Patient perspectives on BCMA-targeted therapies for multiple myeloma: a survey conducted in a patient advocacy group.

Background: Advances in multiple myeloma (MM) treatment have shifted the therapeutic landscape. Understanding patients' perspectives can assist physicians in helping patients make informed decisions. This study aimed to understand the patient decision-making process and gain insights into patient perspectives on B-cell maturation antigen (BCMA)-targeted therapies for MM. Methods: An 18-question survey was completed by patients with MM enrolled in HealthTree® Cure Hub, an online portal helping patients with plasma cell dyscrasias navigate their disease. Results: From October 28, 2022, to January 12, 2023, 325 patients with MM participated in the survey. The mean age (standard deviation) of the respondents was 66 (8) years; 54% were female and 90% were White. Among 218 patients with complete clinical records in the database, the median (min, max) lines of therapy (LOT) was 2 (1,16). Among 61 (28%) patients who had received ≥4 LOTs, 55 (90%) were triple-class exposed. Of the 290 patients who responded to the question about openness to new therapies, 76 (26%) were open to trying a new therapy immediately and 125 (43%) wanted more information on safety and efficacy. Most respondents reported likely or very likely to try a BCMA CAR T-cell therapy (60%) or a bispecific antibody (74%) and some needed more information to decide (16% for CAR T-cell therapy and 13% for bispecific antibody). The most requested information included efficacy, side effects (SEs), eligibility, and administration process for both CAR T-cell and bispecific therapies. When 2 therapies with the same efficacy and duration of response were offered, 69% of respondents would prefer the therapy with a lower risk of severe SEs but requires continuous dosing with no treatment-free interval, and 31% preferred a therapy given once followed by a treatment-free interval but with a potentially higher risk of severe SEs. To receive an effective therapy, the top acceptable trade-offs included frequent monitoring of SEs and initiating a new therapy in a hospital setting, and the least acceptable compromise was caregiver burden. Conclusions: This study found a high level of openness in patients with MM to try BCMA-targeted therapies. Information on efficacy, safety, availability, and eligibility may assist patients on decision-making.

Regulation of cellular and molecular markers of epithelial-mesenchymal transition by Brazilin in breast cancer cells.

Breast cancer is the most common invasive neoplasm and the leading cause of cancer death in women worldwide. The main cause of mortality in cancer patients is invasion and metastasis, where the epithelial-mesenchymal transition (EMT) is a crucial player in these processes. Pharmacological therapy has plants as its primary source, including isoflavonoids. Brazilin is an isoflavonoid isolated from Haematoxilum brasiletto that has shown antiproliferative activity in several cancer cell lines. In this study, we evaluated the effect of Brazilin on canonical markers of EMT such as E-cadherin, vimentin, Twist, and matrix metalloproteases (MMPs). By Western blot, we evaluated E-cadherin, vimentin, and Twist expression and the subcellular localization by immunofluorescence. Using gelatin zymography, we determined the levels of secretion of MMPs. We used Transwell chambers coated with matrigel to determine the in vitro invasion of breast cancer cells treated with Brazilin. Interestingly, our results show that Brazilin increases 50% in E-cadherin expression and decreases 50% in vimentin and Twist expression, MMPs, and cell invasion in triple-negative breast cancer (TNBC) MDA-MB-231 and to a lesser extend in MCF7 ER+ breast cancer cells. Together, these findings position Brazilin as a new molecule with great potential for use as complementary or alternative treatment in breast cancer therapy in the future.

A roadmap for implanting microelectrode arrays to evoke tactile sensations through intracortical microstimulation.

Intracortical microstimulation (ICMS) is a method for restoring sensation to people with paralysis as part of a bidirectional brain-computer interface to restore upper limb function. Evoking tactile sensations of the hand through ICMS requires precise targeting of implanted electrodes. Here we describe the presurgical imaging procedures used to generate functional maps of the hand area of the somatosensory cortex and subsequent planning that guided the implantation of intracortical microelectrode arrays. In five participants with cervical spinal cord injury, across two study locations, this procedure successfully enabled ICMS-evoked sensations localized to at least the first four digits of the hand. The imaging and planning procedures developed through this clinical trial provide a roadmap for other brain-computer interface studies to ensure successful placement of stimulation electrodes.

Early Seizure Prophylaxis in Mild and Moderate Traumatic Brain Injury: A Systematic Review and Meta-Analysis.

Importance: Guidelines recommend seizure prophylaxis for early posttraumatic seizures (PTS) after severe traumatic brain injury (TBI). Use of antiseizure medications for early seizure prophylaxis after mild or moderate TBI remains controversial. Objective: To determine the association between seizure prophylaxis and risk reduction for early PTS in mild and moderate TBI. Data Sources: PubMed, Google Scholar, and Web of Science (January 1, 1991, to April 18, 2023) were systematically searched. Study Selection: Observational studies of adult patients presenting to trauma centers in high-income countries with mild (Glasgow Coma Scale [GCS], 13-15) and moderate (GCS, 9-12) TBI comparing rates of early PTS among patients with seizure prophylaxis with those without seizure prophylaxis. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) reporting guidelines were used. Two authors independently reviewed all titles and abstracts, and 3 authors reviewed final studies for inclusion. A meta-analysis was performed using a random-effects model with absolute risk reduction. Main Outcome Measures: The main outcome was absolute risk reduction of early PTS, defined as seizures within 7 days of initial injury, in patients with mild or moderate TBI receiving seizure prophylaxis in the first week after injury. A secondary analysis was performed in patients with only mild TBI. Results: A total of 64 full articles were reviewed after screening; 8 studies (including 5637 patients) were included for the mild and moderate TBI analysis, and 5 studies (including 3803 patients) were included for the mild TBI analysis. The absolute risk reduction of seizure prophylaxis for early PTS in mild to moderate TBI (GCS, 9-15) was 0.6% (95% CI, 0.1%-1.2%; P = .02). The absolute risk reduction for mild TBI alone was similar 0.6% (95% CI, 0.01%-1.2%; P = .04). The number needed to treat to prevent 1 seizure was 167 patients. Conclusion and Relevance: Seizure prophylaxis after mild and moderate TBI was associated with a small but statistically significant reduced risk of early posttraumatic seizures after mild and moderate TBI. The small absolute risk reduction and low prevalence of early seizures should be weighed against potential acute risks of antiseizure medications as well as the risk of inappropriate continuation beyond 7 days.

Most Cited Articles in Body Contouring: A Bibliometric Analysis of the Past 45 Years.

Introduction: The purpose of this study is to produce a bibliometric review of the 30 most cited articles related to 6 major domains of body contouring-abdominoplasty, thighplasty, brachioplasty, gluteoplasty, body lift, and liposuction-for resident and fellow education. Methods: The authors utilized the Web of Science Citation Index to identify the 30 most cited articles related to surgery for body contouring published from 1975 to 2020. Articles were classified according to their level of evidence, type of study, and country of publication. Results: A total of 336 articles were reviewed to compile our list. The mean number of citations across the articles was 114.7 ± SD 86.1. The highest prevalence of the papers was published between 2000 and 2009 (n = 15, 50%). The country with the highest number of contributions was the United States (n = 22, 73%). Plastic and Reconstructive Surgery served as the main journal of publication for these papers (n = 22, 73.3%). The majority of articles were designated for clinical-type studies (n = 26, 86.7%). No basic science or prevalence study design papers were listed. In terms of level of evidence (LoE), most papers were assigned IV (n = 11, 36.7%) and III (n = 7, 23.3%). Conclusions: Our study reveals that the most cited papers in body contouring are of LoE III and IV. Although the LoE of plastic surgery research, in general, has improved, in the past decade, a call for higher quality papers remains. Overall, this analysis provides an easy, electronic starting point for residents and fellows interested in understanding the field's evolution.

Introduction : La présente étude vise à produire une analyse bibliométrique de 30 articles influents liés à six grands domaines du remodelage corporel (l'abdominoplastie, le redrapage des cuisses, la brachioplastie, la glutéoplastie, le redrapage du corps et la liposuccion) pour la formation des résidents et des étudiants en stage de perfectionnement postdoctoral. Méthodologie : Les auteurs ont utilisé l'index de citation de Web of Science pour extraire les 30 articles les plus cités sur les opérations de remodelage corporel publiés entre 1975 et 2020. Ils ont classé les articles d'après la qualité des preuves, le type d'étude et le pays de publication. Résultats : Au total, les auteurs ont analysé 336 articles pour compiler leur liste. Les articles contenaient un nombre moyen de 114,7± ÉT 86,1 citations. La plus forte prévalence d'articles a été publiée entre 2000 et 2009 (n = 15, 50 %). La majorité des articles provenaient des États-Unis d'Amérique (n = 22, 73 %), et c'est la revue Plastic and Reconstructive Surgery© qui en a publié le plus (n = 22, 73,3 %). La plupart des articles prenaient la forme d'études de type clinique (n = 26, 86,7 %). Aucun article de science fondamentale ni étude de prévalence n'a été répertorié. Pour ce qui est de la qualité des preuves, la plupart des articles ont obtenu un classement de IV (n = 11, 36,7 %) et de III (n = 7, 23,3 %). Conclusions : L'étude révèle que la qualité de preuve de la plupart des articles dans ce domaine était de III et IV. Même si la chirurgie plastique se prête moins bien aux études randomisées et contrôlées que la médecine, elle mérite des articles comportant une meilleure qualité de preuves. Grâce à la présente analyse, les résidents et les étudiants en stage de perfectionnement peuvent accéder rapidement et facilement à des concepts influents pour comprendre l'évolution du domaine par voie électronique. Termes MeSH : abdominoplastie, bibliométrie, chirurgie plastique, études transversales, liposuccion, remodelage corporel.

Innovative Strategy for Developing PEDOT Composite Scaffold for Reversible Oxygen Reduction Reaction.

Metal-air batteries are an emerging technology with great potential to satisfy the demand for energy in high-consumption applications. However, this technology is still in an early stage, facing significant challenges such as a low cycle life that currently limits its practical use. Poly(3,4-ethylenedioxythiophene) (PEDOT) conducting polymer has already demonstrated its efficiency as catalyst for oxygen reduction reaction (ORR) discharge as an alternative to traditional expensive and nonsustainable metal catalysts. Apart from that, in most electrochemical processes, three phenomena are needed: redox activity and electronic and ionic conduction. Material morphology is important to maximize the contact area and optimize the 3 mechanisms to obtain high-performance devices. In this work, porous scaffolds of PEDOT-organic ionic plastic crystal (OIPC) are prepared through vapor phase polymerization to be used as porous self-standing cathodes. The scaffolds, based on abundant elements, showed good thermal stability (200 °C), with potential ORR reversible electrocatalytic activity: 60% of Coulombic efficiency in aqueous medium after 200 cycles.

Portosystemic shunt surgery for severe portal hypertension due to portal thrombosis after bariatric surgery.

Portal vein thrombosis is a rare complication after laparoscopic sleeve gastrectomy, a widely performed bariatric surgery procedure. Occasionally, the development of portal vein thrombosis can progress to more severe conditions, including portal hypertension and cavernomatosis, thereby presenting a complex and challenging clinical scenario. The management of such complications often requires careful consideration; however, surgical intervention in the form of a splenorenal shunt is an exceptional indication. We present the case of a 33-year-old female patient who had previously undergone laparoscopic sleeve gastrectomy in 2014 and subsequently developed portal thrombosis, followed by cavernomatosis and associated complications of portal hypertension. A proximal splenorenal shunt procedure and splenectomy were successfully performed to manage portal hypertension. The presentation of this clinical case aims to contribute to the available evidence and knowledge surrounding this rare and challenging pathology.

Complications and visual outcomes following surgical resection of pediatric optic pathway/hypothalamic gliomas: a systematic review and meta-analysis.

Pediatric optic pathway/hypothalamic gliomas (OPHG) pose challenges in treatment due to their location and proximity to vital structures. Surgical resection plays a key role in the management of OPHG especially when the tumor exhibits mass effect and causes symptoms. However, data regarding outcomes and complications of surgical resection for OPHG remains heterogenous. The authors performed a systematic review on pediatric OPHG in four databases: PubMed, EMBASE, Cochrane Library, and Google Scholar. We included studies that reported on the visual outcomes and complications of OPHG resection. A meta-analysis was performed and reported per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A total of 26 retrospective studies were included. Seven hundred ninety-seven pediatric patients with OPHG undergoing surgical resection were examined. A diagnosis of NF1 was confirmed in 9.7%. Gross total resection was achieved in 36.7%. Intraorbital optic pathway gliomas showed a significantly higher gross total resection rate compared to those located in the chiasmatic/hypothalamic region (75.8% vs. 9.6%). Postoperatively, visual acuity improved in 24.6%, remained unchanged in 68.2%, and worsened in 18.2%. Complications included hydrocephalus (35.4%), anterior pituitary dysfunction (19.6%), and transient diabetes insipidus (29%). Tumor progression post-resection occurred in 12.8%, through a mean follow-up of 53.5 months. Surgical resection remains an essential strategy for treating symptomatic and large pediatric OPHG and can result in favorable vision outcomes in most patients. Careful patient selection is critical. Patients should be monitored for hydrocephalus development postoperatively and followed up to assess for tumor progression and adjuvant treatment necessity.

Choosing T-cell sources determines CAR-T cell activity in neuroblastoma.

Introduction: The clinical success of chimeric antigen receptor-modified T cells (CAR-T cells) for hematological malignancies has not been reproduced for solid tumors, partly due to the lack of cancer-type specific antigens. In this work, we used a novel combinatorial approach consisting of a versatile anti-FITC CAR-T effector cells plus an FITC-conjugated neuroblastoma (NB)-targeting linker, an FITC-conjugated monoclonal antibody (Dinutuximab) that recognizes GD2. Methods: We compared cord blood (CB), and CD45RA-enriched peripheral blood leukapheresis product (45RA) as allogeneic sources of T cells, using peripheral blood (PB) as a control to choose the best condition for anti-FITC CAR-T production. Cells were manufactured under two cytokine conditions (IL-2 versus IL-7+IL-15+IL-21) with or without CD3/CD28 stimulation. Immune phenotype, vector copy number, and genomic integrity of the final products were determined for cell characterization and quality control assessment. Functionality and antitumor capacity of CB/45RA-derived anti-FITC CAR-T cells were analyzed in co-culture with different anti-GD2-FITC labeled NB cell lines. Results: The IL-7+IL-15+IL-21 cocktail, in addition to co-stimulation signals, resulted in a favorable cell proliferation rate and maintained less differentiated immune phenotypes in both CB and 45RA T cells. Therefore, it was used for CAR-T cell manufacturing and further characterization. CB and CD45RA-derived anti-FITC CAR-T cells cultured with IL-7+IL-15+IL-21 retained a predominantly naïve phenotype compared with controls. In the presence of the NB-FITC targeting, CD4+ CB-derived anti-FITC CAR-T cells showed the highest values of co-stimulatory receptors OX40 and 4-1BB, and CD8+ CAR-T cells exhibited high levels of PD-1 and 4-1BB and low levels of TIM3 and OX40, compared with CAR-T cells form the other sources studied. CB-derived anti-FITC CAR-T cells released the highest amounts of cytokines (IFN-γ and TNF-α) into co-culture supernatants. The viability of NB target cells decreased to 30% when co-cultured with CB-derived CAR-T cells during 48h. Conclusion: CB and 45RA-derived T cells may be used as allogeneic sources of T cells to produce CAR-T cells. Moreover, ex vivo culture with IL-7+IL-15+IL-21 could favor CAR-T products with a longer persistence in the host. Our strategy may complement the current use of Dinutuximab in treating NB through its combination with a targeted CAR-T cell approach.

Thalamic stereoelectroencephalography for neuromodulation target selection: Proof of concept and review of literature of pulvinar direct electrical stimulation.

In patients with drug-resistant epilepsy (DRE) who are not candidates for resective surgery, various thalamic nuclei, including the anterior, centromedian, and pulvinar nuclei, have been extensively investigated as targets for neuromodulation. However, the therapeutic effects of different targets for thalamic neuromodulation on various types of epilepsy are not well understood. Here, we present a 32-year-old patient with multifocal bilateral temporoparieto-occipital epilepsy and bilateral malformations of cortical development (MCDs) who underwent bilateral stereoelectroencephalographic (SEEG) recordings of the aforementioned three thalamic nuclei bilaterally. The change in the rate of interictal epileptiform discharges (IEDs) from baseline were compared in temporal, central, parietal, and occipital regions after direct electrical stimulation (DES) of each thalamic nucleus. A significant decrease in the rate of IEDs (33% from baseline) in the posterior quadrant regions was noted in the ipsilateral as well as contralateral hemisphere following DES of the pulvinar. A scoping review was also performed to better understand the current standpoint of pulvinar thalamic stimulation in the treatment of DRE. The therapeutic effect of neuromodulation can differ among thalamic nuclei targets and epileptogenic zones (EZs). In patients with multifocal EZs with extensive MCDs, personalized thalamic targeting could be achieved through DES with thalamic SEEG electrodes.

Genital Surgery Outcomes Using an Individualized Algorithm for Hormone Management in Transfeminine Individuals.

CONTEXT: Transgender and gender diverse (TGD) individuals have greater access to genital surgery (GS) with improved insurance coverage and access to trained surgeons and interdisciplinary gender affirming providers. OBJECTIVE: To determine perioperative medical and behavioral health outcomes in transfeminine (TF) individuals undergoing GS with use of a specific gender-affirming hormone therapy (GAHT) algorithm based on individualized risk factor assessment. DESIGN: Retrospective observational cohort study from 2017-2022. Pre- and post-operative data collected included clinical and biochemical assessment, GAHT regimens, validated behavioral health measures, and post-operative complications. SETTING: Single-center tertiary referral center. PATIENTS: 183 TF individuals, grouped into estradiol continued (Group 1) vs estradiol temporarily discontinued for 2-6 weeks preoperatively (Group 2). MAIN OUTCOME MEASURE(S): Venous thromboembolism (VTE) incidence, non-VTE postoperative complication incidence, and change in behavioral health assessments. RESULTS: The majority of individuals continued estradiol perioperatively [Group 1; 138 (75.4%)]. Individuals who temporarily held estradiol preoperatively [Group 2; 45 (24.6%)] were statistically older (p < 0.01), had higher incidence of cardiometabolic comorbidities (p < 0.01), and higher Caprini scores (p < 0.01). Group 1 was statistically more likely to use oral estradiol (p < 0.01). One episode (0.05%) of VTE occurred (Group 1). There was no significant difference in postoperative complications or behavioral health measures between groups. CONCLUSION: An individualized algorithm for preoperative hormone management for TF GS resulted in perioperative continuation of GAHT for the majority of individuals without significantly increasing the risk for post-operative surgical complications while maintaining stable behavioral health measures perioperatively.

Reduced complexity for sound zones with subband block adaptive filters and a loudspeaker line array.

Sound zones are used to reproduce individual audio content to multiple people in a room using a set of loudspeakers with controllable input signals. To allow the reproduction of individual audio to dynamically change, e.g., due to moving listeners, changes in the number of listeners, or changing room transfer functions, an adaptive formulation is proposed. This formulation is based on frequency domain block adaptive filters and given room transfer functions. To reduce computational complexity, the system is extended to subband processing without cross-adaptive filters. The computational savings come from recognizing that sound zones consist of part-solutions which are inherently band limited, hence, several subbands can be ignored. To validate the theoretical findings, a 27-channel loudspeaker array was constructed, and measurements were performed in anechoic and reflective environments. The results show that the subband solution performs identically to a full-rate solution but at a reduced computational complexity.

Insights into epileptogenesis from post-traumatic epilepsy.

Post-traumatic epilepsy (PTE) accounts for 5% of all epilepsies. The incidence of PTE after traumatic brain injury (TBI) depends on the severity of injury, approaching one in three in groups with the most severe injuries. The repeated seizures that characterize PTE impair neurological recovery and increase the risk of poor outcomes after TBI. Given this high risk of recurrent seizures and the relatively short latency period for their development after injury, PTE serves as a model disease to understand human epileptogenesis and trial novel anti-epileptogenic therapies. Epileptogenesis is the process whereby previously normal brain tissue becomes prone to recurrent abnormal electrical activity, ultimately resulting in seizures. In this Review, we describe the clinical course of PTE and highlight promising research into epileptogenesis and treatment using animal models of PTE. Clinical, imaging, EEG and fluid biomarkers are being developed to aid the identification of patients at high risk of PTE who might benefit from anti-epileptogenic therapies. Studies in preclinical models of PTE have identified tractable pathways and novel therapeutic strategies that can potentially prevent epilepsy, which remain to be validated in humans. In addition to improving outcomes after TBI, advances in PTE research are likely to provide therapeutic insights that are relevant to all epilepsies.

Safety of Concomitant Cortical and Thalamic Stereoencephalography Explorations in Patients With Drug-Resistant Epilepsies.

BACKGROUND AND OBJECTIVES: Intracranial electrophysiology of thalamic nuclei has demonstrated involvement of thalamic areas in the propagation of seizures in focal drug-resistant epilepsy. Recent studies have argued that thalamus stereoencephalography (sEEG) may aid in understanding the epileptogenic zone and treatment options. However, the study of thalamic sEEG-associated hemorrhage incidence has not been investigated in a cohort study design. In this article, we present the largest retrospective cohort study of sEEG patients and compare hemorrhage rates between those with and without thalamic sEEG monitoring. METHODS: Retrospective chart review of clinical and epilepsy history, electrode implantation, rationale, and outcomes was performed for 76 patients (age 20-69 years) with drug-resistant epilepsy who underwent sEEG monitoring at our institution (2019-2022). A subset of 38% of patients (n = 30) underwent thalamic monitoring of the anterior thalamic nucleus (n = 14), pulvinar nucleus (n = 25), or both (n = 10). Planned perisylvian orthogonal sEEG trajectories were extended to 2- to 3-cm intraparenchymally access thalamic area(s).The decision to incorporate thalamic monitoring was made by the multidisciplinary epilepsy team. Statistical comparison of hemorrhage rate, type, and severity between patients with and without thalamic sEEG monitoring was made. RESULTS: Our approach for thalamic monitoring was not associated with local intraparenchymal hemorrhage of thalamic areas or found along extended cortical trajectories, and symptomatic hemorrhage rates were greater for patients with thalamic coverage (10% vs 0%, P = .056), although this was not found to be significant. Importantly, patients with perisylvian electrode trajectories, with or without thalamic coverage, did not experience a higher incidence of hemorrhage (P = .34). CONCLUSION: sEEG of the thalamus is a safe and valuable tool that can be used to interrogate the efficacy of thalamic neuromodulation for drug-resistant epilepsy. While patients with thalamic sEEG did have higher incidence of hemorrhage at any monitoring site, this finding was apparently not related to the method of perisylvian implantation and did not involve any trajectories targeting the thalamus.

Eco-Friendly Sol-Gel Coatings with Organic Corrosion Inhibitors for Lightweight AZ61 Alloy.

The latest advances in technology and materials science have catalyzed a transformative shift towards the adoption of environmentally conscious and lightweight materials across key sectors such as aeronautics, biomedical, and automotive industries. Noteworthy among these innovations are the magnesium-aluminum (Mg-Al) alloys employed in aeronautical applications, contributing to the overall reduction in aircraft weight and subsequently diminishing fuel consumption and mitigating atmospheric emissions. The present work delves into a study of the anti-corrosive properties inherent in various sol-gel coatings, leveraging a range of environmentally friendly corrosion inhibitors, specifically tailored for samples of the AZ61 alloy. Methodologically, the work involves the synthesis and application of sol-gel coatings on AZ61 alloy containing eco-friendly inhibitors: L-cysteine, N-acetyl-cysteine, curcumin and methylene blue. Subsequently, an accelerated corrosion test in a simulated saline environment is performed. Through microstructural and compositional analyses, the best inhibitors responses are achieved with inhibitors containing S, N heteroatoms and conjugated double bonds in their structure, probably due to the creation of a continuous MgCl2 layer. This research contributes to the ongoing discourse on protective eco-coatings, aligning with the broader paradigm shift towards sustainable and lightweight materials in key industries.

Three Genes Involved in Different Signaling Pathways, carS, wcoA, and acyA, Participate in the Regulation of Fusarin Biosynthesis in Fusarium fujikuroi.

The phytopathogenic fungus Fusarium fujikuroi has a rich secondary metabolism which includes the synthesis of very different metabolites in response to diverse environmental cues, such as light or nitrogen. Here, we focused our attention on fusarins, a class of mycotoxins whose synthesis is downregulated by nitrogen starvation. Previous data showed that mutants of genes involved in carotenoid regulation (carS, encoding a RING finger protein repressor), light detection (wcoA, White Collar photoreceptor), and cAMP signaling (AcyA, adenylate cyclase) affect the synthesis of different metabolites. We studied the effect of these mutations on fusarin production and the expression of the fus1 gene, which encodes the key polyketide synthase of the pathway. We found that the three proteins are positive regulators of fusarin synthesis, especially WcoA and AcyA, linking light regulation to cAMP signaling. Genes for two other photoreceptors, the cryptochrome CryD and the Vivid flavoprotein VvdA, were not involved in fusarin regulation. In most cases, there was a correspondence between fusarin production and fus1 mRNA, indicating that regulation is mainly exerted at the transcriptional level. We conclude that fusarin synthesis is subject to a complex control involving regulators from different signaling pathways.

Easy Synthetic Access to High-Melting Sulfurated Copolymers and their Self-Assembling Diblock Copolymers from Phenylisothiocyanate and Oxetane.

Although sulfurated polymers promise unique properties, their controlled synthesis, particularly when it comes to complex and functional architectures, remains challenging. Here, we show that the copolymerization of oxetane and phenyl isothiocyanate selectively yields polythioimidocarbonates as a new class of sulfur containing polymers, with narrow molecular weight distributions (Mn=5-80 kg/mol with D≤1.2; Mn,max=124 kg/mol) and high melting points of up to 181 °C. The method tolerates different substituent patterns on both the oxetane and the isothiocyanate. Self-nucleation experiments reveal that π-stacking of phenyl substituents, the presence of unsubstituted polymer backbones, and the kinetically controlled linkage selectivity are key factors in maximising melting points. The increased tolerance to macro-chain transfer agents and the controlled propagation allows the synthesis of double crystalline and amphiphilic diblock copolymers, which can be assembled into micellar- and worm-like structures with amorphous cores in water. In contrast, crystallization driven self-assembly in ethanol gives cylindrical micelles or platelets.

FOXO1 regulates wound-healing responses in human gingival fibroblasts.

BACKGROUND AND OBJECTIVE: Forkhead box-O 1 (FOXO1) is a transcription factor actively involved in oral wound healing at the epithelial barrier. However, less is known regarding the role of FOXO1 during the tissue repair response in the connective tissue compartment. This study explored the involvement of FOXO1 in the modulation of fibroblast activity related to wound healing. METHODS: Primary cultures of human gingival fibroblasts were obtained from four healthy young donors. Myofibroblastic differentiation, collagen gel contraction, cell migration, cell spreading, and integrin activation were evaluated in the presence or absence of a FOXO1 inhibitor (AS1842856). Variations in mRNA and proteins of interest were evaluated through qRT-PCR and western blot, respectively. Distribution of actin, α-smooth muscle actin, and ß1 integrin was evaluated using immunofluorescence. FOXO1 and TGF-ß1 expression in gingival wound healing was assessed by immunohistochemistry in gingival wounds performed in C57BL/6 mice. Images were analyzed using ImageJ/Fiji. ANOVA or Kruskal-Wallis test followed by Tukey's or Dunn's post-hoc test was performed. All data are expressed as mean ± SD. p < .05 was considered statistically significant. RESULTS: FOXO1 inhibition caused a decrease in the expression of the myofibroblastic marker α-SMA along with a reduction in fibronectin, type I collagen, TGF-ß1, and ß1 integrin mRNA level. The FOXO1 inhibitor also caused decreases in cell migration, cell spreading, collagen gel contraction, and ß1 integrin activation. FOXO1 and TGF-ß1 were prominently expressed in gingival wounds in fibroblastic cells located at the wound bed. CONCLUSION: The present study indicates that FOXO1 plays an important role in the modulation of several wound-healing functions in gingival fibroblast. Moreover, our findings reveal an important regulatory role for FOXO1 on the differentiation of gingival myofibroblasts, the regulation of cell migration, and collagen contraction, all these functions being critical during tissue repair and fibrosis.

The Hearing Function and Ambulatory Blood Pressure in Older Adults.

OBJECTIVE: To examine the association between hearing function, assessed with pure-tone average (PTA) of air conduction thresholds, and 24-hour ambulatory blood pressure (BP) in older adults. STUDY DESIGN: Cross-sectional study. SETTING: A total of 1404 community-dwelling individuals aged ≥65 years from the Seniors-ENRICA cohort were examined. METHODS: Hearing loss was defined as PTA > 40-AudCal hearing loss decibels (dB-aHL) in the better ear for standard frequency (0.5, 1, and 2 kHz), speech frequency (0.5, 1, 2, and 4 kHz), and high frequency (3, 4, and 8 kHz). Circadian BP patterns were calculated as the percentage decline in systolic BP during the night, and participants were classified as dipper, nondipper, and riser. Ambulatory hypertension was defined as BP ≥ 130/80 mm Hg (24 hour), ≥135/85 (daytime), and ≥120/70 (nighttime) or on antihypertensive treatment. Analyses were performed with linear- and logistic-regression models adjusted for the main confounders. RESULTS: In multivariable analyses, the PTA was associated with higher nighttime systolic BP [ß coefficient per 20 dB-aHL increment standard frequency (95% confidence interval, CI): 2.41 mm Hg (0.87, 3.95); ß (95% CI) per 20 dB-aHL increment speech frequency 2.17 mm Hg (0.70, 3.64)]. Among hypertensive patients, hearing loss at standard and high-frequency PTA was associated with the riser BP pattern [odds ratio: 2.01 (95% CI, 1.03-3.93) and 1.45 (1.00-2.09), respectively]; also, hearing loss at standard PTA was linked to uncontrolled nighttime BP [1.81 (1.01-3.24)]. CONCLUSION: PTA was associated with higher nighttime BP, and hearing loss with a riser BP pattern and uncontrolled BP in older hypertensives.

Analysis of cholesterol-recognition motifs of the plasma membrane Ca2+-ATPase.

The plasma membrane Ca2+-ATPase (PMCA) is crucial for the fine tuning of intracellular calcium levels in eukaryotic cells. In this study, we show the presence of CARC sequences in all human and rat PMCA isoforms and we performed further analysis by molecular dynamics simulations. This analysis focuses on PMCA1, containing three CARC motifs, and PMCA4, with four CARC domains. In PMCA1, two CARC motifs reside within transmembrane domains, while the third is situated at the intracellular interface. The simulations depict more stable RMSD values and lower RMSF fluctuations in the presence of cholesterol, emphasizing its potential stabilizing effect. In PMCA4, a distinct dynamic was found. Notably, the total energy differences between simulations with cholesterol and phospholipids are pronounced in PMCA4 compared to PMCA1. RMSD values for PMCA4 indicate a more energetically favorable conformation in the presence of cholesterol, suggesting a robust interaction between CARCs and this lipid in the membranes. Furthermore, RMSF analysis for CARCs in both PMCA isoforms exhibit lower values in the presence of cholesterol compared to POPC alone. The analysis of H-bond occupancy and total energy values strongly suggests the potential interaction of CARCs with cholesterol. Given the crucial role of PMCAs in physiological calcium regulation and their involvement in diverse pathological processes, this study underscores the significance of CARC motifs and their interaction with cholesterol in elucidating PMCA function. These insights into the energetic preferences associated with CARC-cholesterol interactions offer valuable implications for understanding PMCA function in maintaining calcium homeostasis and addressing potential associated pathologies.