Separable Roles for a Caenorhabditis elegans RMI1 Homolog in Promoting and Antagonizing Meiotic Crossovers Ensure Faithful Chromosome Inheritance

During the first meiotic division, crossovers (COs) between homologous chromosomes ensure their correct segregation. COs are produced by homologous recombination (HR)-mediated repair of programmed DNA double strand breaks (DSBs). As more DSBs are induced than COs, mechanisms are required to establish a regulated number of COs and to repair remaining intermediates as non-crossovers (NCOs). We show that the Caenorhabditis elegans RMI1 homolog-1 (RMH-1) functions during meiosis to promote both CO and NCO HR at appropriate chromosomal sites. RMH-1 accumulates at CO sites, dependent on known pro-CO factors, and acts to promote CO designation and enforce the CO outcome of HR-intermediate resolution. RMH-1 also localizes at NCO sites and functions in parallel with SMC-5 to antagonize excess HR-based connections between chromosomes. Moreover, RMH-1 also has a major role in channeling DSBs into an NCO HR outcome near the centers of chromosomes, thereby ensuring that COs form predominantly at off-center positions.     

Pharmacological removal of serum amyloid P component from intracerebral plaques and cerebrovascular Aβ amyloid deposits in vivo

Human amyloid deposits always contain the normal plasma protein serum amyloid P component (SAP), owing to its avid but reversible binding to all amyloid fibrils, including the amyloid β (Aβ) fibrils in the cerebral parenchyma plaques and cerebrovascular amyloid deposits of Alzheimer''s disease (AD) and cerebral amyloid angiopathy (CAA). SAP promotes amyloid fibril formation in vitro, contributes to persistence of amyloid in vivo and is also itself directly toxic to cerebral neurons. We therefore developed (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid (CPHPC), a drug that removes SAP from the blood, and thereby also from the cerebrospinal fluid (CSF), in patients with AD. Here we report that, after introduction of transgenic human SAP expression in the TASTPM double transgenic mouse model of AD, all the amyloid deposits contained human SAP. Depletion of circulating human SAP by CPHPC administration in these mice removed all detectable human SAP from both the intracerebral and cerebrovascular amyloid. The demonstration that removal of SAP from the blood and CSF also removes it from these amyloid deposits crucially validates the strategy of the forthcoming ‘Depletion of serum amyloid P component in Alzheimer''s disease (DESPIAD)’ clinical trial of CPHPC. The results also strongly support clinical testing of CPHPC in patients with CAA.     

Predictive Values of N-Terminal Pro-B-Type Natriuretic Peptide and Cardiac Troponin I for Myocardial Fibrosis in Hypertrophic Obstructive Cardiomyopathy

Background

Both high-sensitivity cardiac troponin T and B-type natriuretic peptide are useful in detecting myocardial fibrosis, as determined by late gadolinium enhancement (LGE) cardiovascular magnetic resonance (CMR), in patients with non-obstructive hypertrophic cardiomyopathy. However, their values to predict myocardial fibrosis in hypertrophic obstructive cardiomyopathy (HOCM) remain unclear. We investigated the role of N-Terminal Pro-B-Type Natriuretic Peptide (NT-proBNP) and cardiac troponin I (cTnI) to identify LGE-CMR in patients with HOCM.

Methods

Peripheral concentrations of NT-proBNP and cTnI were determined in patients with HOCM (n = 163; age = 47.2 ± 10.8 years; 38.7% females). Contrast-enhanced CMR was performed to identify and quantify myocardial fibrosis.

Results

LGE was detected in 120 of 163 patients (73.6%). Patients with LGE had significantly higher levels of NT-proBNP and cTnI than those without LGE (1386.2 [904.6–2340.8] vs. 866.6 [707.2–1875.2] pmol/L, P = 0.003; 0.024 [0.010–0.049] vs. 0.010 [0.005–0.021] ng/ml, P <0.001, respectively). The extent of LGE was positively correlated with log cTnI (r = 0.371, P <0.001) and log NT-proBNP (r = 0.211, P = 0.007). On multivariable analysis, both log cTnI and maximum wall thickness (MWT) were independent predictors of the presence of LGE (OR = 3.193, P = 0.033; OR = 1.410, P < 0.001, respectively), whereas log NT-proBNP was not. According to the ROC curve analysis, combined measurements of MWT ≥21 mm and/or cTnI ≥0.025ng/ml indicated good diagnostic performance for the presence of LGE, with specificity of 95% or sensitivity of 88%.

Conclusions

Serum cTnI is an independent predictor useful for identifying myocardial fibrosis, while plasma NT-proBNP is only associated with myocardial fibrosis on univariate analysis. Combined measurements of serum cTnI with MWT further improve its value in detecting myocardial fibrosis in patients with HOCM.     

Variation of Soil Organic Carbon and Its Major Constraints in East Central Asia

Variation of soil organic carbon (SOC) and its major constraints in large spatial scale are critical for estimating global SOC inventory and projecting its future at environmental changes. By analyzing SOC and its environment at 210 sites in uncultivated land along a 3020km latitudinal transect in East Central Asia, we examined the effect of environmental factors on the dynamics of SOC. We found that SOC changes dramatically with the difference as high as 5 times in north China and 17 times in Mongolia. Regardless, C:N remains consistent about 12. Path analysis indicated that temperature is the dominant factor in the variation of SOC with a direct effect much higher than the indirect one, the former breaks SOC down the year round while the latter results in its growth mainly via precipitation in the winter half year. Precipitation helps accumulate SOC, a large part of the effect, however, is taken via temperature. NH₄⁺-N and topography also affect SOC, their roles are played primarily via climatic factors. pH correlates significantly with SOC, the effect, however, is taken only in the winter months, contributing to the decay of SOC primarily via temperature. These factors explained as much as 79% of SOC variations, especially in the summer months, representing the major constraints on the SOC stock. Soil texture gets increasingly fine southward, it does not, however, constitute an apparent factor. Our results suggested that recent global warming should have been adversely affecting SOC stock in the mid-latitude as temperature dominates other factors as the constraint.     

Mid- to Long-Term Outcomes of Cervical Disc Arthroplasty versus Anterior Cervical Discectomy and Fusion for Treatment of Symptomatic Cervical Disc Disease: A Systematic Review and Meta-Analysis of Eight Prospective Randomized Controlled Trials

Purpose

This study aimed to investigate the mid- to long-term outcomes of cervical disc arthroplasty (CDA) versus anterior cervical discectomy and fusion (ACDF) for the treatment of 1-level or 2-level symptomatic cervical disc disease.

Methods

Medline, Embase, and the Cochrane Central Register of Controlled Trials databases were searched to identify relevant randomized controlled trials that reported mid- to long-term outcomes (at least 48 months) of CDA versus ACDF. All data were analyzed by Review Manager 5.3 software. The relative risk (RR) and 95% confidence intervals (CIs) were calculated for dichotomous variables. The weighted mean difference (WMD) and 95%CIs were calculated for continuous variables. A random effect model was used for heterogeneous data; otherwise, a fixed effect model was used.

Results

Eight prospective randomized controlled trials (RCTs) were retrieved in this meta-analysis, including 1317 and 1051 patients in CDA and ACDF groups, respectively. Patients after an ACDF had a significantly lower rate of follow-up than that after CDA. Pooled analysis showed patients in CDA group achieved significantly higher rates of overall success, Neck Disability Index (NDI) success, neurological success and significantly lower rates of implant/surgery-related serious adverse events and secondary procedure compared with that in ACDF group. The long-term functional outcomes (NDI, Visual Analog Scale (VAS) neck and arm pain scores, the Short Form 36 Health Survey physical component score (SF-36 PCS)), patient satisfaction and recommendation, and the incidence of superior adjacent segment degeneration also favored patients in CDA group with statistical difference. Regarding inferior adjacent segment degeneration, patients in CDA group had a lower rate without statistical significance.

Conclusions

This meta-analysis showed that cervical disc arthroplasty was superior over anterior discectomy and fusion for the treatment of symptomatic cervical disc disease in terms of overall success, NDI success, neurological success, implant/surgery-related serious adverse events, secondary procedure, functional outcomes, patient satisfaction and recommendation, and superior adjacent segment degeneration.     

QTL Mapping of Low-Temperature Germination Ability in the Maize IBM Syn4 RIL Population

Low temperature is the primary factor to affect maize sowing in early spring. It is, therefore, vital for maize breeding programs to improve tolerance to low temperatures at seed germination stage. However, little is known about maize QTL involved in low-temperature germination ability. 243 lines of the intermated B73×Mo17 (IBM) Syn4 recombinant inbred line (RIL) population was used for QTL analysis of low-temperature germination ability. There were significant differences in germination-related traits under both conditions of low temperature (12°C/16h, 18°C/8h) and optimum temperature (28°C/24h) between the parental lines. Only three QTL were identified for controlling optimum-temperature germination rate. Six QTL controlling low-temperature germination rate were detected on chromosome 4, 5, 6, 7 and 9, and contribution rate of single QTL explained between 3.39%~11.29%. In addition, six QTL controlling low-temperature primary root length were detected in chromosome 4, 5, 6, and 9, and the contribution rate of single QTL explained between 3.96%~8.41%. Four pairs of QTL were located at the same chromosome position and together controlled germination rate and primary root length under low temperature condition. The nearest markers apart from the corresponding QTL (only 0.01 cM) were umc1303 (265.1 cM) on chromosome 4, umc1 (246.4 cM) on chromosome 5, umc62 (459.1 cM) on chromosome 6, bnl14.28a (477.4 cM) on chromosome 9, respectively. A total of 3155 candidate genes were extracted from nine separate intervals based on the Maize Genetics and Genomics Database (http://www.maizegdb.org). Five candidate genes were selected for analysis as candidates putatively affecting seed germination and seedling growth at low temperature. The results provided a basis for further fine mapping, molecular marker assisted breeding and functional study of cold-tolerance at the stage of seed germination in maize.     

Diagnostic Performance of Whole-Body PET/MRI for Detecting Malignancies in Cancer Patients: A Meta-Analysis

BackgroundAs an evolving imaging modality, PET/MRI is preliminarily applied in clinical practice. The aim of this study was to assess the diagnostic performance of PET/MRI for tumor staging in patients with various types of cancer.MethodsRelevant articles about PET/MRI for cancer staging were systematically searched in PubMed, EMBASE, EBSCO and the Cochrane Library. Two researchers independently selected studies, extracted data and assessed the methodological quality using the QUADAS tool. The pooled sensitivity, specificity, diagnostic odds ratio (DOR), positive likelihood ratio (PLR), and negative likelihood ratio (NLR) were calculated per patient and per lesion. The summary receiver-operating characteristic (SROC) curves were also constructed, and the area under the curve (AUC) and Q* estimates were obtained.ResultsA total of 38 studies that involved 753 patients and 4234 lesions met the inclusion criteria. On a per-patient level, the pooled sensitivity and specificity with 95% confidence intervals (CIs) were 0.93 (0.90–0.95) and 0.92 (0.89–0.95), respectively. On a per-lesion level, the corresponding estimates were 0.90 (0.88–0.92) and 0.95 (0.94–0.96), respectively. The pooled PLR, NLR and DOR estimates were 6.67 (4.83–9.19), 0.12 (0.07–0.21) and 75.08 (42.10–133.91) per patient and 10.91 (6.79–17.54), 0.13 (0.08–0.19) and 102.53 (59.74–175.97) per lesion, respectively.ConclusionAccording to our results, PET/MRI has excellent diagnostic potential for the overall detection of malignancies in cancer patients. Large, multicenter and prospective studies with standard scanning protocols are required to evaluate the diagnostic value of PET/MRI for individual cancer types.     

A Window into brain development: hdEEG methods to track visual development in nonhuman primates

Electroencephalography (EEG) is widely used to study human brain activity, and is a useful tool for bridging the gap between invasive neural recording assays and behavioral data. High‐density EEG (hdEEG) methods currently used for human subjects for use with infant macaque monkeys, a species that exhibits similar visual development to humans over a shorter time course was adapted. Unlike monkeys, human subjects were difficult to study longitudinally and were not appropriate for direct within‐species comparison to neuronal data. About 27‐channel electrode caps, which allowed collection of hdEEG data from infant monkeys across development were designed. Acuity and contrast sweep VEP responses to grating stimuli was obtained and a new method for objective threshold estimation based on response signal‐to‐noise ratios at different stimulus levels was established. The developmental trajectories of VEP‐measured contrast sensitivity and acuity to previously collected behavioral and neuronal data were compared. The VEP measures showed similar rates of development to behavioral measures, both of which were slower than direct neuronal measures; VEP thresholds were higher than other measures. This is the first usage of non‐invasive technology in non‐human primates. Other means to assess neural sensitivity in infants were all invasive. Use of hdEEG with infant monkeys opens many possibilities for tracking development of vision and other functions in non‐human primates, and can expand our understanding of the relationship between neuronal activity and behavioral capabilities across various sensory and cognitive domains. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 76: 1342–1359, 2016     

Mean Recency Period for Estimation of HIV-1 Incidence with the BED-Capture EIA and Bio-Rad Avidity in Persons Diagnosed in the United States with Subtype B

HIV incidence estimates are used to monitor HIV-1 infection in the United States. Use of laboratory biomarkers that distinguish recent from longstanding infection to quantify HIV incidence rely on having accurate knowledge of the average time that individuals spend in a transient state of recent infection between seroconversion and reaching a specified biomarker cutoff value. This paper describes five estimation procedures from two general statistical approaches, a survival time approach and an approach that fits binomial models of the probability of being classified as recently infected, as a function of time since seroconversion. We compare these procedures for estimating the mean duration of recent infection (MDRI) for two biomarkers used by the U.S. National HIV Surveillance System for determination of HIV incidence, the Aware BED EIA HIV-1 incidence test (BED) and the avidity-based, modified Bio-Rad HIV-1/HIV-2 plus O ELISA (BRAI) assay. Collectively, 953 specimens from 220 HIV-1 subtype B seroconverters, taken from 5 cohorts, were tested with a biomarker assay. Estimates of MDRI using the non-parametric survival approach were 198.4 days (SD 13.0) for BED and 239.6 days (SD 13.9) for BRAI using cutoff values of 0.8 normalized optical density and 30%, respectively. The probability of remaining in the recent state as a function of time since seroconversion, based upon this revised statistical approach, can be applied in the calculation of annual incidence in the United States.