Explore the vast range of titles available.

De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes ( p -value = 1.00 × 10 −5 ) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes ( p -value = 5.01 × 10 −4 ) in contrast to predicted benign de novo mutations. One gene we identify, RBM5 , is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men ( p -value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility. Germline de novo mutations can impact individual fitness, but their role in human male infertility is understudied. Trio-based exome sequencing identifies many new candidate genes affecting male fertility, including an essential regulator of male germ cell pre-mRNA splicing.

Inherited retinal diseases (IRDs) are a major cause of visual impairment. These clinically heterogeneous disorders are caused by pathogenic variants in more than 270 genes. As 30–40% of cases remain genetically unexplained following conventional genetic testing, we aimed to obtain a genetic diagnosis in an IRD cohort in which the genetic cause was not found using whole-exome sequencing or targeted capture sequencing. We performed whole-genome sequencing (WGS) to identify causative variants in 100 unresolved cases. After initial prioritization, we performed an in-depth interrogation of all noncoding and structural variants in genes when one candidate variant was detected. In addition, functional analysis of putative splice-altering variants was performed using in vitro splice assays. We identified the genetic cause of the disease in 24 patients. Causative coding variants were observed in genes such as ATXN7, CEP78, EYS, FAM161A, and HGSNAT. Gene disrupting structural variants were also detected in ATXN7, PRPF31, and RPGRIP1. In 14 monoallelic cases, we prioritized candidate noncanonical splice sites or deep-intronic variants that were predicted to disrupt the splicing process based on in silico analyses. Of these, seven cases were resolved as they carried pathogenic splice defects. WGS is a powerful tool to identify causative variants residing outside coding regions or heterozygous structural variants. This approach was most efficient in cases with a distinct clinical diagnosis. In addition, in vitro splice assays provide important evidence of the pathogenicity of rare variants.

Eamonn Maher and colleagues report germline mutations in DIS3L2 causing the Perlman syndrome of overgrowth and susceptibility to Wilms tumor. DIS3L2 encodes a protein with exoribonuclease activity in the RNA exosome complex. Perlman syndrome is a congenital overgrowth syndrome inherited in an autosomal recessive manner that is associated with Wilms tumor susceptibility. We mapped a previously unknown susceptibility locus to 2q37.1 and identified germline mutations in DIS3L2 , a homolog of the Schizosaccharomyces pombe dis3 gene, in individuals with Perlman syndrome. Yeast dis3 mutant strains have mitotic abnormalities. Yeast Dis3 and its human homologs, DIS3 and DIS3L1, have exoribonuclease activity and bind to the core RNA exosome complex. DIS3L2 has a different intracellular localization and lacks the PIN domain found in DIS3 and DIS3L1; nevertheless, we show that DIS3L2 has exonuclease activity. DIS3L2 inactivation was associated with mitotic abnormalities and altered expression of mitotic checkpoint proteins. DIS3L2 overexpression suppressed the growth of human cancer cell lines, and knockdown enhanced the growth of these cells. We also detected evidence of DIS3L2 mutations in sporadic Wilms tumor. These observations suggest that DIS3L2 has a critical role in RNA metabolism and is essential for the regulation of cell growth and division.

Carica fruit is a main commodity in Dieng plateau. Its seeds is one of the by-products in carica fruit cocktail processing. Carica seeds contain high antioxidants, so that it can be consumed as a functional beverage. The objectives of this study was to determine the shelf life of the product. The processes involved in carica seed powder production were: soaking with citric acid, boiling, fermentation with R. oligosporus inoculum, drying, roasting, and mixing the roasted seeds with dried jackfruit at ratio of 3: 1. The packaging used in this study were glass jar and aluminum foil. The products were stored at 35, 45, and 55°C and analyzed for its chemical and sensory characteristics at every 5 d for 20 d. The shelf life was examined by the acceleration method with Arrhenius equation using moisture content as the critical parameter. Results of the study showed that shelf-life of products packed with aluminum foil at room temperature (25°C) was 1 year and 1 month and at cold temperature (8°C) was 1 year 4 months. Meanwhile, the shelf life of products packed in glass bottles at room temperature (25°C) was 5 months and at cold temperatures (8°C) was 6 months.

Vinasse-molasses, the residue of condensed molasses is a co-product of sugar production. It is not reused in manufacturing process and become polluted. However, Its contents of 48-60% of sugar and high in potassium and sulphates. This study was to evaluate Vinasse-molasses utilization as a replacer of molasses in finishing ration on the growth performance of Peranakan Ongole Cattle. A total of 10 Peranakan Ongole cattle (initial body weight of 209 ± 21 kg) were assigned to molasses group or Vinasse-molasses group. The experiment period was lasted 68 days, preceded by 14 days adaptation period. The experimental diet was composed of 20% forage and 80% concentrate containing 15% molasses or Vinasse-molasses. Parameters observed including final body weight (FBW), average daily gain (ADG), total dry matter intake (DMI), forage intake, concentrate intake, feed efficiency (FE), and income over feed cost (IOFC). The Vinasse-molasses reduced (P<0.05) DMI and concentrate intake followed by IOFC increased (P<0.01) of cattle. However, Vinasse-molasses did not affect (P>0.05) FBW, ADG, forage intake, and FE. It can be concluded that Vinasse-molasses can be utilize as feed ingredient to replace molasses in finishing ration to support the sustainability of beef production.

Water tracing was conducted at Karangbolong Karst as a rapid assessment of the Kalisirah spring hydrological characteristics. This study was conducted to determine the movement of underground flow and the estimation of the Catchment Area using the Todd Nomogram and field observations. The results of flow tracing tests conducted in Pocung Cave indicate that there is underground river network connectivity between Pocung Cave, Jeblosan Sinkhole and Kalisirah Springs. Based on topographic survey and flow tracing test, the calculation of the estimated area of the Kalisirah catchment area is 180 Ha. The results were also validate using other parameters, namely flowrate and rainfall in the research location using Todd Nomogram. The estimated area of the Kalisirah catchment area with the Todd Nomogram is 189.2 Ha. The calculation of the estimated area of Kalisirah catchment area based on topographic survey and water tracing is relevant with the estimated area with Todd Nomogram. Groundwater tracing investigation can be used to determine karst spring catchment area, as a preliminary study to understanding the karst hydrology.

De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10−5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10−4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.

Wolfram syndrome (WFS) is a neurodegenerative genetic condition characterized by juvenile-onset of diabetes mellitus and optic atrophy. We studied clinical features and the molecular basis of severe WFS (neurodegenerative complications) in two consanguineous families from Iran. A clinical and molecular genetic investigation was performed in the affected and healthy members of two families. The clinical diagnosis of WFS was confirmed by the existence of diabetes mellitus and optic atrophy in the affected patients, who in addition had severe neurodegenerative complications. Sequencing of WFS1 was undertaken in one affected member from each family. Targeted mutations were tested in all members of relevant families. Patients had most of the reported features of WFS. Two affected males in the first family had fathered unaffected children. We identified two homozygous mutations previously reported with apparently milder phenotypes: family 1: c.631G>A (p.Asp211Asn) in exon 5, and family 2: c.1456C>T (p.Gln486*) in exon 8. Heterozygous carriers were unaffected. This is the first report of male Wolfram patients who have successfully fathered children. Surprisingly, they also had almost all the complications associated with WFS. Our report has implications for genetic counseling and family planning advice for other affected families.

Concerning on the dependancy of coal on electric generation wordwidely, study on fly ash, thesolid waste of fired coal electricity generation, has been comprehensively conducting, i.e. geopolymer, cenosphere, soil remediation, and adsorbent. However, only few studies dealing with the utilization of bottom ash. Having of about 53% of coal in the 2050 energy mix, Indonesia will be dealing with more than 200 million tonnes of fly ash and bottom ash (FABA). In this study, FABA was mixed in certain proportion of 50:50, 75:25, dan 100:0. The formation of geopolymer was conducted with sodium hydroxide and sodium silicate in certain concentration. Once the mixture had been homogenized, it was casted and cured in varied temperature of 30, 60, dan 90 oC with curing time of 1, 3, 5, 14, 21, dan 28 days. In each curing time, sample was then analyzed using compresive strength apparatus and FTIR in order to observed the geopolimerization of the FABA mixture. It was found that compressive strength representing the macro characteristic of the geopolymer is in line with the CORR analysis of the FTIR results showing that the formation of aluminosilicate is responsible for the mechanical strength of the geopolymer. The higher the bottom ash ratio in the mixture with decrease the strength of the geopolymer in the order of one per second. Higher temperature results higher compresive strength to the value of 42 Mpa (FABA ratio is 75:25 at temperature of 90 oC) above the Indonesian standard for concrete. From this study, kinetics of FABA geopolymerization can be generated in accordance todiffusion model with R2 of 0.9135. Thus the utilization of FABA for geopolymer is going to be a potential solution to overcome the increasing amount of FABA resulted from fired coal electrical generation in Indonesia.

Introduction TDF/FTC/RPV has been shown effective in both naïve and PI‐pre‐treated patients. Less is known about a switch strategy in subjects receiving EFV. Materials and Methods We evaluated viro‐immunologic outcomes, Quality of Life (QoL) and costs of an unselected cohort of patients switching from a TDF/FTC/EFV STR (≥6 months duration) to a TDF/FTC/RPV STR. The considered outcome measures were quality‐adjusted life years (QALYs) as measured with the EQ5D questionnaire and the overall direct health costs. 64 patients with a baseline viral load<50 copies/mL were randomized to immediately switch therapy or to continue TDF/FTC/EFV for four months and then switch to TDF/FTC/RPV. Six patients in the deferred switch group did not actually change cART. Results Patients were mostly males (73.4%) with a mean age of 46 years, a baseline mean HIV‐RNA of 6.4 copies/mL and a mean baseline CD4 count of 588 cells/µL. For the considered follow‐up period, the mean cost per patient resulted 2,563 for TDF/FTC/RPV and 2,572 for TDF/FTC/EFV. Viremia remained undetectable and CD4 stable in all patients. Over time the mean QoL increased in the RPV arm ad slightly decreased in the EFV arm, after four months the mean per patient QALYs was 0.849 for RPV and 0.841 for EFV, respectively (Figure 1). A sharp increment of QoL was observed in the deferred‐switch arm after switch, too. VAS analysis of health status perception also increased overall from 82.78 to 83.79 due to the improvement in the RPV arm. Mean cholesterol levels improved in the RPV arm from 203 to 170 mg/dL, while an increment from 190 to 207 mg/dL was observed in the EFV arm. HDL levels lowered from 49 to 45 and rose from 53 to 54 mg/dL in the RPV and EFV arms, respectively. Triglycerides levels improved both in the RPV arm (from 138 to 112 mg/dL) and in the EFV arm (from 110 to 103 mg/dL). Conclusions Switching from TDF/FTC/EFV to TDF/FTC/RPV is a safe, well tolerated strategy that improves the overall health status of HIV‐treated patients. The switch does not expose patients to a risk of virologic failure due to possible PK interactions of the drugs. RPV compared to EFV proved to be cost‐effective showing lower cost and higher outcome measure values.