic test (RDT) Crystal VC, widely used during outbreaks, detects lipopolysaccharide antigens of Vibrio cholerae O1 and O139, both included in Shanchol. In the context of reactive use of a whole-cell cholera vaccine in a region where cholera cases have been reported, it is essential to know what proportion of vaccinated individuals would be reactive to the RDT and for how long after vaccination.

Methodology/Principal Findings

A total of 108 vaccinated individuals, selected systematically among all persons older than one year, were included at vaccination sites and 106 were included in the analysis. Stools samples of this cohort of vaccinated participants were collected and tested with the RDT every day until the test was negative for two consecutive visits or for a maximum of 7 days. A total of 94.3% of cholera vaccine recipients had a positive test after vaccination; all except one of these positive results were reactive only with the O139 antigen. The mean time to become negative in those with an initial positive result after vaccination was 3.8 days, standard deviation 1.1 days.

Conclusions/Significance

The RDT Crystal VC becomes positive in persons recently vaccinated against cholera, although almost exclusively to the O139 antigen. This reactivity largely disappeared within five days after vaccination. These results suggest that the test can be used normally as soon as 24 hours after vaccination in a context of O1 epidemics, which represent the vast majority of cases, and after a period of five days in areas where V. cholerae O139 is present. The reason why only O139 test line became positive remains to be investigated.