The p21CIP1-CDK4-DREAM axis is a master regulator of genotoxic stress-induced cellular senescence.

Cellular senescence, a major driver of aging, can be stimulated by DNA damage, and is counteracted by the DNA repair machinery. Here we show that in p16INK4a-deficient cells, senescence induction by the environmental genotoxin B[a]P or ionizing radiation (IR) completely depends on p21CIP1. Immunoprecipitation-based mass spectrometry interactomics data revealed that during senescence induction and maintenance, p21CIP1 specifically inhibits CDK4 and thereby activates the DREAM complex. Genome-wide transcriptomics revealed striking similarities in the response induced by B[a]P and IR. Among the top 100 repressed genes 78 were identical between B[a]P and IR and 76 were DREAM targets. The DREAM complex transcriptionally silences the main proliferation-associated transcription factors E2F1, FOXM1 and B-Myb as well as multiple DNA repair factors. Knockdown of p21CIP1, E2F4 or E2F5 diminished both, repression of these factors and senescence. The transcriptional profiles evoked by B[a]P and IR largely overlapped with the profile induced by pharmacological CDK4 inhibition, further illustrating the role of CDK4 inhibition in genotoxic stress-induced senescence. Moreover, data obtained by live-cell time-lapse microscopy suggest the inhibition of CDK4 by p21CIP1 is especially important for arresting cells which slip through mitosis. Overall, we identified the p21CIP1/CDK4/DREAM axis as a master regulator of genotoxic stress-induced senescence.

Translation, cross-cultural adaptation and clinimetric properties of the Brazilian Portuguese version of the Brace Questionnaire.

PURPOSE: To perform a cross-cultural adaptation and validation of the Brazilian-Portuguese versions of the Brace Questionnaire in adolescent idiopathic scoliosis. METHODS: A forward-backward translation process was employed to produce a Brazilian Portuguese version of the Brace Questionnaire, followed by comprehensive cross-cultural adaptation stages. The measurements of internal consistency and test-retest reliability were assessed by Cronbach's a and intraclass correlation coefficient (ICC), respectively. The Pearson's correlation coefficient was used to analyze the concurrent validity by comparison with the Scoliosis Research Society-22r questionnaire. RESULTS: A total of 84 scoliosis patients (age 13.4 ± 2.0 years, thoracic Cobb angle 33.3° ± 13.8°, and lumbar Cobb angle 29.8° ± 14.3°) were included. The Brace Questionnaire showed excellent internal consistency (Cronbach α = 0.93) and moderate reliability (ICC = 0.86). The correlations between the Brace Questionnaire and Scoliosis Research Society-22 were r = 0.66; p = 0.011. In addition, it was found that the Brazilian version of the Brace Questionnaire does not have ceiling and floor effects. CONCLUSIONS: The Brazilian-Portuguese adaptation of the brace questionnaire shows excellent reliability and can be a valid tool for psychometric assessment in adolescent idiopathic scoliosis.

Effect of traditional rehabilitation programme versus telerehabilitation in adolescents with idiopathic scoliosis during the COVID-19 pandemic: a cohort study.

BACKGROUND: Telerehabilitation has become increasingly popular since the SARS-CoV-2 (COVID-19) outbreak. However, studies are needed to understand the effects of remote delivery of spine treatment approaches. OBJECTIVES: To verify and compare the effects of traditional rehabilitation programmes (in-person) and telerehabilitation (online) on the progression of scoliotic curvature in adolescents with idiopathic scoliosis during the COVID-19 pandemic, and to verify the acceptability, appropriateness, and feasibility among patients and physiotherapists regarding both treatments. METHODS: This is a cohort study (prospective analysis of 2 intervention groups: telerehabilitation (online) and traditional rehabilitation (in-person). A total of 66 adolescents with idiopathic scoliosis were included. Recruitment was conducted through the Clinical Center in Scoliosis Care (January-December 2020). Participants were divided into 2 intervention groups: telerehabilitation (online) (n = 33) and traditional rehabilitation programme (in-person) (n = 33). Both groups also were supplied with a spinal orthopaedic brace. Scoliosis was confirmed by a spine X-ray examination (Cobb angle). Radiographic parameters measured were: Cobb angles (thoracic and lumbar). The method of Nash and Moe (thoracic and lumbar) was also evaluated based on the relationship between the vertebral pedicles and the centre of the vertebral body in the X-rays. Assessments were performed at baseline (T0) and after 6 months of the intervention protocol (T6). Patient and physiotherapist reports were evaluated on the acceptability, appropriateness, and feasibility of the interventions. RESULTS: Adolescents with idiopathic scoliosis showed a significant decrease in the Cobb angle (main scoliotic curvature), with a 4.9° for the traditional rehabilitation programme and 2.4° for the telerehabilitation. Thoracic and lumbar Cobb angles did not show significant changes after the intervention in both groups or between groups. Thoracic and lumbar Nash and Moe scores scores also did not show significant differences after 6 months of in-person or telerehabilitation intervention, or between groups. The intervention by telerehabilitation was acceptable, appropriate, and feasible for patients and physiotherapists. CONCLUSION: Use of the rehabilitation programme for adolescents with idiopathic scoliosis, delivered via telerehabilitation during the COVID-19 pandemic, was encouraging for future applications due to the improved effect on reducing the Cobb angle, preventing progression of scoliosis. In addition, telerehabilitation showed good acceptability among patients and physiotherapists. Traditional rehabilitation programmes (in-person) in adolescents with idiopathic scoliosis also showed a reduction in the Cobb angle.

Reliability and validity between two instruments for measuring spine sagittal parameters in adolescents with idiopathic scoliosis during various stages of growth / Confiabilidad y validez entre dos instrumentos para medir parámetros sagitales de la columna vertebral en adolescentes con escoliosis idiopática durante varias etapas de crecimiento

Abstract Introduction: Adolescent idiopathic scoliosis (AIS) is the most common and severe spinal deformity, which affects children and adolescents in the stage of neuromotor development and skeletal maturity of the sagittal curvatures of the spine. The literature presents several radiation-free instruments to assess and monitor the progression of scoliotic curvature angles in the AIS. However, the reliability and validity of the inclinometer at different stages of growth in relation to X-ray parameters has not been understood to date. Objective: To evaluate the reliability of the inclinometer and its validity with the X-ray exam on the sagittal parameters of the spine in the early and late growth stages of adolescents with AIS. Methods: A cross-sectional study was conducted with 39 adolescents with AIS who were divided into two groups: the initial growth phase (10-13 years) and the late growth phase (14-18 years). The evaluated sagittal parameters of the spine were the angle of the thoracic kyphosis and the angle of the lumbar lordosis, both measured by the X-ray image examination and the inclinometer. Results: The inclinometer showed excellent inter- and intra-examiner reliability for the different growth phases, early and late, with a strong association with the X-ray (gold standard; r = 0.84; p = 0.308 and r = 0.75; p = 0.517). The angle of lumbar lordosis was different between the inclinometer and X-ray instruments in the early and late stages of growth (p < 0.001), with moderate reliability and a less significant correlation with the gold standard of radiography (r = 0.38; p = 0.001 and r = 0.49; p = 0.024). Conclusion: The inclinometer showed excellent reliability and validity for the sagittal parameter of thoracic kyphosis in the early and late stages of growth. The angle of lumbar lordosis measured by inclinometer proved to be of moderate reliability and weak validity when considering the phases of skeletal growth, showing it to be an inefficient instrument for monitoring the lumbar scoliotic curvature for AIS.

Resumen Introducción: La escoliosis idiopática del adolescente (EIA) es la deformidad espinal más común y severa, que afecta a niños y adolescentes en la etapa de desarrollo neuromotor y madurez esquelética de las curvaturas sagitales de la columna. La literatura presenta varios instrumentos libres de radiación para evaluar y monitorear la progresión de los ángulos de curvatura escolióticos en el AIS. Sin embargo, hasta la fecha no se ha entendido la fiabilidad y validez del inclinómetro en diferentes etapas de crecimiento en relación con los parámetros de rayos X. Objectivo: Evaluar la confiabilidad del inclinómetro y su validez con el examen de rayos X sobre los parámetros sagitales de la columna vertebral en las etapas de crecimiento temprano y tardío de adolescentes con EIA. Materiales y métodos: Se realizó un estudio transversal con 39 adolescentes con EIA que se dividieron en dos grupos: la fase de crecimiento inicial (10-13 años) y la fase de crecimiento tardío (14-18 años). Los parámetros sagitales de la columna evaluados fueron el ángulo de la cifosis torácica y el ángulo de la lordosis lumbar, ambos medidos por el examen de imagen de rayos X y el inclinómetro. Resultados: El inclinómetro mostró una excelente confiabilidad inter e intraexaminador para las diferentes fases de crecimiento, temprana y tardía, con una fuerte asociación con la radiografía (estándar de oro; r = 0.84; p = 0.308 y r = 0.75; p = 0,517). El ángulo de lordosis lumbar fue diferente entre el inclinómetro y los instrumentos de rayos X en las etapas tempranas y tardías del crecimiento (p < 0,001), con confiabilidad moderada y una correlación menos significativa con el estándar de oro de la radiografía (r = 0,38; p = 0,001 y r = 0,49; p = 0,024). Conclusión: El inclinómetro mostró excelente confiabilidad y validez para el parámetro sagital de cifosis torácica en etapas tempranas y tardías de crecimiento. El ángulo de lordosis lumbar medido por inclinómetro demostró ser de confiabilidad moderada y validez débil al considerar las fases de crecimiento esquelético, mostrándose como un instrumento ineficiente para monitorear la curvatura escoliótica lumbar para EIA.

The Effects of Short- and Long-Term Spinal Brace Use with and without Exercise on Spine, Balance, and Gait in Adolescents with Idiopathic Scoliosis.

Background and Objectives: Adolescent idiopathic scoliosis (AIS) is a prevalent spinal disorder in adolescents. Previous studies have shown biomechanical changes of the gait in the lower limb of AIS patients. To minimize the progression of scoliotic curvature, a spinal brace is used, which has been shown to be efficient. Usually, a brace is worn strictly for 20-22 h every day. To our knowledge, no study has assessed the short- and long-term effects of spinal brace use with or without an exercise program (6 months) to improve clinical and biomechanical parameters. The aim of our study was to verify the effects of short- and long-term spinal brace use, with or without an exercise program on the spine, body balance, and plantar load distribution during gait in AIS. Materials and Methods: A prospective randomized study was conducted with intention-to-treat analysis in forty-five adolescents diagnosed with AIS undergoing conservative treatment at a center specialized in spinal rehabilitation. Adolescents were evaluated at two stages of intervention: (1) spinal orthopedic brace, with acute use 24 h/day (n = 22) and (2) spinal orthopedic brace, with acute use between 15-18 h/day associated with a specific rehabilitation exercise protocol for six consecutive months (six months and 12 total sessions, n = 23). The evaluated parameters were: spine pain, using a visual analog scale (VAS); Cobb angle measurement using radiograph exams, as well as the Risser sign; and static balance and plantar pressure of the feet during gait, carried out using a pressure platform. Results: AIS patients showed significant improvements in the main scoliotic curvature, with a 12-degree reduction in Cobb angle pre- and post-short-term immediate use of spinal brace and a 5.3 degree correction after six months of spinal brace use in combination with specific exercises (long term). In addition, short- and long-term brace use with an exercise program showed a significant increase in anteroposterior and mediolateral balance and a reduction in plantar overload on the heel during gait, with an effect size between moderate and high. Conclusions: Intervention via the short- or long-term use of a spinal brace combined with specific exercises in adolescents with idiopathic scoliosis proved to be effective for correcting scoliotic curvature. In addition, intervention also showed improvements to the antero-posterior and mediolateral body balance and a reduction in the plantar load on the rearfoot region during gait, demonstrating effective mechanical action on the spine.

Stabilizing Polysorbate 20 and 80 Against Oxidative Degradation.

Polysorbates are stabilizers typically required in therapeutic protein formulations. On account of their chemical structure, polysorbates are prone to degradation, which can render a pharmaceutical product instable or incompliant. The purpose of this study was to investigate if the addition of butylhydroxytoluene (BHT) and butylhydroxyanisole (BHA) protects polysorbate 20 (PS20) and polysorbate 80 (PS80) against oxidative degradation. PS20 and PS80 solutions containing BHA, BHT-or as control without an antioxidant-were stressed by exposure to air at 40°C for 7 weeks. The following assays were performed: ferrous oxidation-xylenol orange assay, liquid chromatography coupled to UV and mass spectrometry (MS), pH measurement, liquid chromatography fluorescence micelle assay, headspace-gas chromatography coupled with MS. PS20 and PS80 solutions containing an antioxidant were found to be more stable, as demonstrated by lower peroxide levels, lower free fatty acid contents, stable pH, intact polysorbate micelle structure/composition, and less volatile degradants. PS20 and PS80 solutions containing BHT or BHA are more stable against oxidative degradation compared to nonstabilized solutions. It might be beneficial to formulate bulk polysorbate with the antioxidant(s) to ensure stabilization during all process steps.

Molybdenum-based two-dimensional materials: Synthesis, dispersion, exfoliation and thin film deposition.

We report a simple and effective route to synthesize, disperse, exfoliate and process different molybdenum-based 2-dimensional (2D) materials. Starting from a reaction between ammonium molybdate and ammonium sulfide solutions, a powder consisting of a mixture between amorphous molybdenum oxide and sulfide is obtained. By tuning the atmosphere and the temperature, different compositions can be prepared by thermal treatment of this sample: heat treatments in ambient atmosphere produce MoO3 with different morphologies, controllable according to the chosen temperature. On the other hand, heat treatments in inert atmosphere produce mixtures between crystalline 2D MoS2 and MoO3. Further handling of these mixtures with acetonitrile separates the components due to the different solvent/solid affinities, with the layered MoS2 becoming homogeneously dispersed, and the MoO3 agglomerating as a solid easily removed by centrifugation. The resulting sulfide dispersions in acetonitrile present high stability, and they are constituted by exfoliated MoS2, which means that acetonitrile is a tri-functional agent, separating the sulfide/oxide mixture, exfoliating the sulfide and stabilizing the dispersion. The MoS2 dispersions were used to produce homogeneous, freestanding and transparent thin films through the liquid-liquid interfacial route, which were easily deposited over different substrates and characterized by different techniques.

The conserved ADAMTS-like protein lonely heart mediates matrix formation and cardiac tissue integrity.

Here we report on the identification and functional characterization of the ADAMTS-like homolog lonely heart (loh) in Drosophila melanogaster. Loh displays all hallmarks of ADAMTSL proteins including several thrombospondin type 1 repeats (TSR1), and acts in concert with the collagen Pericardin (Prc). Loss of either loh or prc causes progressive cardiac damage peaking in the abolishment of heart function. We show that both proteins are integral components of the cardiac ECM mediating cellular adhesion between the cardiac tube and the pericardial cells. Loss of ECM integrity leads to an altered myo-fibrillar organization in cardiac cells massively influencing heart beat pattern. We show evidence that Loh acts as a secreted receptor for Prc and works as a crucial determinant to allow the formation of a cell and tissue specific ECM, while it does not influence the accumulation of other matrix proteins like Nidogen or Perlecan. Our findings demonstrate that the function of ADAMTS-like proteins is conserved throughout evolution and reveal a previously unknown interaction of these proteins with collagens.

Superior 'theory of mind' in borderline personality disorder: an analysis of interaction behavior in a virtual trust game.

To gain further insight into interpersonal dysfunction in Borderline Personality Disorder (BPD) we investigated the effects of emotional cues and the fairness of a social partner on the ability to infer other peoples' intentions in a virtual social exchange. 30 BPD patients and 30 nonpatients were asked to play a multiround trust game with four virtual trustees. The trustees varied in regard to fairness and presence of emotional facial cues which were both linked to repayment ratio. BPD patients adjusted their investment to the fairness of their partner. In contrast, nonpatients disregarded the trustees' fairness in the presence of emotional facial expressions. Both groups performed equally in an emotion recognition task and assessed the trustees' fairness comparably. When the unfair trustee provided emotional cues, BPD patients assessed their own behavior as more fair, while the lack of cues led patients to assess their own behavior as unfair. BPD patients are superior in the attribution of mental states to interaction partners when emotional cues are present. While the emotional expressions of a partner dominated the exchange behavior in nonpatients, BPD patients used the objective fairness of their social counterparts to guide their own behavior despite the existence of emotional cues.