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Improvement in feed conversion efficiency can improve the sustainability of beef cattle production, but genomic selection for feed efficiency affects many underlying molecular networks and physiological traits. This study describes the differences between steer progeny of two influential Angus bulls with divergent genomic predictions for residual feed intake (RFI). Eight steer progeny of each sire were phenotyped for growth and feed intake from 8 mo. of age (average BW 254 kg, with a mean difference between sire groups of 4.8 kg) until slaughter at 14-16 mo. of age (average BW 534 kg, sire group difference of 28.8 kg). Terminal samples from pituitary gland, skeletal muscle, liver, adipose, and duodenum were collected from each steer for transcriptome sequencing. Gene expression networks were derived using partial correlation and information theory (PCIT), including differentially expressed (DE) genes, tissue specific (TS) genes, transcription factors (TF), and genes associated with RFI from a genome-wide association study (GWAS). Relative to progeny of the high RFI sire, progeny of the low RFI sire had -0.56 kg/d finishing period RFI (P = 0.05), -1.08 finishing period feed conversion ratio (P = 0.01), +3.3 kg^0.75 finishing period metabolic mid-weight (MMW; P = 0.04), +28.8 kg final body weight (P = 0.01), -12.9 feed bunk visits per day (P = 0.02) with +0.60 min/visit duration (P = 0.01), and +0.0045 carcass specific gravity (weight in air/weight in air-weight in water, a predictor of carcass fat content; P = 0.03). RNA-seq identified 633 DE genes between sire groups among 17,016 expressed genes. PCIT analysis identified >115,000 significant co-expression correlations between genes and 25 TF hubs, i.e. controllers of clusters of DE, TS, and GWAS SNP genes. Pathway analysis suggests low RFI bull progeny possess heightened gut inflammation and reduced fat deposition. This multi-omics analysis shows how differences in RFI genomic breeding values can impact other traits and gene co-expression networks.

Intraflagellar transport (IFT) of ciliary precursors such as tubulin from the cytoplasm to the ciliary tip is involved in the construction of the cilium, a hairlike organelle found on most eukaryotic cells. However, the molecular mechanisms of IFT are poorly understood. Here, we found that the two core IFT proteins IFT74 and IFT81 form a tubulin-binding module and mapped the interaction to a calponin homology domain of IFT81 and a highly basic domain in IFT74. Knockdown of IFT81 and rescue experiments with point mutants showed that tubulin binding by IFT81 was required for ciliogenesis in human cells.

Early treatment of acute hepatitis C virus (HCV) infection with interferon alfa is highly effective, but can be associated with frequent side-effects. We investigated the safety and efficacy of an interferon-free regimen for treatment of acute HCV infection. In this prospective, open-label, multicentre, single-arm pilot study, we enrolled adults (≥18 years) with acute HCV genotype 1 monoinfection from ten centres in Germany. Patients were given ledipasvir (90 mg) plus sofosbuvir (400 mg) as a fixed-dose combination tablet once daily for 6 weeks. The primary efficacy outcome was the proportion of patients with sustained virological response (defined as undetectable HCV RNA 12 weeks after the end of treatment; other primary outcomes were safety and tolerability of ledipasvir plus sofosbuvir. The primary analysis population consisted of all patients who received at least one dose of study drug. Safety was also assessed in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02309918. Between Nov 19, 2014, and Nov 10, 2015, we enrolled 20 patients. Median HCV RNA viral load at baseline was 4·04 log10 IU/mL (1·71–7·20); 11 patients were infected with HCV genotype 1a and nine patients with genotype 1b. All patients achieved a sustained virological response 12 weeks after the end of treatment (20 [100%] of 20 patients). Treatment was well tolerated; there were no drug-related serious adverse events. Up to 12 weeks after treatment, 22 possible or probable drug-related adverse events were reported. There was one serious adverse event, which was judged unrelated to the study drug; one patient was admitted to hospital for surgery of a ruptured cruciate ligament. Treatment for 6 weeks with ledipasvir plus sofosbuvir was well tolerated and highly effective in patients with acute HCV genotype 1 monoinfection. Short-duration treatment of acute hepatitis C might prevent the spread of HCV in high-risk populations. Gilead Sciences, HepNet Study-House/German Liver Foundation, and German Centre for Infection Research (DZIF).

The polyunsaturated nature of n-3 fatty acids makes them prone to oxidative damage. However, it is not clear if n-3 fatty acids are simply a passive site for oxidative attack or if they also modulate mitochondrial reactive oxygen species (ROS) production. The present study used fat-1 transgenic mice, that are capable of synthesizing n-3 fatty acids, to investigate the influence of increases in n-3 fatty acids and resultant decreases in the n-6:n-3 ratio on liver mitochondrial H(2)O(2) production and electron transport chain (ETC) activity. There was an increase in n-3 fatty acids and a decrease in the n-6:n-3 ratio in liver mitochondria from the fat-1 compared to control mice. This change was largely due to alterations in the fatty acid composition of phosphatidylcholine and phosphatidylethanolamine, with only a small percentage of fatty acids in cardiolipin being altered in the fat-1 animals. The lipid changes in the fat-1 mice were associated with a decrease (p<0.05) in the activity of ETC complex I and increases (p<0.05) in the activities of complexes III and IV. Mitochondrial H(2)O(2) production with either succinate or succinate/glutamate/malate substrates was also decreased (p<0.05) in the fat-1 mice. This change in H(2)O(2) production was due to a decrease in ROS production from ETC complex I in the fat-1 animals. These results indicate that the fatty acid changes in fat-1 liver mitochondria may at least partially oppose oxidative stress by limiting ROS production from ETC complex I.

Registry-based randomized controlled trials (RCTs) are presumed to include a less-selected patient population and thus to have enhanced generalizability compared to conventional RCTs. However, this view disregards the levels of patient selection in registry-based RCTs: the registry selection level and the trial selection level. At both levels, systematic selection can occur and generalizability can be diminished. Nevertheless, using a registry as a basis for recruitment, randomization, and data collection results in an advantage: the trial selection takes place within the registry framework, where baseline characteristics of non-enrolled patients are automatically documented as well. By comparing the baseline variables of the enrolled and non-enrolled patients, the trial selection can always be investigated, which gives a sound basis for discussing the generalizability to the registry population.

In planning a clinical trial for demonstrating the efficacy of pioglitazone to resolve leukoplakia and erythroplakia in Fanconi anemia patients we had to discuss the need for a randomized controlled trial particularly under sample-size restrictions as very promising results were available from a single-arm clinical trial. Unfortunately, at a later stage, we had to suffer from the fact that single-arm clinical trials may sometimes mislead. When revisiting our planning at a later stage of a grant application, results of a randomized controlled trial had become available which were less impressive, but may still be of clinical interest. However, these results were perceived as disappointing in the light of previously raised hopes based on the results of the single-arm trial. We highlight some major problems when research is based on single-arm trials compared to randomized controlled trials. After debunking common arguments for the conduct of single-arm trials in rare disease we conclude that particularly in rare disease research should be based on randomized building blocks simply because more robust evidence is generated. The plea for single-arm trials should be substituted by a plea for cooperation of all stakeholders to provide best evidence for decision making under sample-size restrictions.

According to a report by PEN America, 40% of banned and challenged books have BIPOC protagonists, and 41% have LGBTQ protagonists and/or LGBTQ major plots or themes. Iowa just passed a law prohibiting gender and sexual orientation \"instruction\" from schools, which prompted one administrator to ask ChatGPT which books she should ban from her district's libraries. And in Arkansas, the governor recently suggested that an Advanced Placement African American Studies course spreads \"hate against America.\" Censorship surges in school libraries are not a new or uniquely 2020s problem. In the early 1980s, the American Library Association's (ALA) Office for Intellectual Freedom recorded a spike in ban attempts because some parents were fearful that their kids were being taught secular humanism. Robert Morris wrote in 1987, \"there continues today a pervasive climate in our nation to censor what students can read and what material libraries can carry. This conservative attitude would rid our schools of free inquiry and deprive them of any diversity of opinion.\"

Citrus germplasm programs can benefit from high-throughput polymerase chain reaction (PCR)-based methods for the detection of graft-transmissible pathogens in propagative materials. These methods increase diagnostic capacity, and thus contribute to the prevention of disease spread from nurseries to citrus orchards. High quality nucleic acids, as determined by purity, concentration, and integrity, are a prerequisite for reliable PCR detection of citrus pathogens. Citrus tissues contain high levels of polyphenols and polysaccharides, which can affect nucleic acid quality and inhibit PCR reactions. Various commercially available RNA isolation methods are used for citrus and include: phenol-chloroform (TRIzol ® , Thermo Fisher Scientific); silica columns (RNeasy ® Plant Mini Kit, Qiagen); and magnetic beads-based methods (MagMAX™-96 Viral RNA Isolation Kit, Thermo Fisher Scientific). To determine the quality of RNA and its impact on the detection of graft-transmissible citrus pathogens in reverse transcription (RT) PCR-based assays, we compared these three RNA isolation methods. We assessed RNA purity, concentration, and integrity from citrus inoculated with different viruses and viroids. All three RNA isolation methods produced high quality RNA, and its use in different RT-PCR assays resulted in the detection of all targeted citrus viruses and viroids with no false positive or negative results. TRIzol ® yielded RNA with the highest concentration and integrity values but some samples required serial dilutions to remove PCR inhibitors and detect the targeted pathogens. The RNeasy ® kit produced the second highest concentration and purity of RNA, and similar integrity to TRIzol ® . MagMAX™ isolation also provided high quality RNA but most importantly produced RNA with consistent results clustered around a median value for concentration, purity, and integrity. Subsequently, MagMAX™-96 was combined with the semi-automated MagMAX™ Express-96 Deep Well Magnetic Particle Processor, for high-throughput sample processing. MagMAX™-96 enabled the diagnostic laboratory of the Citrus Clonal Protection Program-National Clean Plant Network at the University of California, Riverside to process over 16,500 samples from citrus budwood source trees between 2010 and 2019. This high-throughput approach dramatically reduced the incidence of viroids in citrus nurseries and was key to the successful implementation of the mandatory Citrus Nursery Stock Pest Cleanliness Program in California.

Objectives A selective intensified prevention (SIP) was introduced at individual schools in deprived areas in Marburg County (Germany) in 1995. The outcome of the program was evaluated in sixth graders (mean age: 12.06 years) in comparison to a control region. Materials and methods Caries experience was recorded by applying International Caries Detection and Assessment System (ICDAS) II criteria. Tooth brushing habits and other independent variables were examined psychometrically. To compare the mean caries scores, non parametric tests were applied. The influence of various independent variables on caries experience was assessed by stepwise backward logistic regression analysis. The matching criteria age, gender, ethnicity and maternal education were used to parallelize the samples. Results ICDAS scores of 2–6 were detected uniformly more often in the control region than in the test group. Combining ICDAS scores 3–6, children from the control region (mean D 3–6 MFT: 1.73) showed roughly double the caries experience compared to the test group (mean D 3–6 MFT: 0.88, p  < 0.005). The D 5,6 MFT score of the test group amounted to 0.50, and the corresponding value of the reference group was 0.77 ( p  = 0.043). Multivariate analysis disclosed fissure sealants, early start of tooth brushing and topical fluoride application to be associated with the prevention of dental caries. High frequency of sugar intake was associated with the presence of dentine lesions. Conclusions The results of our study confirm the positive effect of SIP on the dental health of 12-year-old pupils living in deprived areas. Clinical relevance On the basis of ICDAS II, targeted preventive measures can be applied in children with increased caries risk. Frequent applications of fluoride varnish inhibit the progression of initial lesions in this group.

Hepatitis D is the most severe form of chronic viral hepatitis. Treatment guidelines recommend 1 year of peginterferon alfa, which is effective in 25–30% of patients only. Whether prolonged therapy with peginterferon alfa-2a for 96 weeks and combination therapy with tenofovir disoproxil fumarate (TDF) would increase hepatitis D virus (HDV) RNA suppression is unknown. We aimed to explore whether prolonged treatment of HDV with 96 weeks of peginterferon would increase HDV RNA response rates and reduces post-treatment relapses. We did two parallel, investigator-initiated, multicentre, double-blind randomised, controlled trials at 14 study sites in Germany, Greece, Romania, and Turkey. Patients with chronic HDV infection and compensated liver disease who were aged 18 years or older were eligible for inclusion. All patients were HBsAg positive for at least 7 months, anti-HDV positive for at least 3 months, and HDV-RNA positive at the local laboratory at the screening visit. Patients were ineligible if alanine aminotransferase levels were higher than ten times above the upper limit of normal and if platelet counts were lower than 90 000 per μL, or if they had received interferon therapy or treatment with a nucleoside and nucleotide analogue within the preceding 6 months. Patients were randomly assigned by blinded stratified block randomisation (1:1) to receive 180 μg of peginterferon alfa-2a weekly plus either TDF (300 mg once daily) or placebo for 96 weeks. The primary endpoint was the percentage of patients with undetectable HDV RNA at the end of treatment assessed by intention to treat. The trials are registered as NCT00932971 and NCT01088659. Between June 24, 2009, and Feb 28, 2011, we randomly assigned 59 HDV RNA-positive patients to receive peginterferon alfa-2a plus TDF and 61 to receive peginterferon alfa-2a plus placebo, including 48 (40%) patients with cirrhosis to the two treatment groups (23 in the peginterferon alfa-2a plus TDF group and 25 in the peginterferon alfa-2a plus placebo group). The primary endpoint was achieved in 28 (48%) of 59 patients in the peginterferon alfa-2a plus TDF group and in 20 (33%) of 61 patients in the peginterferon alfa-2a plus placebo group (odds ratio 1·84, 95% CI 0·86–3·91, p=0·12). We recorded 944 adverse events (459 in the peginterferon alfa-2a plus TDF group and 485 in the peginterferon alfa-2a plus placebo group). The most common adverse events were haematological, behavioural (eg, fatigue), musculoskeletal, influenza-like syndromes, and psychiatric complaints. Addition of TDF resulted in no significant improvement in HDV RNA response rates at the end of treatment. These findings highlight that alternative treatment options are needed for hepatitis D. The HepNet Study-House (a project of the German Liver Foundation founded by the German Liver Foundation, the German Ministry for Education and Research, and the German Center for Infectious Disease Research), Hoffmann-La Roche, and Gilead Sciences.