Complete Loss Research Articles

Observation of Nonlinear Exceptional Points with a Complete Basis in Dynamics.

The exotic physics associated with exceptional points (EPs) is always under the scrutiny of theoretical and experimental science. Recently, considerable effort has been invested in the combination of nonlinearity and non-Hermiticity. The concept of nonlinear EPs (NEPs) has been introduced, which can avoid the loss of completeness of the eigenbasis in dynamics while retaining the key features of linear EPs. Here, we present the first direct experimental demonstration of a NEP based on two non-Hermition coupled circuit resonators combined with a nonlinear saturable gain. At the NEP, the response of the eigenfrequency to perturbations demonstrates a third-order root law and the eigenbasis of the Hamiltonian governing the system dynamics is still complete. Our results bring this counterintuitive aspect of the NEP to light and possibly open new avenues for applications.

Motion-aware object tracking for aerial images with deep features and discriminative correlation filter

AbstractObject tracking is a challenging task which is required for different problems such as surveillance, traffic analysis and human-computer interaction. The problem of tracking an object can be considered in different categories such as single object tracking, multiple object tracking, short-term tracking, long-term tracking, tracking by detection and detection-free tracking. This study focuses on detection-free tracking for ground targets on aerial images. The studies in the literature show that correlation filter and deep learning based object trackers perform well recently. This paper proposes a new correlation filter-based tracker containing a strategy for re-detection issue. We improve the performance of correlation filter-based tracker by adding a lightweight re-detection ability to the correlation filter tracker in case of a long occlusion or complete loss of target. We use deep features to train Discriminative Correlation Filter(DCF) by integrating sub-networks from pre-trained ResNet and SAND models. The experimental results on the popular UAV123L dataset show that the proposed method(MADCF) improves the performance of DCF tracker and have a reasonable performance for long-term tracking problem. Moreover, we prepare a new tracking dataset (PESMOD tracking) consisting of UAV images, and we evaluate the proposed method and state-of-the-art method in this dataset. We observed that the proposed method performs much better in ground target tracking from VIVID and PESMOD aerial datasets. The proposed MADCF tracker performs better for small targets tracked by UAVs compared to the deep learning-based trackers. The source code and prepared dataset are available at http://github.com/mribrahim/MADCF

Aversion to a High Salt Taste is Disturbed in Patients With CKD

IntroductionA reduced salt intake is a vital lifestyle modification in the management of hypertension. Initiatives aimed at decreasing the intake of salt are based on the preference by humans for a salt taste. Salt intake behavior appears to be affected by the balance between attraction to a low salt taste and aversion to a high salt taste. However, aversion to a high salt taste has not yet been quantitively investigated in both healthy individuals and CKD patients. MethodsAssessments of gustatory and aversion thresholds for salt, bitter, sour, and sweet tastes were performed using a stimulant-impregnated test strip in healthy subjects and CKD patients. ResultsIn a pilot taste test of 125 healthy subjects, the number of participants with an aversive reaction increased at higher salt concentrations. The threshold for normal taste perception was arbitrarily defined as 10% NaCl, with 47.2% of healthy subjects displaying an aversive reaction. In taste tests performed by 70 CKD patients, 10% were unable to recognize a salt taste, even at the highest concentration (20% NaCl), suggesting a significant impairment in taste perception in CKD patients. Only 15.7% of CKD patients exhibited a normal aversion to NaCl, while 78.6% showed the complete loss of aversion to salt. ConclusionThe present results confirmed the anticipated aversive response to a high salt taste in humans and demonstrated its impairment in CKD patients, implying that CKD patients have reduced resistance to a high salt intake.

Chiral recognition without π−π-interactions: Highly efficient chiral strong cation exchangers lacking an aromatic unit in the molecular structure

Current state-of-the-art chiral stationary phases (CSPs) enable chiral resolution of almost any racemic mixture of choice. The exceptions represent ionizable and ionized substances that fail at any attempts to resolve on commercially available CSPs. These compounds, however, can be efficiently separated on chiral ion exchangers. Commercially available Cinchona alkaloids-based chiral weak ion-exchangers are typically used for chiral resolution of organic acids, while zwitterion ion-exchangers are efficient in the resolution of acids, bases, and zwitterions. The latter possess in their structure a cation exchange unit, which alone can serve as a cornerstone of chiral strong cation exchangers facilitating chiral separation of various basic racemic mixtures.Although chiral strong cation exchangers (cSCX) are efficient CSPs, their structural variations have not been thoroughly studied so far. It was assumed that the mechanism of chiral recognition of basic compounds by cSCX is based predominantly on π-π-interactions, hydrogen bonding and steric interactions (CSP I). To verify this assumption, we aimed in our study on the design and synthesis of cSCX first lacking lateral polar substituents on the aromatic unit in the selector's structure (CSP II), and second, to replace the aromatic unit by a cyclohexane ring (CSP III and IV), thereby to omit completely the π-π-interactions. We hypothesized that this structural change should lead to a partial or complete loss of enantiorecognition power of the selectors. Surprisingly, the non-aromatic cSCXs have shown chiral recognition capability comparable to that of previously described chiral cation exchange-type CSPs: from 16 analytes screened, 11 analytes were baseline resolved and 5 partially resolved on CSP I, while non-aromatic CSP III resolved 10 analytes baseline and 6 partially.We discuss the structural motifs of the known cSCX and the novel non-aromatic selectors in a relationship with their chromatographic performance using a set of basic analytes. Moreover, we present a theory of an effective chiral recognition mechanism by two novel non-aromatic cSCXs based on the chromatographic results and quantum mechanical calculations.

Technology for Production of Wheat Doubled Haploid via Maize Pollen Induction—Updated Review

Chromosome elimination resulting in haploids is achieved by rapid loss of chromosomes from one parent during the zygote stage and is an important procedure to produce doubled haploid (DH) lines in plants. During crosses between an emasculated wheat (Triticum aestivum L.) and maize (Zea mays L.) as pollen donors, the complete loss of maize chromosomes results in wheat haploid embryos. Through embryo rescue and chromosome doubling processes, pure lines with stable traits can be quickly obtained. The technique is called the “Wheat × Maize System”. Although this technology is not new, it remains a practical approach to date. In order to optimize and improve this technology and to achieve its maximum potential in the winter wheat area of China, this paper reviews the previous and ongoing research and technical procedures for the production of wheat DH lines via the maize pollen induction and presents outlooks on DH research and its application in wheat breeding.

The C-terminus is essential for the stability of the mycobacterial channel protein MspA.

Outer membrane proteins perform essential functions in uptake and secretion processes in bacteria. MspA is an octameric channel protein in the outer membrane of Mycobacterium smegmatis and is structurally distinct from any other known outer membrane protein. MspA is the founding member of a family with more than 3000 homologs and is one of the most widely used proteins in nanotechnological applications due to its advantageous pore structure and extraordinary stability. While a conserved C-terminal signal sequence is essential for folding and protein assembly in the outer membrane of Gram-negative bacteria, the molecular determinants of these processes are unknown for MspA. In this study, we show that mutation and deletion of methionine 183 in the highly conserved C-terminus of MspA and mutation of the conserved tryptophan 40 lead to a complete loss of protein in heat extracts of M. smegmatis. Swapping these residues partially restores the heat stability of MspA indicating that methionine 183 and tryptophan 40 form a conserved sulfur-π electron interaction, which stabilizes the MspA monomer. Flow cytometry showed that all MspA mutants are surface-accessible demonstrating that oligomerization and membrane integration in M. smegmatis are not affected. Thus, the conserved C-terminus of MspA is essential for its thermal stability, but it is not required for protein assembly in its native membrane, indicating that this process is mediated by a mechanism distinct from that in Gram-negative bacteria. These findings will benefit the rational design of MspA-like pores to tailor their properties in current and future applications.

Application of supraclavicular island flap in oral and maxillofacial reconstruction.

(a) Evaluate the reliability of the supraclavicular flap in cervico-orofacial region; (b) investigate the role of computed tomography angiography (CTA) in predicting the post-operative viability of the flap; (c) assess the speech, feeding, and esthetics after reconstruction using this flap. Eleven patients included in this study underwent either conventional or delayed harvesting of the supraclavicular flap (SCF). All the patients had diagnostic computed tomography angiography (CTA) of the supraclavicular flap before the surgery. The mean harvesting time of the flap was 45.45 ± 4.16min. The average length of the flap was 22.64 ± 1.12cm, whereas the mean width of the flap was 6.14 ± 1.14cm. The flap survived in 9 patients, while two patients had complete flap loss. After the surgery, three patients complained of speech difficulties. Two patients had swallowing problems. After the surgery, three patients complained of speech difficulties. Two patients had swallowing problems. Only two patients complained of weakness in the donor site. None of the patients reported that the weakness or pain at the donor site affected their daily activities or quality of life. The pedicled SCF represents a safe and feasible option that can be used to reconstruct a wide array of maxillofacial oncologic defects. However, a study with a larger sample size is recommended to achieve more reliable clinical results for the modified delayed technique modification in terms of their effect on the survival of the supraclavicular flap.

A158 DEVELOPMENT OF MODELS TO SUDY THE INTERACTION BETWEEN CANCER STEM CELLS AND THE MICROENVIRONMENT IN COLON CANCER

Abstract Background Colon cancer affects 1 in 15 people and is the 3rd deadliest cancer worldwide. The standard of care consists of surgical resection combined with 5-fluorouracil (5-FU) chemotherapy. However, relapses remain frequent due to a partial or complete loss of sensitivity to treatment, also known as chemoresistance. Over the last decades, studies have revealed the importance of intratumoral heterogeneity in this phenomenon, and in particular of two components: cancer stem cells (CSCs) and the microenvironment. CSCs are cells with a high capacity of self-renewal, potency (ability to give rise to different cell types) and resistance to anti-cancer treatments. The microenvironment, for its part, comprises all the components surrounding tumour cells, such as cancer-associated fibroblasts (CAFs). Although their respective importance in resistance has been well studied, it is important to better understand their respective modulation during resistance as well as their interactions. Aims Identify the specific changes occurring in CSCs and CAFs, as well as their interactions, during the induction of 5-FU resistance in colon cancer. Methods To achieve this goal, we are establishing 5-FU resistant models using organoid lines from colon cancer patients. First, we validated that parental organoids maintain their expected cellular heterogeneity by immunofluorescence. We also confirmed that our parental organoids are sensitive to 5-FU by measuring the survival through a WST1 assay. Results Indeed, we showed the presence of CSCs (ALDH1+) and proliferative cells (Ki67+), among others. With a baseline IC50 of 5µM, we concluded that they can be used to generate a 5-FU resistant line. In addition, our initial findings suggest that the conditioned media of CAF cultures decreases the sensitivity of parental organoids to 5-FU, emphasizing the need to study deeper the interaction between these two tumor components Conclusions In summary, our preliminary results suggest that the interaction between tumor cells and CAFs modulates the response to chemotherapy. We are currently exploring whether CSCs are particularly involved in this phenomenon. In addition, we are developing patient-derived xenograft models (PDX) sensitive or resistant to 5-FU in order to study in vivo the interactions between CAFs and CSCs. At the end, this project will provide a better understanding of the changes required for resistance, paving the way for new targeted therapies Funding Agencies Canada foundation for innovation, Canada Research Chairs

Loss of or decrease in CD30 expression in four patients with anaplastic large cell lymphoma after brentuximab vedotin-containing therapy.

Brentuximab vedotin (BV), CD30 specific antibody drug conjugate, has been used to treat anaplastic large cell lymphoma (ALCL) and classic Hodgkin lymphoma (CHL); it is also used in the treatment of other CD30-positive peripheral T-cell lymphomas. We aimed to investigate the incidence and clinicopathological characteristics of patients with ALCL or CHL with loss of or decrease in CD30 expression after BV-containing therapy. Twelve and nine patients with refractory/relapsed CHL and ALCL, respectively, were analyzed after receiving BV-containing therapy. In four ALCL patients (44%), CD30 expression was lost/decreased in re-biopsy materials, including one with complete loss and three with a reduction of less than 20%. All 12 CHL patients showed consistent CD30 expression levels after BV treatment. Compared with five ALCL patients with consistent CD30 expression, four ALCL patients with a loss of/decrease in CD30 expression received a higher cumulative dose of BV (P = 0.014) and revealed a lower intensity of CD30 expression in initial biopsy materials (P = 0.017). The subtypes of ALCL (ALK positive, ALK negative, and primary cutaneous) were not related to the loss of/decrease in CD30 expression. In conclusion, 44% of ALCL patients, regardless of histological subtypes, showed a loss of/decrease in CD30 expression after receiving BV-containing therapy, but this phenomenon was not observed in CHL patients. A higher cumulative dose of BV and a lower amount of CD30 antigen in tumor cells in the initial biopsy materials might be predictors of a loss of/decrease in CD30 expression in ALCL patients.

Ferritin-nanocaged aggregation-induced emission nanoaggregates for NIR-II fluorescence-guided noninvasive, controllable male contraception

Controllable contraception in male animals was demonstrated through the utilization of gold nanorods' photothermal effect to accomplish mild testicular hyperthermia. However, the challenges arising from testicular administration and the non-biodegradability of nanoparticles hinder further clinical implementation. Therefore, a straightforward, non-invasive, and enhanced contraception approach is required. This study explores the utilization of human heavy chain ferritin (HFn) nanocarriers loaded with aggregation-induced emission luminogens (AIEgens) for noninvasive, controllable male contraception guided by Near-Infrared-II (NIR-II) fluorescence imaging. The HFn-caged AIEgens (HFn@BBT) are delivered via intravenous injection and activated by near-infrared irradiation. Lower hyperthermia treatment induces partial damage to the testes and seminiferous tubules, reducing fertility indices by approximately 100% on the 7th day, which gradually recovers to 80% on the 60th day. Conversely, implementation of elevated hyperthermia therapy causes total destruction of both testes and seminiferous tubules, leading to a complete loss of fertility on the 60th day. Additionally, the use of AIEgens in NIR-II imaging offers improved fluorescence efficiency and penetration depth. The findings of this study hold significant promise for the advancement of safe and effective male contraceptive methods, addressing the need for noninvasive and controllable approaches to reproductive health and population control.

Ocular Manifestations of Von Hippel-Lindau Disease: a Rare Sight- Threatening Condition

Introduction : Von Hippel-Lindau (VHL) disease is a rare phacomatosis characterized by multi-organ neoplasia which usually manifests in young adulthood. Ocular manifestations of this disease are frequently presented initially before the involvement of other organ systems.
 Case Illustration : An 18-year-old girl came with a chief complaint of photopsia in the left eye and complete vision loss in the right eye for five years. The visual acuity of the right eye was no light perception and the left eye was 0.8. The anterior segment of the right eye showed iris neovascularization. The posterior segment of the left eye demonstrated multiple elevated red-yellowish lesions fed by a dilated and tortuous vessel. The head CT scan revealed multiple lesions at the pons and cerebellum. The patient was diagnosed with multiple retinal and brain hemangioblastomas due to VHL disease, neovascular glaucoma, and chronic retinal detachment of the right eye due to sequelae of VHL. The patient was treated with cryotherapy and laser photocoagulation of the left eye. Five-month post-cryotherapy follow-up showed the lesions were still active then she underwent the second cryotherapy. The lesions became whitish in appearance with smaller feeder vessels one month after the second cryotherapy and the visual acuity was preserved.
 Discussion : Retinal hemangioblastoma is the most common ocular manifestation of VHL disease. Prolonged ischemia causes sight-threatening complications including neovascular glaucoma and exudative retinal detachment. Prompt treatment of detected lesions is crucial for visual preservation.
 Conclusion : Early detection of VHL ocular manifestations plays a critical role in establishing the diagnosis and initiating treatment for a better prognosis.

Post-COVID-19 patients suffer from chemosensory, trigeminal, and salivary dysfunctions

Recent literature indicates that post-COVID-19 patients suffer from a plethora of complications, including chemosensory dysfunction. However, little attention has been given to understand the interactions between chemosensory, trigeminal, and salivary dysfunctions in these patients. The aims of this study were (1) to investigate the prevalence and combinations of chemosensory, trigeminal, and salivary dysfunctions, (2) to identify the odorants/tastants that are compromised, and (3) to explore possible associations between the four dysfunctions in post-COVID-19 patients. One hundred post-COVID-19 patients and 76 healthy controls (pre-COVID-19) were included in this cross-sectional, case-controlled study. Participants' smell, taste, trigeminal, and salivary functions were assessed. The patients had a significantly higher prevalence of parosmia (80.0%), hyposmia (42.0%), anosmia (53.0%), dysgeusia (34.0%), complete ageusia (3.0%), specific ageusia (27.0%), dysesthesia (11.0%) and dry mouth (18.0%) compared to controls (0.0% for all parameters, except 27.6% for hyposmia). Complete loss of bitter taste was the most prevalent specific ageusia (66.7%) and coffee was the most common distorted smell (56.4%). Seven different combinations of dysfunction were observed in the patients, the most common being a combination of olfactory and gustatory dysfunction (48.0%). These findings indicate that post-COVID-19 patients experience a range of chemosensory, trigeminal, and salivary disturbances, occurring in various combinations.

Peroxin MoPex22 Regulates the Import of Peroxisomal Matrix Proteins and Appressorium-Mediated Plant Infection in Magnaporthe oryzae.

Magnaporthe oryzae, the pathogen responsible for rice blast disease, utilizes specialized infection structures known as appressoria to breach the leaf cuticle and establish intracellular, infectious hyphae. Our study demonstrates that the peroxin MoPex22 is crucial for appressorium function, specifically for the development of primary penetration hyphae. The ∆Mopex22 mutant exhibited slow growth, reduced aerial hyphae, and almost complete loss of virulence. Specifically, despite the mutant's capability to form appressoria, it showed abnormalities during appressorium development, including reduced turgor, increased permeability of the appressorium wall, failure to form septin rings, and significantly decreased ability to penetrate host cells. Additionally, there was a delay in the degradation of lipid droplets during conidial germination and appressorium development. Consistent with these findings, the ΔMopex22 mutant showed an inefficient utilization of long-chain fatty acids and defects in cell wall integrity. Moreover, our findings indicate that MoPex22 acts as an anchor for MoPex4, facilitating the localization of MoPex4 to peroxisomes. Together with MoPex4, it affects the function of MoPex5, thus regulating the import of peroxisomal matrix proteins. Overall, these results highlight the essential role of MoPex22 in regulating the transport of peroxisomal matrix proteins, which affect fatty acid metabolism, glycerol accumulation, cell wall integrity, growth, appressorium development, and the pathogenicity of M. oryzae. This study provides valuable insights into the significance of peroxin functions in fungal biology and appressorium-mediated plant infection.

INFLUENCE OF PULSE ELECTROMAGNETIC RADIATION ON PERFORMANCE OF ELECTRIC RADIO PRODUCTS

The subject matter is the processes of analysis of the occurrence of reversible and irreversible failures of semiconductor devices under conditions of exposure to electromagnetic radiation. It is shown that the influence of pulsed electromagnetic radiation is accompanied by the emergence of currents in the conductive elements of products and the emergence of their internal fields. The mechanisms for the occurrence of instabilities of natural oscillations of semiconductor components of electrical and radio products, caused by their interaction with flows of charged particles, have been determined. The presence of instabilities of this kind has a significant impact on the spectral (operating) characteristics of electrical radio products. The results obtained in the work make it possible to assess the degree of influence of pulsed electromagnetic radiation on the operating (volt-ampere) characteristics of electrical radio products. The aim is a model of the mechanisms of the emergence and development of instabilities of natural oscillations of semiconductor structures, components of electrical radio products (communication equipment), in the presence of currents and voltages induced by pulsed electromagnetic radiation. The implementation of such a model is due to the possibility of transforming the energy of a flow of charged particles induced by external electromagnetic radiation into the energy of natural vibrations of a semiconductor structure, taking into account the properties of the structure itself (size, concentration of free carriers, permeability). The transformation of the energy of currents induced by electromagnetic radiation into natural vibrations of a semiconductor structure is determined by two effects (transition or Cherenkov radiation) depending on the location of the structure relative to the direction of the currents. The objectives are: the main electromagnetic effects affecting performance of electrical radio products (ERI) under exposure conditions external pulsed radiation and also indicates characteristic changes ERI parameters that determine their functional purpose, which are a consequence of these effects. The methods used are the method of successive approximations over a small parameter, which allows one to determine the spectrum of natural oscillations of a semiconductor device and the mode of their amplification (instability). The following results are obtained. The results of studies characterizing the malfunction of electrical radio products under conditions of exposure to third-party electromagnetic radiation are presented, as well as the main parameters characterizing the electromagnetic resistance of electronic devices to the effects of pulsed currents and voltages. The characteristic types of malfunctions of semiconductor devices (SCD), components of electronic components, in areas of irreversible and reversible failures, as well as the levels of intensities and currents of electric and magnetic fields affecting the SPD, separating the areas of reversible and irreversible failures, are given. Using the energy approach, a physical model of the occurrence of one of the types of reversible failures of the semiconductor element base (the appearance of S-shaped sections of currentvoltage characteristics) has been developed. This physical model makes it possible to determine the criteria for the electromagnetic resistance of a number of semiconductor devices to the effects of external pulsed radiation and also to obtain calculated ratios for assessing the degree of deviation of the operating characteristics of the PPP from the norm. Conclusion. Development of design relationships that determine the modes of amplification (generation) of oscillations of electrical radio products, making it possible to determine the degree of distortion of their current-voltage characteristics (reversible failures) and complete loss of performance (irreversible failures) depending on the parameters of external electromagnetic radiation. The results obtained in the work can be used in the development of amplifiers, generators and frequency converters operating in the millimeter and submillimeter range that are resistant to external electromagnetic radiation. Quantitative estimates of the criterion for reversible failures (instability increments) show that the amount of radiation energy lies within the sensitivity of modern submillimeter radiation receivers and is the cause of failures.

A Deep Sequencing Strategy for Investigation of Virus Variants within African Swine Fever Virus-Infected Pigs.

African swine fever virus (ASFV) is the causative agent of African swine fever, an economically important disease of pigs, often with a high case fatality rate. ASFV has demonstrated low genetic diversity among isolates collected within Eurasia. To explore the influence of viral variants on clinical outcomes and infection dynamics in pigs experimentally infected with ASFV, we have designed a deep sequencing strategy. The variant analysis revealed unique SNPs at <10% frequency in several infected pigs as well as some SNPs that were found in more than one pig. In addition, a deletion of 10,487 bp (resulting in the complete loss of 21 genes) was present at a nearly 100% frequency in the ASFV DNA from one pig at position 6362-16849. This deletion was also found to be present at low levels in the virus inoculum and in two other infected pigs. The current methodology can be used for the currently circulating Eurasian ASFVs and also adapted to other ASFV strains and genotypes. Comprehensive deep sequencing is critical for following ASFV molecular evolution, especially for the identification of modifications that affect virus virulence.

The use of customized 3D-printed mandibular prostheses with pressure-reducing device: A clinical trial.

Segmental bone defects of the mandible result in the complete loss of the affected region. We had incorporated the pressure-reducing device (PRD) designs into the customized mandible prostheses (CMP) and conducted a clinical trial to evaluate this approach. Seven patients were enrolled in this study. We examined the association among the history of radiotherapy, the number of CMP regions, the number of chin regions involved, and CMP exposure. We included five men and two women with an average age of 55 years. We excised tumors with an average weight of 147.8 g and the average weight of the CMP was 68.5 g. No significant difference between the two weights was noted (p = 0.3882). Three patients received temporary dentures and the CMP remained stable in all patients. The use of PRD in CMP may address the previous challenges associated with CMP, but further research is necessary.

Occlusion of the Lateral Semicircular Canal, Endolymphatic Sac Surgery, and Cochlear Implantation: A Low Destructive Treatment for Unilateral Ménière’s Disease and Deafness

Introduction: Surgical treatment of Ménière’s disease (MD) and deafness aims to treat vertigo and hearing disabilities. Current treatment options like labyrinthectomy and cochlear implantation (CI) have shown acceptable results but are destructive. Less destructive procedures, like the occlusion of the lateral semicircular canal and endolymphatic sac surgery, have been shown to be successful in vertigo control. The combination of both procedures with CI has not been investigated; therefore the objective of this study was to investigate the outcome of this combination in patients with single-sided MD and moderately severe to complete sensorineural hearing loss. Methods: In this retrospective study, 10 patients with single-sided MD and moderately severe to complete sensorineural hearing loss were included. In all of them, a single-staged surgery, which consisted of CI, endolymphatic sac surgery, and occlusion of the lateral semicircular canal, was performed. The surgery was performed after a failed conservative therapy trial. The clinical outcome was evaluated by the Dizziness Handicap Inventory (DHI) and audiological tests. These were assessed preoperatively, 3 and 6 months after surgery. An MRI with a hydrops sequence was performed to support the clinical diagnosis. Results: After the combined surgery, the mean DHI testing improved significantly from 71 to 30. Mean audiological monosyllabic speech testing outcome with the cochlea implant was 65% at 65 dB. The residual hearing of 2 patients could be preserved after the surgical procedure. Conclusion: The combination of occlusion of the lateral semicircular canal, endolymphatic sac surgery, and CI is an efficient low traumatic treatment for patients with a single-sided MD and moderately severe to complete sensorineural hearing loss.

A noncanonical splicing variant c.875-5 T > G in von Willebrand factor causes in-frame exon skipping and type 2A von Willebrand disease

IntroductionA novel variant involving noncanonical splicing acceptor site (c.875-5 T > G) in propeptide coding region of von Willebrand factor (VWF) was identified in a patient with type 2A von Willebrand disease (VWD), who co-inherited with a null variant (p.Tyr271*) and presented characteristic discrepancy of plasma level of VWF antigen and activity, and a selective reduction of both intermediate-molecular-weight (IMWMs) and high-molecular-weight VWF multimers (HMWMs). Materials and methodsVWF mRNA transcripts obtained from peripheral leukocytes and platelets of the patients were investigated to analyze the consequence of c.875-5 T > G on splicing. The impact of the variant on expression and multimer assembly was further analyzed by in vitro expression studies in AtT-20 cells. The intracellular processing of VWF mutant and the Weibel-Palade bodies (WPBs) formation was evaluated by immunofluorescence staining and electron microscopy. ResultsThe mRNA transcript analysis revealed that c.875-5 T > G variant led to exon 8 skipping and an in-frame deletion of 41 amino acids in the D1 domain of VWF (p.Ser292_Glu333delinsLys), yielding a truncated propeptide. Consistent with the patient's laboratory manifestations, the AtT-20 cells transfected with mutant secreted less VWF, with the VWF antigen level in conditioned medium 47 % of wild-type. A slight retention in the endoplasmic reticulum was observed for the mutant. Almost complete loss of IMWMs and HMWMs in the medium and impaired WPBs formation in the cell, indicating truncated VWF propeptide lost its chaperon-like function for VWF multimerization and tubular storage. ConclusionsThe VWF splicing site variant (c.875-5 T > G) causes propeptide truncation, severely compromising VWF multimer assembly and tubular storage.

Adiponectin secretion by perivascular adipose tissue supports impaired vasodilation in a mouse model of accelerated vascular smooth muscle cell and adipose tissue aging

ObjectivePerivascular adipose tissue (PVAT) function during aging has not been investigated in detail so far and its effect on vasodilation remains to be fully elucidated. The aim of this study was to investigate endothelium-dependent vasodilation of thoracic aorta in a mouse model of accelerated, selective vascular smooth muscle and PVAT aging, induced by SM22α-Cre-driven genetic deletion of the endonuclease ERCC1 (SMC-KO mice) versus healthy littermates (LM). We hypothesized that PVAT enhances vasodilation in LM, possibly through adiponectin secretion, which might be compromised in SMC-KO animals. MethodsThoracic aorta was isolated from SMC-KO animals and LM and segments with and without PVAT were mounted in wire myography setups. The endothelium-dependent vasodilation was assessed via acetylcholine dose-response curves and pathway contribution was studied. Moreover, adiponectin secretion was measured after stimulating the aortic segments with PVAT with acetylcholine. ResultsAdiponectin, secreted by PVAT, led to increased NO-contribution to endothelium-dependent vasodilation in healthy LM, although this did not increase maximum relaxation due to loss of EDH. Endothelium-dependent vasodilation was decreased in SMC-KO animals due to reduced NO-contribution and complete EDH loss. Despite strong lipodystrophy the PVAT partially compensated for lost vasodilation in SMC-KO. LM PVAT contained acetylcholinesterase that attenuated acetylcholine responses. This was lost in SMC-KO. ConclusionsPVAT-derived adiponectin is able to partially compensate for age-related decline in NO-mediated vasodilation, even during strong lipodystrophy, in conditions of absence of compensating EDH. In aorta with healthy PVAT acetylcholinesterase modulates vascular tone, but this is lost during aging, further compensating for decreased acetylcholine responsiveness. Thus, preservation of adiponectin levels, through relatively increased production in lipodystrophic PVAT, and reduction of cholinesterase might be regulatory mechanisms of the PVAT to preserve cholinergic vasodilation during aging.

Filamin C Deficiency Impairs Sarcomere Stability and Activates Focal Adhesion Kinase through PDGFRA Signaling in Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Truncating mutations in filamin C (FLNC) are associated with dilated cardiomyopathy and arrhythmogenic cardiomyopathy. FLNC is an actin-binding protein and is known to interact with transmembrane and structural proteins; hence, the ablation of FLNC in cardiomyocytes is expected to dysregulate cell adhesion, cytoskeletal organization, sarcomere structural integrity, and likely nuclear function. Our previous study showed that the transcriptional profiles of FLNC homozygous deletions in human pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are highly comparable to the transcriptome profiles of hiPSC-CMs from patients with FLNC truncating mutations. Therefore, in this study, we used CRISPR-Cas-engineered hiPSC-derived FLNC knockout cardiac myocytes as a model of FLNC cardiomyopathy to determine pathogenic mechanisms and to examine structural changes caused by FLNC deficiency. RNA sequencing data indicated the significant upregulation of focal adhesion signaling and the dysregulation of thin filament genes in FLNC-knockout (FLNCKO) hiPSC-CMs compared to isogenic hiPSC-CMs. Furthermore, our findings suggest that the complete loss of FLNC in cardiomyocytes led to cytoskeletal defects and the activation of focal adhesion kinase. Pharmacological inhibition of PDGFRA signaling using crenolanib (an FDA-approved drug) reduced focal adhesion kinase activation and partially normalized the focal adhesion signaling pathway. The findings from this study suggest the opportunity in repurposing FDA-approved drug as a therapeutic strategy to treat FLNC cardiomyopathy.