Translation and validation of the Tinnitus Functional Index (TFI) into Kannada: a tool for clinical and research use in the Indian population.

PURPOSE: The Tinnitus Functional Index (TFI) is a widely recognized measure for evaluating tinnitus and is frequently used in both therapeutic and research contexts. Unfortunately, TFI is currently not available in any Indian languages. In a multilingual country like India, cross-cultural adaptation, translation, and validation of such scales in regional languages are critical to improving their use for clinical and research purposes. Therefore, this study focused on translating and validating the TFI in Kannada for use among the Indian population. MATERIALS AND METHODS: The original version of TFI was translated with the help of audiologists and linguistic experts who were proficient in Kannada. The translated version was content validation by five audiologists and a cognitive debriefing by native speakers to check the familiarity of words. The final version (TFI-K) was then administered to 181 participants with tinnitus. Along with the TFI, other scales like Tinnitus Handicap Inventory (THI) were also obtained to check the convergent validity. The obtained data was then subjected to various statistical analyses like internal consistency, convergent and discriminant validity, and factor analysis. RESULTS: The TFI-K was found to have an excellent internal consistency (Cronbach's α = 0.974) and good convergent validity (p < 0.001; r = 0.778) with THI-K. A principal component analysis with varimax rotation showed communalities ranging from 0.64 to 0.91. Scree plots with the TFI-K component showed a sharp decline after the first factor and approximately four factors above the eigenvalue of 1. The factor analysis results suggest that the TFI-K has a structurally intact 8-factor loading, with a few exceptions that are discussed in detail. CONCLUSION: The TFI-K has demonstrated remarkable dependability and satisfactory integrity, making it a valuable tool for assessment and treatment planning in clinical and research settings.

Tinnitus is known to impinge multiple domains.Assessing multiple domains provides a comprehensive understanding of the impact of tinnitus.Tinnitus Functional Index (TFI) has been cross-culturally translated into Kannada.Tinnitus Functional Index in Kannada (TFI-K) is reliable and valid and can be used clinically and in research.

Outcomes of co-designed communities of practice that support members to address public health issues.

Communities of practice are commonly used to support members in responding to public health issues. This study evaluated the outcomes of five co-designed communities of practice to determine if members' expectations were met, if knowledge sharing between members extended to knowledge translation, and if that supported members in addressing public health issues. Data were collected through an initial needs assessment, observations were made during community of practice sessions over 1 year, and qualitative interviews were conducted at the end of that year. The findings provided evidence that members' expectations were met, knowledge sharing took place within the communities of practice, and personal benefits gained supported members in advancing knowledge sharing with other members to knowledge translation outside their community of practice. Results demonstrate three outcomes of knowledge translation for members: disseminating knowledge to others, applying knowledge to make small-scale changes in practice and leveraging the knowledge to expand its reach beyond members' organizations. While the scale and speed of expanding outcomes were below initial expectations as indicated in the initial needs assessments, members remained optimistic about achieving larger-scale impacts in the future. This study showed that communities of practice achieve gradual progress rather than quick wins. Co-design supports the facilitators in meeting members' needs, which can positively contribute to members sharing knowledge and translating that knowledge to support their practice to address public health issues.

Impact of tRNA-induced proline-to-serine mistranslation on the transcriptome of Drosophila melanogaster.

Mistranslation is the misincorporation of an amino acid into a polypeptide. Mistranslation has diverse effects on multicellular eukaryotes and is implicated in several human diseases. In Drosophila melanogaster, a serine transfer RNA (tRNA) that misincorporates serine at proline codons (P→S) affects male and female flies differently. The mechanisms behind this discrepancy are currently unknown. Here, we compare the transcriptional response of male and female flies to P→S mistranslation to identify genes and cellular processes that underlie sex-specific differences. Both males and females downregulate genes associated with various metabolic processes in response to P→S mistranslation. Males downregulate genes associated with extracellular matrix organization and response to negative stimuli such as wounding, whereas females downregulate aerobic respiration and ATP synthesis genes. Both sexes upregulate genes associated with gametogenesis, but females also upregulate cell cycle and DNA repair genes. These observed differences in the transcriptional response of male and female flies to P→S mistranslation have important implications for the sex-specific impact of mistranslation on disease and tRNA therapeutics.

Interplay between mistranslation and oxidative stress in Escherichia coli.

Mistakes in translation are mostly associated with toxic effects in the cell due to the production of functionally aberrant and misfolded proteins. However, under certain circumstances mistranslation can have beneficial effects and enable cells to preadapt to other stress conditions. Mistranslation may be caused by mistakes made by aminoacyl-tRNA synthetases, essential enzymes that link amino acids to cognate tRNAs. There is an Escherichia coli strain expressing isoleucyl-tRNA synthetase mutant variant with inactivated editing domain which produces mistranslated proteomes where valine (Val) and norvaline (Nva) are misincorporated into proteins instead of isoleucine. We compared this strain with the wild-type to determine the effects of such mistranslation on bacterial growth in oxidative stress conditions. When the cells were pre-incubated with 0.75 mmol/L Nva or 1.5 mmol/L Val or Nva and exposed to hydrogen peroxide, no beneficial effect of mistranslation was observed. However, when the editing-deficient strain was cultivated in medium supplemented with 0.75 mmol/L Val up to the early or mid-exponential phase of growth and then exposed to oxidative stress, it slightly outgrew the wild-type grown in the same conditions. Our results therefore show a modest adaptive effect of isoleucine mistranslation on bacterial growth in oxidative stress, but only in specific conditions. This points to a delicate balance between deleterious and beneficial effects of mistranslation.

Understanding molecular characteristics of extracellular vesicles derived from different types of mesenchymal stem cells for therapeutic translation.

Mesenchymal stem cells (MSCs) have been studied for decades as candidates for cellular therapy, and their secretome, including secreted extracellular vesicles (EVs), has been identified to contribute significantly to regenerative and reparative functions. Emerging evidence has suggested that MSC-EVs alone, could be used as therapeutics that emulate the biological function of MSCs. However, just as with MSCs, MSC-EVs have been shown to vary in composition, depending on the tissue source of the MSCs as well as the protocols employed in culturing the MSCs and obtaining the EVs. Therefore, the importance of careful choice of cell sources and culture environments is receiving increasing attention. Many factors contribute to the therapeutic potential of MSC-EVs, including the source tissue, isolation technique, and culturing conditions. This review illustrates the molecular landscape of EVs derived from different types of MSC cells along with culture strategies. A thorough analysis of publicly available omic datasets was performed to advance the precision understanding of MSC-EVs with unique tissue source-dependent molecular characteristics. The tissue-specific protein and miRNA-driven Reactome ontology analysis was used to reveal distinct patterns of top Reactome ontology pathways across adipose, bone marrow, and umbilical MSC-EVs. Moreover, a meta-analysis assisted by an AI technique was used to analyze the published literature, providing insights into the therapeutic translation of MSC-EVs based on their source tissues.

Widespread changes to the translational landscape in a maize microRNA biogenesis mutant.

MicroRNAs are short, non-coding RNAs that repress gene expression in both plants and animals and have diverse functions related to growth, development, and stress responses. The ribonuclease, DICER-LIKE1 (DCL1) is required for two steps in plant miRNA biogenesis: cleavage of the primary miRNAs (pri-miRNAs) to release a hairpin structure, called the precursor miRNA (pre-miRNA) and cleavage of the pre-miRNA to generate the miRNA/miRNA* duplex. The mature miRNA guides the RNA-induced silencing complex to target RNAs with complementary sequences, resulting in translational repression and/or RNA cleavage of target mRNAs. However, the relative contribution of translational repression versus mRNA degradation by miRNAs remains unknown at the genome-level in crops, especially in maize. The maize fuzzy tassel (fzt) mutant contains a hypomorphic mutation in DCL1 resulting in broad developmental defects. While most miRNAs are reduced in fzt, the levels of miRNA-targeted mRNAs are not dramatically increased, suggesting that translational regulation by miRNAs may be common. To gain insight into the repression mechanism of plant miRNAs, we combined ribosome profiling and RNA-sequencing to globally survey miRNA activities in maize. Our data indicate that translational repression contributes significantly to regulation of most miRNA targets and that approximately one-third of miRNA targets are regulated primarily at the translational level. Surprisingly, ribosomes appear altered in fzt mutants suggesting that DCL1 may also have a role in ribosome biogenesis. Thus, DICER-LIKE1 shapes the translational landscape in plants through both miRNA-dependent and miRNA-independent mechanisms.

Genome-wide quantification of RNA flow across subcellular compartments reveals determinants of the mammalian transcript life cycle.

Dissecting the regulatory mechanisms controlling mammalian transcripts from production to degradation requires quantitative measurements of mRNA flow across the cell. We developed subcellular TimeLapse-seq to measure the rates at which RNAs are released from chromatin, exported from the nucleus, loaded onto polysomes, and degraded within the nucleus and cytoplasm in human and mouse cells. These rates varied substantially, yet transcripts from genes with related functions or targeted by the same transcription factors and RNA-binding proteins flowed across subcellular compartments with similar kinetics. Verifying these associations uncovered a link between DDX3X and nuclear export. For hundreds of RNA metabolism genes, most transcripts with retained introns were degraded by the nuclear exosome, while the remaining molecules were exported with stable cytoplasmic lifespans. Transcripts residing on chromatin for longer had extended poly(A) tails, whereas the reverse was observed for cytoplasmic mRNAs. Finally, machine learning identified molecular features that predicted the diverse life cycles of mRNAs.

Adding first-line PD-1 inhibition to anti-VEGF and XELOX in pMMR metastatic colorectal cancer: Steppingstones, stumbling blocks, and next phase.

In the randomized, double-blind, multicenter study by Wang et al.,1 the addition of serplulimab (a PD-1 antibody) to anti-VEGF (HLX04; a bevacizumab biosimilar) together with chemotherapy (XELOX) was deemed to be tolerable and safe and may improve progression-free survival. However, even if adverse events were comparable, oncological endpoints including survival need to be confirmed in the next phase 3 study.

Preclinical study and phase II trial of adapting low-dose radiotherapy to immunotherapy in small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) provide modest but unsatisfactory benefits for extensive-stage small cell lung cancer (ES-SCLC). Developing strategies for treating ES-SCLC is critical. METHODS: We preliminarily explored the outcomes of salvage low-dose radiotherapy (LDRT) plus ICI on refractory SCLC patients. Next, we evaluated the combinational efficacy in murine SCLC. The tumor immune microenvironment (TIME) was analyzed for mechanistic study. Subsequently, we conducted a multicenter, prospective phase II trial that administered concurrent thoracic LDRT plus chemoimmunotherapy to treatment-naive ES-SCLC patients (MATCH trial, NCT04622228). The primary endpoint was confirmed objective response rate (ORR), and the key secondary endpoints included progression-free survival (PFS) and safety. FINDINGS: Fifteen refractory SCLC patients treated with LDRT plus ICI were retrospectively reviewed. The ORR was 73.3% (95% confidence interval [CI], 44.9-92.2). We identified a specific dose of LDRT (15 Gy/5 fractions) that exhibited growth retardation and improved survival in murine SCLC when combined with ICIs. This combination recruited a special T cell population, TCF1+ PD-1+ CD8+ stem-like T cells, from tumor-draining lymph nodes into the TIME. The MATCH trial showed a confirmed ORR of 87.5% (95% CI, 75.9-94.8). The median PFS was 6.9 months (95% CI, 5.4-9.3). CONCLUSIONS: These findings verified that LDRT plus chemoimmunotherapy was safe, feasible, and effective for ES-SCLC, warranting further investigation. FUNDING: This research was funded by West China Hospital (no. ZYJC21003), the National Natural Science Foundation of China (no. 82073336), and the MATCH trial was fully funded by Roche (China) Holding Ltd. (RCHL) and Shanghai Roche Pharmaceuticals Ltd. (SRPL).

Adaptation and Validation of the Persian Version of the Voice Handicap Index-10 (VHI-10).

OBJECTIVES: Voice disorders can profoundly impact health, quality of life, job performance, and social interactions. Traditional evaluations have expanded to include quality-of-life assessments, emphasizing self-reported outcomes. The Voice Handicap Index (VHI) stands out among relevant questionnaires, with the VHI-10 being a concise derivative. This study was conducted to translate and validate the Voice Handicap Index-10 (VHI-10) questionnaire for Persian speakers, enhancing clinical assessments of voice disorders and quality of life. METHODS: This cross-sectional study, conducted in Iran, involved (1) translating the VHI-10 into Persian, (2) confirming face and content validity using Content Validity Ratio (CVR), and Content Validity Index (CVI), and (3) evaluating its reliability through a survey. A panel of experts confirmed the validity, and reliability of the study, which was assessed using Cronbach's alpha, Spearman-Brown, and Guttman coefficients. The survey involved 225 participants, including 150 healthy people and 75 patients with voice disorders, who were selected using a convenience sampling method. RESULTS: All question items demonstrated a CVI greater than 0.79 and a CVR between 0.62 and 1. Reliability analysis yielded high Cronbach's alpha values for functional, physical, and emotional domains (0.909) and total (0.961). The mean overall scores of VHI-10 for healthy and disordered groups were 18.78 and 0.74, respectively. The VHI-10 effectively discriminated between healthy and disordered groups in all domains, with an accuracy of 97.33%. The determined cut-off point was 4.5, with a strong area under the Receiver Operating Characteristic (ROC) curve (0.989). CONCLUSION: This study successfully adapted and validated the Persian version of the VHI-10. The questionnaire demonstrated high reliability and validity, distinguishing between individuals with and without voice disorders. This Persian version is now a valuable tool for speech and language pathologists conducting clinical voice evaluations in Iran and also it could be applied in studies to determine the effects of voice problems on participant's quality of life.

ArzEn-MultiGenre: An aligned parallel dataset of Egyptian Arabic song lyrics, novels, and subtitles, with English translations.

ArzEn-MultiGenre is a parallel dataset of Egyptian Arabic song lyrics, novels, and TV show subtitles that are manually translated and aligned with their English counterparts. The dataset contains 25,557 segment pairs that can be used to benchmark new machine translation models, fine-tune large language models in few-shot settings, and adapt commercial machine translation applications such as Google Translate. Additionally, the dataset is a valuable resource for research in various disciplines, including translation studies, cross-linguistic analysis, and lexical semantics. The dataset can also serve pedagogical purposes by training translation students and aid professional translators as a translation memory. The contributions are twofold: first, the dataset features textual genres not found in existing parallel Egyptian Arabic and English datasets, and second, it is a gold-standard dataset that has been translated and aligned by human experts.

Cross-Cultural Adaptation and Psychometric Validation of the Quality of Life Index Among Hausa-Speaking People with Spinal Cord Injury in Northwest Nigeria.

Background: Quality of life (QoL) is an important outcome that is used to measure the success of healthcare interventions. Valid and reliable instruments are required to assess QoL. Hence, we conducted this study to adapt and validate the QoL Index (QLI) among Hausa-speaking people with spinal cord injury (SCI) in northwest Nigeria. Method: Using the International Society for Pharmacoeconomic and Outcome Research principles of good practice and the consensus-based standards for the selection of health measurement instruments guidelines, the QLI-SCI version was translated into Hausa language and tested for content validity, internal consistency, and test-retest reliability among people with SCI in northwest Nigeria. Result: The Hausa QLI (HQLI) demonstrated good content validity (CVI = 92.18%), internal consistency (Cronbach's alpha = 0.855), and test-retest reliability (ICC =0.949 [95% CI, 0.916-0.969]). Conclusion: The HQLI can be deployed to assess QoL among Hausa-speaking people with SCI, thus promoting robust measurement of QoL in an SCI population.

Genetics of rheumatoid arthritis.

In the past four decades, a plethora of genetic association studies have been carried out in cohorts of patients with rheumatoid arthritis. These studies have highlighted key aspects of disease pathogenesis and suggested causal mechanisms. In this review, we discuss major advances in our understanding of the genetic architecture of rheumatoid arthritis susceptibility, severity and treatment response and explain how genetics supports current models of disease pathogenesis and outcome. We outline future research directions, like Mendelian randomisation, and present a number of potential avenues for clinical translation, including risk and outcome prediction, patient stratification into treatment response groups and pharmacological applications.

Translational impacts of enzymes that modify ribosomal RNA around the peptidyl transferase centre.

Large ribosomal RNAs (rRNAs) are modified heavily post-transcriptionally in functionally important regions but, paradoxically, individual knockouts (KOs) of the modification enzymes have minimal impact on Escherichia coli growth. Furthermore, we recently constructed a strain with combined KOs of five modification enzymes (RluC, RlmKL, RlmN, RlmM and RluE) of the 'critical region' of the peptidyl transferase centre (PTC) in 23S rRNA that exhibited only a minor growth defect at 37°C (although major at 20°C). However, our combined KO of modification enzymes RluC and RlmE (not RluE) resulted in conditional lethality (at 20°C). Although the growth rates for both multiple-KO strains were characterized, the molecular explanations for such deficits remain unclear. Here, we pinpoint biochemical defects in these strains. In vitro fast kinetics at 20°C and 37°C with ribosomes purified from both strains revealed, counterintuitively, the slowing of translocation, not peptide bond formation or peptidyl release. Elongation rates of protein synthesis in vivo, as judged by the kinetics of ß-galactosidase induction, were also slowed. For the five-KO strain, the biggest deficit at 37°C was in 70S ribosome assembly, as judged by a dominant 50S peak in ribosome sucrose gradient profiles at 5 mM Mg2+. Reconstitution of this 50S subunit from purified five-KO rRNA and ribosomal proteins supported a direct role in ribosome biogenesis of the PTC region modifications per se, rather than of the modification enzymes. These results clarify the importance and roles of the enigmatic rRNA modifications.

Optimization of extended Kozak elements enhances recombinant proteins expression in CHO cells.

In eukaryotes, the localization of small ribosomal subunits to mRNA transcripts requires the translation of Kozak elements at the starting site. The sequence of Kozak elements affects the translation efficiency of protein synthesis. However, whether the upstream nucleotide of Kozak sequence affects the expression of recombinant proteins in Chinese hamster ovary (CHO) cells remains unclear. In order to find the optimal sequence to enhance recombinant proteins expression in CHO cells, -10 to +4 sequences around ATG in 100 CHO genes were compared, and the extended Kozak elements with different translation intensities were constructed. Using the classic Kozak element as control, the effects of optimized extended Kozak elements on the secreted alkaline phosphatase (SEAP) and human serum albumin (HSA) gene were studied. The results showed that the optimized extended Kozak sequence can enhance the stable expression level of recombinant proteins in CHO cells. Furthermore, it was found that the increased expression level of the recombinant protein was not related with higher transcription level. In summary, optimizing extended Kozak elements can enhance the expression of recombinant proteins in CHO cells, which contributes to the construction of an efficient expression system for CHO cells.

A Conceptual Framework from the Philippines to Analyse Organisational Capacities for Health Policy and Systems Research.

Organisations that perform Health Policy and Systems Research (HPSR) need robust capacities, but it remains unclear how these organisations should look like in practice. We sought to define 'HPSRIs' (pronounced as 'hip-srees', i.e., 'Health Policy and Systems Research Institutions') as organisational models and developed a conceptual framework for assessing their capacities based on a set of attributes. We implemented a multi-method study in the Philippines that comprised: a qualitative analysis of perspectives from 33 stakeholders in the HPSR ecosystem on the functions, strengths, and challenges of HPSRIs; a workshop with 17 multi-sectoral representatives who collectively developed a conceptual framework for assessing organisational capacities for HPSRIs based on organisational attributes; and a survey instrument development process that determined indicators for assessing these attributes. We defined HPSRIs to be formally constituted organisations (or institutions) with the minimum essential function of research. Beyond the research function, our framework outlined eight organisational attributes of well-performing HPSRIs that were grouped into four domains, namely: research expertise: (1) excellent research, (2) capacity building driven; leadership and management: (3) efficient administration, (4) financially sustainable; policy translation: (5) policy orientation, (6) effective communication; and networking: (7) participatory approach, (8) convening influence. We developed a self-assessment instrument around these attributes that HPSRIs could use to inform their respective organisational development and collectively discuss their shared challenges. In addition to developing the framework, the workshop also analysed the positionality of HPSRIs and their interactions with other institutional actors in the HPSR ecosystem and recommend the importance of enhancing these interactions and assigning responsibility to a national/regional authority that will foster the community of HPSRIs. When tailored to their context, HPSRIs that function at the nexus of research, management, policy, and networks help achieve the main purpose of HPSR, which is to 'achieve collective health goals and contribute to policy outcomes.'

SigmaR1 shapes rough endoplasmic reticulum membrane sheets.

Rough endoplasmic reticulum (ER) sheets are a fundamental domain of the ER and the gateway into the secretory pathway. Although reticulon proteins stabilize high-curvature ER tubules, it is unclear whether other proteins scaffold the flat membranes of rough ER sheets. Through a proteomics screen using ER sheet-localized RNA-binding proteins as bait, we identify the sigma-1 receptor (SigmaR1) as an ER sheet-shaping factor. High-resolution live cell imaging and electron tomography assign SigmaR1 as an ER sheet-localized factor whose levels determine the amount of rough ER sheets in cells. Structure-guided mutagenesis and in vitro reconstitution on giant unilamellar vesicles further support a mechanism whereby SigmaR1 oligomers use their extended arrays of amphipathic helices to bind and flatten the lumenal leaflet of ER membranes to oppose membrane curvature and stabilize rough ER sheets.

MGST3 regulates BACE1 protein translation and amyloidogenesis by controlling the RGS4-mediated AKT signaling pathway.

Microsomal glutathione transferase 3 (MGST3) regulates eicosanoid and glutathione metabolism. These processes are associated with oxidative stress and apoptosis, suggesting that MGST3 might play a role in the pathophysiology of Alzheimer's disease (AD). Here, we report that knockdown (KD) of MGST3 in cell lines reduced the protein level of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and the resulting amyloidogenesis. Interestingly, MGST3 KD did not alter intracellular ROS level but selectively reduced the expression of apoptosis indicators which could be associated with the receptor of cysteinyl leukotrienes (cysLTs), the downstream metabolites of MGST3 in arachidonic acid pathway. We then showed that the effect of MGST3 on BACE1 was independent of cysLTs but involved a translational mechanism. Further RNA-seq analysis identified that regulator of G-protein signaling 4 (RGS4) was a target gene of MGST3. Silencing of RGS4 inhibited BACE1 translation and prevented MGST3 KD-mediated reduction of BACE1. The potential mechanism was related to AKT activity, as the protein level of phosphorylated AKT (p-AKT) was significantly reduced by silencing of MGST3 and RGS4, and the AKT inhibitor abolished the effect of MGST3/RGS4 on p-AKT and BACE1. Together, MGST3 regulated amyloidogenesis by controlling BACE1 protein expression, which was mediated by RGS4 and downstream AKT signaling pathway.

Characterization of ribosome stalling and no-go mRNA decay stimulated by the Fragile X protein, FMRP.

Loss of functional fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS) and is the leading monogenic cause of autism spectrum disorders and intellectual disability. FMRP is most notably a translational repressor and is thought to inhibit translation elongation by stalling ribosomes as FMRP-bound polyribosomes from brain tissue are resistant to puromycin and nuclease treatment. Here, we present data showing that the C-terminal non-canonical RNA-binding domain of FMRP is essential and sufficient to induce puromycin-resistant mRNA•ribosome complexes. Given that stalled ribosomes can stimulate ribosome collisions and no-go mRNA decay (NGD), we tested the ability of FMRP to drive NGD of its target transcripts in neuroblastoma cells. Indeed, FMRP and ribosomal proteins, but not poly(A)-binding protein, were enriched in isolated nuclease-resistant disomes compared to controls. Using siRNA knockdown and RNA-seq, we identified 16 putative FMRP-mediated NGD substrates, many of which encode proteins involved in neuronal development and function. Increased mRNA stability of 4 putative substrates was also observed when either FMRP was depleted or NGD was prevented via RNAi. Taken together, these data support that FMRP stalls ribosomes but only stimulates NGD of a small select set of transcripts, revealing a minor role of FMRP that would be misregulated in FXS.