Tuning tRNAs for improved translation.

Transfer RNAs have been extensively explored as the molecules that translate the genetic code into proteins. At this interface of genetics and biochemistry, tRNAs direct the efficiency of every major step of translation by interacting with a multitude of binding partners. However, due to the variability of tRNA sequences and the abundance of diverse post-transcriptional modifications, a guidebook linking tRNA sequences to specific translational outcomes has yet to be elucidated. Here, we review substantial efforts that have collectively uncovered tRNA engineering principles that can be used as a guide for the tuning of translation fidelity. These principles have allowed for the development of basic research, expansion of the genetic code with non-canonical amino acids, and tRNA therapeutics.

[Update of the German S3 guideline on renal cell carcinoma]. / Aktualisierte S3-Leitlinie Nierenzellkarzinom.

BACKGROUND: Renal cell carcinoma is the third most common tumor among urological tumors. In Germany more than 14,000 people are affected every year. The sex ratio is 2/3 men and 1/3 women. OBJECTIVES: The S3 guideline is intended to provide all disciplines dealing with renal cell carcinoma with the current status of diagnostics, therapy and follow-up care of the patients with this tumor. MATERIALS AND METHODS: The first version of the German guideline on renal cell carcinoma was published in 2015. The development was carried out at S3 level, which means that a structured, evidence-based literature search was carried out, recommendations and statements were developed in topic-related working groups and were approved by an interdisciplinary group of officials elected by the different medical societies. The chapters were gradually revised in 2017, 2020 and 2021 to reflect new aspects. This article provides information about the most important innovations of the most recent update from 2023. RESULTS: In the epidemiology subsection, the substance trichlorethene has been added as a risk factor for the development of renal cell carcinoma. While there were no new data on neoadjuvant therapy, the checkpoint inhibitor pembrolizumab was the first substance to demonstrate improved disease-specific and overall survival in the adjuvant situation. The combination nivolumab plus cabozantinib and lenvatinib plus pembrolizumab were included in the chapter on systemic therapy for metastatic clear cell renal cell carcinoma. New are the chapters on non-clear cell renal cell carcinoma and hereditary tumors. CONCLUSIONS: The S3 guideline provides a structured, evidence-based overview of all aspects of renal cell carcinoma.

Evaluation of ECG-Gated, High-Pitch Thoracoabdominal Angiographies With Dual-Source Photon-Counting Detector Computed Tomography.

PURPOSE: The aim of this study was to evaluate the radiation dose, image quality, and the potential of virtual monoenergetic imaging (VMI) reconstructions of high-pitch computed tomography angiography (CTA) of the thoracoabdominal aorta on a dual-source photon-counting detector-CT (PCD-CT) in comparison with an energy-integrating detector-CT (EID-CT), with a special focus on low-contrast attenuation. METHODS: Consecutive patients being referred for an electrocardiogram (ECG)-gated, high-pitch CTA of the thoracoabdominal aorta prior to transcatheter aortic valve replacement (TAVR), and examined on the PCD-CT, were included in this prospective single-center study. For comparison, a retrospective patient group with ECG-gated, high-pitch CTA examinations of the thoracoabdominal aorta on EID-CT with a comparable scan protocol was matched for gender, body mass index, height, and age. Virtual monoenergetic imaging reconstructions from 40 to 120 keV were performed. Enhancement and noise were measured in 7 vascular segments and the surrounding air as mean and standard deviation of CT values. The radiation dose was noted and signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated. Finally, a subgroup analysis was performed, comparing VMI reconstructions from 40 keV to 70 keV in patients with at least a 50% decrease in contrast attenuation between the ascending aorta and femoral arteries. RESULTS: Fifty patients (mean age 77.0±14.5 years; 31 women) were included. The radiation dose was significantly lower on the PCD-CT (4.2±1.4 vs. 7.2±2.2 mGy; p<0.001). With increasing keV, vascular noise, SNR, and CNR decreased. Intravascular attenuation was significantly higher on VMI at levels from 40 to 65, compared with levels of 120 keV (p<0.01 and p<0.005, respectively). On the PCD-CT, SNR was significantly higher in keV levels 40 and 70 (all p<0.001), and CNR was higher at keV levels 40 and 45 (each p<0.001), compared with scans on the EID-CT. At VMI ≤60 keV, image noise was also significantly higher than that in the control group. The subgroup analysis showed a drastically improved diagnostic performance of the low-keV images in patients with low-contrast attenuation. CONCLUSION: The ECG-gated CTA of the thoracoabdominal aorta in high-pitch mode on PCD-CT have significantly lower radiation dose and higher objective image quality than EID-CT. In addition, low-keV VMI can salvage suboptimal contrast studies, further reducing radiation dose by eliminating the need for repeat scans. CLINICAL IMPACT: ECG-gated CT-angiographies of the thoracoabdominal aorta can be acquired with a lower radtiation dose and a better image quality by using a dual-source photon-countinge detector CT. Furthermore, the inherent spectral data offers the possiblity to improve undiagnostic images and thus saves the patient from further radiation and contrast application.

Bevacizumab mitigates codon-specific effects of trifluridine/tipiracil on efficacy outcome parameters in metastatic colorectal cancer.

BACKGROUND: Molecular informed therapy changed treatment patterns of metastatic colorectal cancer (mCRC). Recently KRAS G12, the most prevalent RAS mutation in mCRC, was investigated to be a negative predictive marker for the efficacy of trifluridine/tipiracil (FTD/TPI). Whether this proposed selectivity remains when FTD/TPI is combined with bevacizumab remains elusive. We aimed to describe the efficacy of FTD/TPI + bevacizumab depending on the RAS mutational status in a real-world population. PATIENTS AND METHODS: Patients from five different cancer centers in Austria who received FTD/TPI + bevacizumab in any treatment line having available information on their molecular profile were eligible. Data were retrospectively collected by chart review. Survival data were compared using log-rank test. Multivariate Cox regression models included several established covariates. RESULTS: One hundred and twenty-three patients with mCRC were included in this study. Median overall survival (OS) was highly similar in the RAS wild type (WT) [9.63 months (95% confidence interval [CI] 8.055-13.775 months)] and the RAS mutant cohorts [8.78 months (95% CI 8.055-11.014 months)], which was confirmed in a multivariable model adjusting for potential confounders; hazard ratio (HR): 1.05 (95% CI 0.618-1.785; P = 0.857). In addition, no effect of KRAS G12 status on patient outcome was observed. In detail, OS was 8.88 months (95% CI 7.332-12.921 months) in patients with KRAS G12 mutation, compared to 9.47 months (95% CI 8.088-11.375 months) in patients with RAS WT/no-KRAS G12 disease [HR: 0.822 (95% CI 0.527-1.282; P = 0.387)]. CONCLUSION: This real-world study indicates that the efficacy of FTD/TPI + bevacizumab is independent of RAS mutational status and that bevacizumab may therefore mitigate the potentially limited efficacy of FTD/TPI monotherapy in the KRAS G12-mutated population.

[Rehabilitation after Spinal Cord Injury : Current trends and principles]. / Rehabilitation nach einer Querschnittlähmung : Aktuelle Trends und Grundlagen.

Traumatic and non traumatic spinal cord injury are rare and an orphan disease in comparison to common diseases. Those affected represent a very special patient population in the treatment even at the site of the accident and in emergency medicine and require a high level of professional expertise. The rehabilitation with the complexity of a spinal cord injury can only succeed with a multiprofessional team that is less focused on the often similar diagnoses according to the International Classification of Diseases (ICD) but on functional disorders and associated activity impairments. Only then the best possible integration and participation/inclusion in sociocultural and professional life can be achieved. In addition to the importance of classical physiotherapy and occupational therapy, this article highlights important but often missing team players, such as neurourology and electrical stimulation. In addition, the problems of frequent and some less recognized complications, such as autonomic dysfunction and the benefits of airway management are highlighted. For a comprehensive overview of rehabilitation in spinal cord injury, reference textbooks and guidelines are recommended that are cited in the text.

Inhibition of Mertk Signaling Enhances Bone Healing after Tooth Extraction.

Regeneration of alveolar bone is an essential step in restoring healthy function following tooth extraction. Growth of new bone in the healing extraction socket can be variable and often unpredictable when systemic comorbidities are present, leading to the need for additional therapeutic targets to accelerate the regenerative process. One such target is the TAM family (Tyro3, Axl, Mertk) of receptor tyrosine kinases. These proteins have been shown to help resolve inflammation and maintain bone homeostasis and thus may have therapeutic benefits in bone regeneration following extraction. Treatment of mice with a pan-TAM inhibitor (RXDX-106) led to accelerated alveolar bone fill following first molar extraction in a mouse model without changing immune infiltrate. Treatment of human alveolar bone mesenchymal stem cells with RXDX-106 upregulated Wnt signaling and primed the cells for osteogenic differentiation. Differentiation of human alveolar bone mesenchymal stem cells with osteogenic media and TAM-targeted inhibitor RXDX-106 (pan-TAM), ASP-2215 (Axl specific), or MRX-2843 (Mertk specific) showed enhanced mineralization with pan-TAM or Mertk-specific inhibitors and no change with Axl-specific inhibitor. First molar extractions in Mertk-/- mice had increased alveolar bone regeneration in the extraction socket relative to wild type controls 7 d postextraction. Flow cytometry of 7-d extraction sockets showed no difference in immune cell numbers between Mertk-/- and wild type mice. RNAseq of day 7 extraction sockets showed increased innate immune-related pathways and genes associated with bone differentiation in Mertk-/- mice. Together, these results indicate that TAM receptor signaling, specifically through Mertk, can be targeted to enhance bone regeneration after injury.

Evaluation of run-off computed tomography angiography on a first-generation photon-counting detector CT scanner - Comparison with low-kVp energy-integrating CT.

PURPOSE: To assess the overall imaging performance (radiation dose and image quality) of a photon-counting detector CT (PCD-CT) in comparison with a state-of-the-art energy-integrating detector CT (EID-CT) in run-off CTAs. METHODS: Consecutive patients who underwent run-off CTA on a PCD-CT were included (PCD-CT cohort). A retrospective cohort of patients who had undergone run-off CTA on an EID-CT was matched for gender, body mass index, height, and age (EID-CT cohort). Virtual monoenergetic imaging (VMI) reconstructions for various keV settings (40-120 keV) were generated. CT values and noise were semiautomatically measured for 13 vascular segments of the abdomen, pelvis, and lower extremities. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated for each segment. Subjective image quality was evaluated by two radiologists along the dimensions 'vessel attenuation', 'vessel sharpness', and 'overall image quality' using 5-point Likert scales. RESULTS: Forty patients (age 70.9 ± 9.8 years; 14 women) were included in the PCD-CT cohort and matched with a corresponding number of EID-CT patients. Overall, there was an inverse correlation of signal and noise but also of SNR and CNR with keV levels used for VMI reconstructions. SNR and CNR in the 40 - 60 keV range exceeded EID-CT levels significantly. Subjective image quality was substantially higher at lower keV levels and showed no significant difference to EID-CT. CONCLUSION: Low keV VMI reconstructions of run-off CTA scans on a PCD-CT result in substantially higher SNR and CNR than 80 kVp and 100 kVp EID-CT acquisitions with equal subjective image quality.

Impact on daily mobility and risk of falling in bilateral vestibulopathy.

OBJECTIVE: To study the behavioral relevance of postural and ocular-motor deficits on daily activity and risk of falling in patients with bilateral vestibular hypofunction (BVH). METHODS: Thirty patients with BVH and 30 age- and gender-matched healthy controls participated in a continuous 2-week assessment of daily activities and mobility using a body-worn inertial sensor and a 6-month prospective fall risk assessment. At inclusion, patients and controls further underwent a multi-modal clinical, score- and instrument-based assessment of general health and balance status. We analyzed the relationship between clinical, lab-, and sensor-based measures and their validity to identify those patients at a risk of general, frequent, and severe falling. RESULTS: Patients exhibited impairments in daily activity in particular in terms of reduced ambulatory activity (p = 0.009). 43% of patients experienced falls (13% in controls, p = 0.008) and 70% of these patients reported recurrent falling (0% in controls, p = 0.001) during prospective assessment. Severe fall-related injuries that would require medical attention neither occurred in patients nor in controls. Classificatory models based on multi-modal clinical, lab-, and sensor-based measures of balance and mobility identified patients who fell with an accuracy of 93% and patients who recurrently fell with an accuracy of 89%. CONCLUSION: BVH is linked to particular impairments of patients' daily activities which in turn are related to patients' fall risk. Hence, off-laboratory measures of daily mobility may supplement standard clinical assessment in BVH to more adequately capture the burden of disease and to reliably identify those patients at a specific risk of falling.

Targeted tibio-peroneal re-entry during subintimal revascularization using the Outback® catheter.

BACKGROUND: Re-entry devices are used regularly in subintimal recanalization of chronic occlusions of the iliac and femoro-popliteal arteries and significantly contribute to the high success rate of these interventions. However, the use in tibio-peroneal arteries has only been described in few cases so far. The present work is a retrospective evaluation of the Outback® re-entry device for gaining targeted true lumen access at the level of the tibio-peroneal arteries. METHODS: From 9/2017 until 10/2020 the Outback® catheter was used in case of failed spontaneous re-entry at the level of the tibio-peroneal arteries in 14 patients either instead of the usual retrograde approach via a pedal/distal-crural access (n = 11) or in combination with it (n = 3). Baseline demographic and clinical data, morphologic characteristics of the occlusions, procedural succedss, as well as the Society of Vascular Surgery (SVS) runoff score before and after revascularization were documented. RESULTS: All patients (median age: 78 years; range: 66-93) suffered from peripheral artery occlusive disease Rutherford stage 4 to 6 with a median lesion length of 12 cm (range: 7-35). Technical and procedural success was achieved in all 14 patients. The mean re-entry accuracy was 0.25 cm (range: 0-0.8). The SVS runoff score improved from a median of 14.5 (interquartile range IQR: 10.8-16.4) to 7 (IQR: 6.3-7) (p < 0.01). CONCLUSIONS: The use of the Outback® catheter for targeted tibio-peroneal re-entry is associated with a high technical and procedural success rate and should be considered in case of otherwise failed ante- and retrograde recanalization.

PMS2: a potential prognostic protein marker in oral squamous cell carcinoma.

BACKGROUND: An increase in oral squamous cell carcinoma (OSCC) cases was observed despite the reduction in exposure to classic risk factors. Although the exact cause of this trend remains unknown, epigenetic factors could be contributing to an increased occurrence of these tumors. This study aims to assess the influence of PMS2 protein immunoexpression on the prognosis of patients with OSCC. MATERIAL AND METHODS: This study comprised 76 cases of OSCC treated between 2011 and 2016. Immunohistochemical staining for PMS2 was performed. For evaluation, 10 fields per histological section were photographed at a 400x magnification and positively-stained cells were counted with Image J. Mann-Whitney and Kruskal-Wallis tests were used to compare the immunolabeling pattern with the clinical-pathological and prognostic characteristics. Survival analysis was performed with Chi-square, Long-Rank Mantel-Cox and Cox regression tests (p<0.05). RESULTS: An overexpression of PMS2 was observed in N0/1 tumors and in oral cancers found in unusual locations. In patients ≤60 years of age, high levels of PMS2 (>60%; p=0.041) were associated with low survival (p=0.029). In multivariate analysis, surgery combined with chemotherapy (p=0.030) and high PMS2 immunoexpression (p=0.042) significantly increased the risk of death for ≤60 years old patients. CONCLUSIONS: The findings of this study indicate that PMS2 can be a potential prognostic protein marker in OSCC patients 60 years of age and younger.

Using online tools at the Bovine Genome Database to manually annotate genes in the new reference genome.

With the availability of a new highly contiguous Bos taurus reference genome assembly (ARS-UCD1.2), it is the opportune time to upgrade the bovine gene set by seeking input from researchers. Furthermore, advances in graphical genome annotation tools now make it possible for researchers to leverage sequence data generated with the latest technologies to collaboratively curate genes. For many years the Bovine Genome Database (BGD) has provided tools such as the Apollo genome annotation editor to support manual bovine gene curation. The goal of this paper is to explain the reasoning behind the decisions made in the manual gene curation process while providing examples using the existing BGD tools. We will describe the sources of gene annotation evidence provided at the BGD, including RNA-seq and Iso-Seq data. We will also explain how to interpret various data visualizations when curating gene models, and will demonstrate the value of manual gene annotation. The process described here can be applied to manual gene curation for other species with similar tools. With a better understanding of manual gene annotation, researchers will be encouraged to edit gene models and contribute to the enhancement of livestock gene sets.

Independent domains of daily mobility in patients with neurological gait disorders.

The aim of this study was to establish a comprehensive and yet parsimonious model of daily mobility activity in patients with neurological gait disorders. Patients (N = 240) with early-stage neurological (peripheral vestibular, cerebellar, hypokinetic, vascular or functional) gait disorders and healthy controls (N = 35) were clinically assessed with standardized scores related to functional mobility, balance confidence, quality of life, cognitive function, and fall history. Subsequently, daily mobility was recorded for 14 days by means of a body-worn inertial sensor (ActivPAL®). Fourteen mobility measures derived from ActivPAL recordings were submitted to principle component analysis (PCA). Group differences within each factor obtained from PCA were analyzed and hierarchical regression analysis was performed to identify predictive characteristics from clinical assessment for each factor. PCA yielded five significant orthogonal factors (i.e., mobility domains) accounting for 92.3% of the total variance from inertial-sensor-recordings: ambulatory volume (38.7%), ambulatory pattern (22.3%), postural transitions (13.3%), sedentary volume (10.8%), and sedentary pattern (7.2%). Patients' mobility performance only exhibited reduced scores in the ambulatory volume domain but near-to-normal scores in all remaining domains. Demographic characteristics, clinical scores, and fall history were differentially associated with each domain explaining 19.2-10.2% of their total variance. This study supports a low-dimensional five-domain model for daily mobility behavior in patients with neurological gait disorders that may facilitate monitoring the course of disease or therapeutic intervention effects in ecologically valid and clinically relevant contexts. Further studies are required to explore the determinants that may explain performance differences of patients within each of these domains and to examine the consequences of altered mobility behavior with respect to patients' risk of falling and quality of life.

Durable targeting of B-lymphocytes in living mice.

Transfer to and enduring expression of genes in B cells has proved a vexing challenge. We report here a novel method for the specific and durable targeting of B lymphocytes in living mice. The method involves generation of lentiviruses pseudotyped with an anti-CD19 antibody. CD19 targeting viruses injected in the spleen of living mice efficiently transduced B cells and plasma cells detected by flow cytometry analysis of GFP expression. Expression of the reporter gene could be detected in the intact animal by external imaging for more than a year and was enhanced by booster immunization. Our method thus enables the specific delivery, expression and localization by external imaging of exogenous genes to the B cells and plasma cells of living individuals.

Noisy vestibular stimulation improves vestibulospinal function in patients with bilateral vestibulopathy.

OBJECTIVES: To examine the mechanism underlying previously reported ameliorating effects of noisy galvanic vestibular stimulation (GVS) on balance performance in patients with bilateral vestibulopathy (BVP) and determine those patients (incomplete versus complete vestibular loss) that might benefit from this intervention. METHODS: Vestibulospinal reflex thresholds were determined in 12 patients with BVP [2 with complete loss (cBVP) and 10 with residual function (rBVP)]. Patients were stimulated with 1 Hz sinusoidal GVS of increasing amplitudes (0-1.9 mA). Coherence between GVS input and stimulation-induced body motion was determined and psychometric function fits were subsequently used to determine individual vestibulospinal reflex thresholds. The procedure was repeated with an additional application of imperceptible white noise GVS (nGVS). RESULTS: All patients with rBVP but none with cBVP exhibited stimulation-induced vestibulospinal reflex responses with a mean threshold level of 1.26 ± 0.08 mA. Additional nGVS resulted in improved processing of weak subthreshold vestibular stimuli (p = 0.015) and thereby effectively decreased the vestibulospinal threshold in 90% of patients with rBVP (mean reduction 17.3 ± 3.9%; p < 0.001). CONCLUSION: The present findings allow to identify the mechanism by which nGVS appears to stabilize stance and gait performance in patients with BVP. Accordingly, nGVS effectively lowers the vestibular threshold to elicit balance-related reflexes that are required to adequately regulate postural equilibrium. This intervention is only effective in the presence of a residual vestibular functionality, which, however, applies for the majority of patients with BVP. Low-intensity noise stimulation thereby provides a non-invasive treatment option to optimize residual vestibular resources in BVP.

Stochastic resonance in the human vestibular system - Noise-induced facilitation of vestibulospinal reflexes.

BACKGROUND: There is strong evidence that the presence of noise can enhance information processing in sensory systems via stochastic resonance (SR). OBJECTIVES: To examine the presence of SR in human vestibulospinal reflex function. METHODS: Healthy subjects were stimulated with 1 Hz sinusoidal GVS of varying amplitudes (0-1.9 mA). Coherence between GVS input and stimulation-induced motion responses was determined and psychometric function fits were subsequently used to determine individual vestibulospinal reflex thresholds. This procedure was repeated with additional application of imperceptible white noise GVS (nGVS). RESULTS: nGVS significantly facilitated the detectability of weak subthreshold vestibular inputs (p < 0.001) and thereby effectively lowered the vestibulospinal threshold in 90% of participants (p < 0.001, mean reduction: 17.5 ± 14.6%). CONCLUSION: This finding provides evidence for the presence of SR-dynamics in the human vestibular system and gives a functional explanation for previously observed ameliorating effects of low-intensity vestibular noise stimulation on balance control in healthy subjects and patients with vestibular hypofunction.

Rear-side resonator architecture for the passive coherent combining of high-brightness laser diodes.

We describe a new coherent beam combining architecture based on passive phase locking of emitters in an extended cavity on the rear facet and their coherent combination on the front facet. This rear-side technique provides strong optical feedback for phase locking while maintaining a high electrical-to-optical efficiency. Two high-brightness high-power tapered laser diodes are coherently combined using a Michelson-based cavity. The combining efficiency is above 82% and results in an output power of 6.7 W in a nearly diffraction-limited beam with an M(4σ)(2)≤1.2. A semi-active automatic adjustment of the current enhances the long-term stability of the combination, while the short-term stability is passively ensured by the extended cavity. This new laser configuration exhibits the simplicity of passive self-organizing architectures while providing a power conversion efficiency of 27% that is comparable to master oscillator power amplifier architectures.

Origins of cattle on Chirikof Island, Alaska, elucidated from genome-wide SNP genotypes.

Feral livestock may harbor genetic variation of commercial, scientific, historical or esthetic value. The origins and uniqueness of feral cattle on Chirikof Island, Alaska, are uncertain. The island is now part of the Alaska Maritime Wildlife Refuge and Federal wildlife managers want grazing to cease, presumably leading to demise of the cattle. Here we characterize the cattle of Chirikof Island relative to extant breeds and discern their origins. Our analyses support the inference that Yakut cattle from Russia arrived first on Chirikof Island, then ~120 years ago the first European taurine cattle were introduced to the island, and finally a large wave of Hereford cattle were introduced on average 40 years ago. In addition, this mixture of European and East-Asian cattle is unique compared with other North American breeds and we find evidence that natural selection in the relatively harsh environment of Chirikof Island has further impacted their genetic architecture. These results provide an objective basis for decisions regarding conservation of the Chirikof Island cattle.

Effective critical electric field for runaway-electron generation.

In this Letter we investigate factors that influence the effective critical electric field for runaway-electron generation in plasmas. We present numerical solutions of the kinetic equation and discuss the implications for the threshold electric field. We show that the effective electric field necessary for significant runaway-electron formation often is higher than previously calculated due to both (1) extremely strong dependence of primary generation on temperature and (2) synchrotron radiation losses. We also address the effective critical field in the context of a transition from runaway growth to decay. We find agreement with recent experiments, but show that the observation of an elevated effective critical field can mainly be attributed to changes in the momentum-space distribution of runaways, and only to a lesser extent to a de facto change in the critical field.