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Cochlear implants (CIs) restore activity in the deafened auditory system via electrical stimulation of the auditory nerve. As the spread of electric current in biological tissues is rather broad, the spectral information provided by electrical CIs is limited. Optogenetic stimulation of the auditory nerve has been suggested for artificial sound coding with improved spectral selectivity, as light can be conveniently confined in space. Yet, the foundations for optogenetic sound coding strategies remain to be established. Here, we parametrized stimulus-response-relationships of the auditory pathway in gerbils for optogenetic stimulation. Upon activation of the auditory pathway by waveguide-based optogenetic stimulation of the spiral ganglion, we recorded neuronal activity of the auditory midbrain, in which neural representations of spectral, temporal, and intensity information can be found. Screening a wide range of optical stimuli and taking the properties of optical CI emitters into account, we aimed to optimize stimulus paradigms for potent and energy-efficient activation of the auditory pathway. We report that efficient optogenetic coding builds on neural integration of millisecond stimuli built from microsecond light pulses, which optimally accommodate power-efficient laser diode operation. Moreover, we performed an activity-level-dependent comparison of optogenetic and acoustic stimulation in order to estimate the dynamic range and the maximal stimulation intensity amenable to single channel optogenetic sound encoding, and indicate that it complies well with speech comprehension in a typical conversation (65 dB). Our results provide a first framework for the development of coding strategies for future optogenetic hearing restoration.

An innovative laser based photoacoustic (PA) gas sensing concept with intrinsic miniaturization potential was developed and investigated for methane trace gas detection. An interband cascade laser (ICL) with an optical power of 8.5 mW targets a methane (CH4) absorption line feature around 3057.7 cm−1 (or 3270 nm). The ICL was focused into the sound port of a MEMS microphone, where the PA signal was generated and detected using a wavelength modulation concept (2f-WMS-PAS). The MEMS microphone was successfully implemented as an intrinsically miniaturized PA cell being gas sensing volume, acoustic resonator and sound transducer at once. Frequencies between 2 kHz and 100 kHz were investigated and used for methane detection. A sensitive and resonant methane detection at 41.8 kHz was investigated by concentration variations between 0 and 10 ppm CH4 in N2. A limit of detection (3σ-LOD) of 329 ppb was estimated. The long term stability of this sensor was investigated by the measurement of methane in ambient air. A noise equivalent concentration (NEC) of 14 ppb (parts per billion) at an average time of 10 s was estimated. This value corresponds to a normalized noise equivalent absorption (NNEA) of 2⋅10−8 W cm−1 Hz−1/2. Using the MEMS microphone directly as PA cell offers the possibility for an extremely miniaturized, highly sensitive and very cost-efficient photoacoustic trace gas sensor.

Summary: Background: Integrating behavioral intervention into motor rehabilitation is essential for improving paretic arm use in daily life. Demands on therapist time limit adoption of behavioral programs like Constraint-Induced Movement (CI) therapy, however. Self-managed motor practice could free therapist time for behavioral intervention, but there remains insufficient evidence of efficacy for a self-management approach. Methods: This completed, parallel, five-site, pragmatic, single-blind trial established the comparative effectiveness of using in-home gaming self-management as a vehicle to redirect valuable therapist time towards behavioral intervention. Community-dwelling adults with post-stroke (>6 months) mild/moderate upper extremity hemiparesis were randomized to receive one of 4 different interventions over a 3-week period: 5 h of behaviorally-focused intervention plus gaming self-management (Self-Gaming), the same with additional behaviorally-focused telerehabilitation (Tele-Gaming), 5 h of Traditional motor-focused rehabilitation, or 35 h of CI therapy. Primary outcomes assessed everyday arm use (Motor Activity Log Quality of Movement, MAL) and motor speed/function (Wolf Motor Function Test, WMFT) immediately before treatment, immediately after treatment, and 6 months later. Intent-to-treat analyses were implemented with linear mixed-effects models on data gathered from March 15, 2016 to November 21, 2019. ClinicalTrials.gov, NCT02631850. Results: Of 193 enrolled participants, 167 began treatment and were analyzed, 150 (90%) completed treatment, and 115 (69%) completed follow-up. Tele-Gaming and Self-Gaming produced clinically meaningful MAL gains that were 1·0 points (95% CI 0·8 to 1·3) and 0·8 points (95% CI 0·5 to 1·0) larger than Traditional care, respectively. Self-Gaming was less effective than CI therapy (-0·4 points, 95% CI -0·6 to -0·2), whereas Tele-Gaming was not (-0·2 points, 95% CI -0·4 to 0·1). Six-month retention of MAL gains across all groups was 57%. All had similar clinically-meaningful WMFT gains; six-month retention of WMFT gains was 92%. Interpretation: Self-managed motor-gaming with behavioral telehealth visits has outcomes similar to in-clinic CI therapy. It addresses most access barriers, requiring just one-fifth as much therapist time that is redirected towards behavioral interventions that enhance the paretic arm's involvement in daily life. Funding: PCORI, NIH

Variants in Phosphomannomutase 2 (PMM2) lead to PMM2-CDG, the most frequent congenital disorder of glycosylation (CDG). We here describe the disease course of a ten-month old patient who presented with the classical PMM2-CDG symptoms as cerebellar hypoplasia, retinitis pigmentosa, seizures, short stature, hepato- and splenomegaly, anaemia, recurrent vomiting and inverted mamillae. A severe form of tetralogy of Fallot was diagnosed and corrective surgery was performed at the age of 10 months. At the end of the cardiopulmonary bypass, a sudden oedematous reaction of the myocardium accompanied by biventricular pump failure was observed immediately after heparin antagonization with protamine sulfate. The patient died seven days after surgery, since myocardial function did not recover on ECMO support. We here describe the first patient carrying the homozygous variant g.18313A > T in the PMM2 gene (NG_009209.1) that either can lead to c.394A > T (p.I132F) or even loss of 100 bp due to exon 5 skipping (c.348_447del; p.G117Rfs*4) which is comparable to a null allele. Proliferation and doubling time of the patient's fibroblasts were affected. In addition, we show that the induction of cellular stress by elevating the cell culture temperature to 40 °C led to a decrease of the patients' PMM2 transcript as well as PMM2 protein levels and subsequently to a significant loss of residual activity. We assume that metabolic stressful processes occurring after cardiac surgery led to the drop of the patient's PMM activity below a life-sustaining niveau which paved the way for the fatal outcome.

Summary: DNA methylation plays crucial roles in chromatin structure and gene expression. Aberrant DNA methylation patterns, including global hypomethylation and regional hypermethylation, are associated with cancer and implicated in oncogenic events. How DNA methylation is regulated in developmental and cellular processes and dysregulated in cancer is poorly understood. Here, we show that PRMT6, a protein arginine methyltransferase responsible for asymmetric dimethylation of histone H3 arginine 2 (H3R2me2a), negatively regulates DNA methylation and that PRMT6 upregulation contributes to global DNA hypomethylation in cancer. Mechanistically, PRMT6 overexpression impairs chromatin association of UHRF1, an accessory factor of DNMT1, resulting in passive DNA demethylation. The effect is likely due to elevated H3R2me2a, which inhibits the interaction between UHRF1 and histone H3. Our work identifies a mechanistic link between protein arginine methylation and DNA methylation, which is disrupted in cancer. : Veland et al. find that PRMT6, an arginine methyltransferase responsible for histone H3 arginine 2 (H3R2) methylation, negatively regulates maintenance DNA methylation by impairing UHRF1 recruitment to chromatin. The authors also find that PRMT6 upregulation contributes to global DNA hypomethylation in cancer cells. Keywords: PRMT6, arginine methylation, UHRF1, DNMT1, DNA methylation, cancer

Summary: Chromatin remodeling is required for genome function and is facilitated by ATP-dependent complexes, such as nucleosome remodeling and deacetylase (NuRD). Among its core components is the chromodomain helicase DNA binding protein 3 (CHD3) whose functional significance is not well established. Here, we show that CHD3 co-localizes with the other NuRD subunits, including HDAC1, near the H3K9ac-enriched promoters of the NuRD target genes. The tandem PHD fingers of CHD3 bind histone H3 tails and posttranslational modifications that increase hydrophobicity of H3K9—methylation or acetylation (H3K9me3 or H3K9ac)—enhance this interaction. Binding of CHD3 PHDs promotes H3K9Cme3-nucleosome unwrapping in vitro and perturbs the pericentric heterochromatin structure in vivo. Methylation or acetylation of H3K9 uniquely alleviates the intra-nucleosomal interaction of histone H3 tails, increasing H3K9 accessibility. Collectively, our data suggest that the targeting of covalently modified H3K9 by CHD3 might be essential in diverse functions of NuRD. : Tencer et al. find that CHD3 co-localizes with the other subunits of the NuRD complex and H3K9ac at NuRD target genes. The authors further demonstrate that the PHD fingers of CHD3 associate with histone H3 tails, and this association is augmented through methylation or acetylation of H3K9. Keywords: CHD3, NuRD, PHD finger, H3K9me3, H3K9ac, histone, chromatin

Set2-mediated histone methylation at H3K36 regulates diverse activities, including DNA repair, mRNA splicing, and suppression of inappropriate (cryptic) transcription. Although failure of Set2 to suppress cryptic transcription has been linked to decreased lifespan, the extent to which cryptic transcription influences other cellular functions is poorly understood. Here, we uncover a role for H3K36 methylation in the regulation of the nutrient stress response pathway. We found that the transcriptional response to nutrient stress was dysregulated in SET2-deleted (set2Δ) cells and was correlated with genome-wide bi-directional cryptic transcription that originated from within gene bodies. Antisense transcripts arising from these cryptic events extended into the promoters of the genes from which they arose and were associated with decreased sense transcription under nutrient stress conditions. These results suggest that Set2-enforced transcriptional fidelity is critical to the proper regulation of inducible and highly regulated transcription programs.

MORC3 is linked to inflammatory myopathies and cancer; however, the precise role of MORC3 in normal cell physiology and disease remains poorly understood. Here, we present detailed genetic, biochemical, and structural analyses of MORC3. We demonstrate that MORC3 is significantly upregulated in Down syndrome and that genetic abnormalities in MORC3 are associated with cancer. The CW domain of MORC3 binds to the methylated histone H3K4 tail, and this interaction is essential for recruitment of MORC3 to chromatin and accumulation in nuclear bodies. We show that MORC3 possesses intrinsic ATPase activity that requires DNA, but it is negatively regulated by the CW domain, which interacts with the ATPase domain. Natively linked CW impedes binding of the ATPase domain to DNA, resulting in a decrease in the DNA-stimulated enzymatic activity. Collectively, our studies provide a molecular framework detailing MORC3 functions and suggest that its modulation may contribute to human disease.

Summary: Spt6 is a histone chaperone that associates with RNA polymerase II and deposits nucleosomes in the wake of transcription. Although Spt6 has an essential function in nucleosome deposition, it is not known whether this function is influenced by post-translational modification. Here, we report that casein kinase II (CKII) phosphorylation of Spt6 is required for nucleosome occupancy at the 5′ ends of genes to prevent aberrant antisense transcription and enforce transcriptional directionality. Mechanistically, we show that CKII phosphorylation of Spt6 promotes the interaction of Spt6 with Spn1, a binding partner required for chromatin reassembly and full recruitment of Spt6 to genes. Our study defines a function for CKII phosphorylation in transcription and highlights the importance of post-translational modification in histone chaperone function. : Dronamraju et al. show that the N terminus of Spt6 is phosphorylated by casein kinase II, which is required for proper Spt6-Spn1 interaction. CKII phosphorylation of Spt6 is pivotal to maintain nucleosome occupancy at the 5′ ends of genes, suppression of antisense transcription from the 5′ ends, and resistance to genotoxic agents. Keywords: Spt6, CKII, Spn1, nucleosome occupancy, SILAC

The protein stability and chromatin functions of UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) are regulated in a cell-cycle-dependent manner. We report a structural characterization of the complex between UHRF1 and the deubiquitinase USP7. The first two UBL domains of USP7 bind to the polybasic region (PBR) of UHRF1, and this interaction is required for the USP7-mediated deubiquitination of UHRF1. Importantly, we find that the USP7-binding site of the UHRF1 PBR overlaps with the region engaging in an intramolecular interaction with the N-terminal tandem Tudor domain (TTD). We show that the USP7-UHRF1 interaction perturbs the TTD-PBR interaction of UHRF1, thereby shifting the conformation of UHRF1 from a TTD-“occluded” state to a state open for multivalent histone binding. Consistently, introduction of a USP7-interaction-defective mutation to UHRF1 significantly reduces its chromatin association. Together, these results link USP7 interaction to the dynamic deubiquitination and chromatin association of UHRF1.

How epigenetic information is transmitted from generation to generation remains largely unknown. Deletion of the C. elegans histone H3 lysine 4 dimethyl (H3K4me2) demethylase spr-5 leads to inherited accumulation of the euchromatic H3K4me2 mark and progressive decline in fertility. Here, we identified multiple chromatin-modifying factors, including H3K4me1/me2 and H3K9me3 methyltransferases, an H3K9me3 demethylase, and an H3K9me reader, which either suppress or accelerate the progressive transgenerational phenotypes of spr-5 mutant worms. Our findings uncover a network of chromatin regulators that control the transgenerational flow of epigenetic information and suggest that the balance between euchromatic H3K4 and heterochromatic H3K9 methylation regulates transgenerational effects on fertility.

Condensin is a central regulator of mitotic genome structure with mutants showing poorly condensed chromosomes and profound segregation defects. Here, we identify NCT, a complex comprising the Nrc1 BET-family tandem bromodomain protein (SPAC631.02), casein kinase II (CKII), and several TAFs, as a regulator of condensin function. We show that NCT and condensin bind similar genomic regions but only briefly colocalize during the periods of chromosome condensation and decondensation. This pattern of NCT binding at the core centromere, the region of maximal condensin enrichment, tracks the abundance of acetylated histone H4, as regulated by the Hat1-Mis16 acetyltransferase complex and recognized by the first Nrc1 bromodomain. Strikingly, mutants in NCT or Hat1-Mis16 restore the formation of segregation-competent chromosomes in cells containing defective condensin. These results are consistent with a model where NCT targets CKII to chromatin in a cell-cycle-directed manner in order to modulate the activity of condensin during chromosome condensation and decondensation.

The histone lysine demethylase KDM5B regulates gene transcription and cell differentiation and is implicated in carcinogenesis. It contains multiple conserved chromatin-associated domains, including three PHD fingers of unknown function. Here, we show that the first and third, but not the second, PHD fingers of KDM5B possess histone binding activities. The PHD1 finger is highly specific for unmodified histone H3 (H3K4me0), whereas the PHD3 finger shows preference for the trimethylated histone mark H3K4me3. RNA-seq analysis indicates that KDM5B functions as a transcriptional repressor for genes involved in inflammatory responses, cell proliferation, adhesion, and migration. Biochemical analysis reveals that KDM5B associates with components of the nucleosome remodeling and deacetylase (NuRD) complex and may cooperate with the histone deacetylase 1 (HDAC1) in gene repression. KDM5B is downregulated in triple-negative breast cancer relative to estrogen-receptor-positive breast cancer. Overexpression of KDM5B in the MDA-MB 231 breast cancer cells suppresses cell migration and invasion, and the PHD1-H3K4me0 interaction is essential for inhibiting migration. These findings highlight tumor-suppressive functions of KDM5B in triple-negative breast cancer cells and suggest a multivalent mechanism for KDM5B-mediated transcriptional regulation.

Death Inducer Obliterator 3 (Dido3) is implicated in the maintenance of stem cell genomic stability and tumorigenesis. Here, we show that Dido3 regulates the expression of stemness genes in embryonic stem cells through its plant homeodomain (PHD) finger. Binding of Dido3 PHD to histone H3K4me3 is disrupted by threonine phosphorylation that triggers Dido3 translocation from chromatin to the mitotic spindle. The crystal structure of Dido3 PHD in complex with H3K4me3 reveals an atypical aromatic-cage-like binding site that contains a histidine residue. Biochemical, structural, and mutational analyses of the binding mechanism identified the determinants of specificity and affinity and explained the inability of homologous PHF3 to bind H3K4me3. Together, our findings reveal a link between the transcriptional control in embryonic development and regulation of cell division.

Competing Interests: Declaration of competing interest None.

Background: Whole-Body CT (WBCT) is frequently used in emergency situations for promptly diagnosing paediatric polytrauma patients, given the challenges associated with obtaining precise details about the mechanism and progression of trauma. However, WBCT does not lead to reduced mortality in paediatric patients, but is associated with high radiation exposure. We therefore wanted to develop a screening tool for CT demand-driven emergency room (ER)-trauma diagnostic to reduce radiation exposure in paediatric patients., Methods: A retrospective study in a Level I trauma centre in Germany was performed. Data from 344 paediatric emergency patients with critical mechanism of injury who were pre-announced by the ambulance for the trauma room were collected. Patients' symptoms, clinical examination, extended Focused Assessment with Sonography for Trauma (eFAST), routinely, laboratory tests and blood gas and - when obtained - WBCT images were analysed. To identify potential predictors of severe injuries (ISS > 23), 300 of the 344 cases with complete data were subjected to regression analyses model., Results: Multiple regression analysis identified cGCS, base excess (BE), medically abnormal results from eFAST screening, initial unconsciousness, and injuries involving three or more body regions as significant predictors for a screening tool for decision-making to perform WBCT or selective CT. The developed Paediatric polytrauma CT-Indication (PePCI)-Score was divided into three risk categories and achieved a sensitivity of 87 % and a specificity of 71 % when comparing the low and medium risk groups with the high risk group. Comparing only the low-risk group with the high-risk group for the decision to perform WBCT, 32/35 (91 %) of patients with an ISS >23 were correctly identified, as were 124/137 (91 %) with lower ISS scores., Conclusion: With the newly developed PePCI-Score, the frequency of WBCT in a paediatric emergency patients collective can be significantly reduced according to our data. After prospective validation, the initial assessment of paediatric trauma patients in the future could be made not only by the mechanism of injury, but also by the new PePCI-Score, deriving on clinical findings after thorough clinical assessment and the discretion of the trauma team., Competing Interests: Declaration of competing interest All authors declare that they have no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Pelvic fractures are serious and oftentimes require immediate medical attention. Pelvic binders have become a critical tool in the management of pelvic injuries, especially in the prehospital setting. Proper application of the pelvic binder is essential to achieve the desired result. This study evaluates the effectiveness of prehospitally applied pelvic binders in improving outcomes for patients with pelvic fractures., Methods: This retrospective cohort study analyzed 66 patients with unstable pelvic ring fracture classified as AO61B or 61C, who were treated at a Level I hospital in the emergency room between January 2014 and December 2018. The ideal position for a pelvic binder was determined, and patients were divided into three sub-groups based on whether they received a pelvic binder in the ideal position, outside the optimal range, or not at all. The primary outcome measure was the survival rate of the patients., Results: 66 trauma patients with unstable pelvic fractures were enrolled, with a mean age of 53.8 years, who presented to our ER between 2014 and 2018. The mean ISS score was 21.9, with 60.3 % of patients having a moderate to severe injury (ISS > 16 points). Pelvic binder usage did not differ significantly between patients with an ISS < or ≥ 16 points. A total of 9 patients (13.6 %) died during hospitalization, with a mean survival time of 8.1 days. The survival rate did not differ significantly between patients with or without a pelvic binder, or between those with an ideally placed pelvic binder versus those with a binder outside the ideal range. The ISS score, heart rate, blood pressure at admission, and hemoglobin level were significantly different between the group of patients who died and those who survived, indicating their importance in predicting outcomes., Conclusion: Our study found that prehospital pelvic binders did not significantly impact patient outcomes for unstable pelvic fractures, with injury severity score (ISS) being the strongest predictor of survival. Assessing injury severity and managing blood loss remain crucial for these patients. While pelvic binders may not impact survival significantly, they still play a role in stabilizing pelvic fractures and managing blood loss., Competing Interests: Declaration of competing interest The authors report there are no competing interests to declare., (Copyright © 2024. Published by Elsevier Ltd.)

Background: Distal femur fractures occur with an incidence of 4.5/100,000 and show a prevalence of 0.4%. Causes include low-impact trauma in older patients and high-impact trauma in younger patients without pre-existing medical conditions. The aim of this study was to perform a comprehensive evaluation of trauma mechanisms, trauma-promoting factors, comorbidities, medication history and type of surgical care to provide an overview of the causes of injury and the most appropriate therapeutic approach., Methods: In this multicenter cohort study a retrospective analysis of 229 patients who sustained a distal femur fracture between January 2011 and December 2020 was performed. Individual fracture patterns, fracture predisposing factors, concomitant disease profiles, medication history, treatment strategy and associated complications were analyzed., Results: 229 patients were included in the retrospective analysis. A total of 113-type 33 A, 50-type 33 B and 66-type 33 C fractures were diagnosed, of whom 92% received a lateral locking plate osteosynthesis. There was a complication in 14.4% of all cases, of which 6.1% were attributable to infection. Significant risk factors for developing a complication were an increased BMI (29.9 ± 8.5 kg/m2; p = 0.04), fracture displacement of over half a shaft width (p < 0.001) and AOC fractures (p < 0,016), specifically C2 fractures (p < 0,008)., Conclusion: In this multicenter retrospective cohort study, lateral locking plate osteosynthesis was the method of choice and was selected in over 90% of cases, regardless of the fracture classification and risk factors. A complication rate of 14.4% emphasizes the necessary analysis of patient- and care-specific risk factors and a resulting adjustment of the therapy strategy. An increased BMI (29.9 ± 8.5 kg/m 2 ; p = 0.04), fracture displacement of over half a shaft width (p < 0.001) and AOC fractures (p < 0,016), specifically C2 fractures (p < 0,008) increase the risk of developing a complication and should prompt an early switch to a treatment strategy that provides more stability., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)