Identification of the First Single GSDME Exon 8 Structural Variants Associated with Autosomal Dominant Hearing Loss

GSDME, also known as DFNA5, is a gene implicated in autosomal dominant nonsyndromic hearing loss (ADNSHL), affecting, at first, the high frequencies with a subsequent progression over all frequencies. To date, all the GSDME pathogenic variants associated with deafness lead to skipping of exon 8. In two families with apparent ADNSHL, massively parallel sequencing (MPS) integrating a coverage-based method for detection of copy number variations (CNVs) was applied, and it identified the first two causal GSDME structural variants affecting exon 8. The deleterious impact of the c.991-60_1095del variant, which includes the acceptor splice site sequence of exon 8, was confirmed by the study of the proband’s transcripts. The second mutational event is a complex rearrangement that deletes almost all of the exon 8 sequence. This study increases the mutational spectrum of the GSDME gene and highlights the crucial importance of MPS data for the detection of GSDME exon 8 deletions, even though the identification of a causal single-exon CNV by MPS analysis is still challenging.

Covariance predicts conserved protein residue interactions important to the emergence and continued evolution of SARS-CoV-2 as a human pathogen

SARS-CoV-2 is one of three recognized coronaviruses (CoVs) that have caused epidemics or pandemics in the 21st century and that likely emerged from animal reservoirs. Differences in nucleotide and protein sequence composition within related lower case Greek beta-coronaviruses are often used to better understand CoV evolution, host adaptation, and their emergence as human pathogens. Here we report the comprehensive analysis of amino acid residue changes that have occurred in lineage B lower case Greek betacoronaviruses (sarbecoviruses) that show covariance with each other. This analysis revealed patterns of covariance within conserved viral proteins that potentially define conserved interactions within and between core proteins encoded by SARS-CoV-2 related lower case Greek beta-coranaviruses. We identified not only individual pairs but also networks of amino acid residues that exhibited statistically high frequencies of covariance with each other using an independent pair model followed by a tandem model approach. Using 149 different CoV genomes that vary in their relatedness, we identified networks of unique combinations of alleles that can be incrementally traced genome by genome within different phylogenic lineages. Remarkably, covariant residues and their respective regions most abundantly represented are implicated in the emergence of SARS-CoV-2 and are also enriched in dominant SARS-CoV-2 variants.

Consequences of quantum noise control for the relaxation resonance frequency and phase noise in heterogeneous Silicon/III–V lasers

We have recently introduced a new semiconductor laser design which is based on an extreme, 99%, reduction of the laser mode absorption losses. In previous reports, we showed that this was achieved by a laser mode design which confines the great majority of the modal energy (> 99%) in a low-loss Silicon guiding layer rather than in highly-doped, thus lossy, III–V p$${}^+$$ + and n$${}^+$$ + layers, which is the case with traditional III–V lasers. The resulting reduced electron-field interaction was shown to lead to a commensurate reduction of the spontaneous emission rate by the excited conduction band electrons into the laser mode and thus to a reduction of the frequency noise spectral density of the laser field often characterized by the Schawlow–Townes linewidth. In this paper, we demonstrate theoretically and present experimental evidence of yet another major beneficial consequence of the new laser design: a near total elimination of the contribution of amplitude-phase coupling (the Henry $$\alpha $$ α parameter) to the frequency noise at “high” frequencies. This is due to an order of magnitude lowering of the relaxation resonance frequency of the laser. Here, we show that the practical elimination of this coupling enables yet another order of magnitude reduction of the frequency noise at high frequencies, resulting in a quantum-limited frequency noise spectral density of 130 Hz$$^2$$ 2 /Hz (linewidth of 0.4 kHz) for frequencies beyond the relaxation resonance frequency 680 MHz. This development is of key importance in the development of semiconductor lasers with higher coherence, particularly in the context of integrated photonics with a small laser footprint without requiring any sort of external cavity.

Antiviral CD19 + CD27 + Memory B Cells Are Associated with Protection from Recurrent Asymptomatic Ocular Herpes Infection

Reactivation of herpes simplex virus 1 (HSV-1) from latently infected neurons of the trigeminal ganglia (TG) leads to blinding recurrent herpetic disease in symptomatic (SYMP) individuals. Although the role of T cells in herpes immunity seen in asymptomatic (ASYMP) individuals is heavily explored, the role of B cells is less investigated. In the present study, we evaluated whether B cells are associated with protective immunity against recurrent ocular herpes. The frequencies of circulating HSV-specific memory B cells and of memory follicular helper T cells (CD4 + T fh cells), that help B cells produce antibodies, were compared between HSV-1 infected SYMP and ASYMP individuals. The levels of IgG/IgA and neutralizing antibodies were compared in SYMP and ASYMP individuals. We found that: ( i ) the ASYMP individuals had increased frequencies of HSV-specific CD19 + CD27 + memory B cells; and ( ii ) high frequencies of HSV-specific switched IgG + CD19 + CD27 + memory B cells detected in ASYMP individuals were directly proportional to high frequencies of CD45R0 + CXCR5 + CD4 + memory T fh cells. However, no differences were detected in the level of HSV-specific IgG/IgA antibodies in SYMP and ASYMP individuals. Using the UV-B-induced HSV-1 reactivation mouse model, we found increased frequencies of HSV-specific antibody-secreting plasma HSV-1 gD + CD138 + B cells within the TG and circulation of ASYMP mice compared to SYMP mice. In contrast, no significant differences in the frequencies of B cells were found in the cornea, spleen, and bone-marrow. Our findings suggest that circulating antibody-producing HSV-specific memory B cells recruited locally to the TG may contribute to protection from symptomatic recurrent ocular herpes. IMPORTANCE Reactivation of herpes simplex virus 1 (HSV-1) from latently infected neurons of the trigeminal ganglia (TG) leads to blinding recurrent herpetic disease in symptomatic (SYMP) individuals. Although the role of T cells in herpes immunity against blinding recurrent herpetic disease is heavily explored, the role of B cells is less investigated. In the present study, we found that in both asymptomatic (ASYMP) individuals and ASYMP mice there was increased frequencies of HSV-specific memory B cells that were directly proportional to high frequencies of memory T fh cells. Moreover, following UV-B induce reactivation, we found increased frequencies of HSV-specific antibody-secreting plasma B cells within the TG and circulation of ASYMP mice, compared to SYMP mice. Our findings suggest that circulating antibody-producing HSV-specific memory B cells recruited locally to the TG may contribute to protection from recurrent ocular herpes.

Assessment of COVID-19 mRNA vaccination titer and side effects in healthy volunteers

Objectives An effective vaccine against SARS-CoV-2 is essential to mitigate the COVID-19 pandemic. In these several months, a number of groups have started to report humoral responses and side effects after BNT162b2 vaccinations. Although these reports demonstrate the safety and efficacy, further studies are warranted to verify these findings. Here we examined the levels of SARS-CoV-2 antibodies in Japanese healthy volunteers who underwent BNT162b2 vaccine, to assess the humoral responses and side effects. Methods Forty-one healthy volunteers’ samples were used for the measurement of SARS-CoV-2 antibodies with chemiluminescent assays against the Receptor Binding Domain (RBD) of the virus. We also measured the side effects of the vaccination. Results Although the levels of IgM varied, all participants were seronegative for IgM and IgG before vaccination, and both IgM and IgG were significantly increased after the vaccinations. We further analyzed the humoral responses in relation to age, and found that the IgG levels for 14 days and 35 days, and IgM levels for 14 days after vaccination showed clear declining trends with age. Commonly reported side effects in the participants were sore arm/pain (90.0%) after the first dose, and generalized weakness/fatigue (70.0%), fever (57.5%), and sore arm/pain (90.0%) after the second dose. Conclusions BNT162b2 vaccination generates sufficient production of IgG especially after the second dose, though the response decreases age-dependently. The high frequencies of generalized weakness/fatigue, fever, and sore arm/pain were not negligible, especially after the second dose. This may be associated with the age characteristics of the population.

Wood-based composite materials for ultralight lens antennas in 6G systems

Extremely high frequencies used in future wireless communication systems such as 6G require low loss materials to avoid wasting power and maintain acceptable efficiency . Furthermore, especially in the internet...

Радиопоглощающие и радиоэкранирующие характеристики феррит-полимерных композитов Mn-Zn феррит/П (ТФЭ-ВДФ)

The article discusses the electromagnetic absorbing and shielding properties of ferrite-polymer composites of the composition Mn-Zn ferrite/fluoroplast-42, obtained by pressing a mixture of powders with heating. The measurement of the complex magnetic and dielectric permittivity spectra, as well as the reflection coefficient spectra was carried out in the frequency range 0.1 - 7 GHz. Using the obtained spectra, a comprehensive analysis of the absorbing characteristics of the composites was carried out, and the factors responsible for the absorption were determined. Fitting of the composites magnetic permeability spectra show that the process of natural ferromagnetic resonance prevails over the resonance of domain walls, and a decrease in the concentration of ferrite inclusions leads to a significant shift in the frequency of natural ferromagnetic resonance to high frequencies. It was found that for composites with a thickness of 5 - 10 mm, compositions with a mass fraction of ferrite ≤ 0.4 show radio-absorbing properties, while compositions with a fraction of ≥ 0.6 show shielding properties.

GCM2 Variants in Familial and Multiglandular Primary Hyperparathyroidism

Context Multiglandular and familial parathyroid disease constitute important fractions of primary hyperparathyroidism (PHPT). Germline missense variants of GCM2, a regulator of parathyroid development, were observed in familial isolated hyperparathyroidism (FIHP) and sporadic PHPT. However, as these previously-reported GCM2 variants occur at relatively high frequencies in the population, understanding their potential clinical utility will require both additional penetrance data and functional evidence relevant to tumorigenicity. Objective Determine the frequency of GCM2 variants-of-interest among patients with sporadic multigland or familial parathyroid disease, and assess their penetrance. Design and Patients DNA encoding PHPT-associated GCM2 germline-variants were PCR-amplified and sequenced from 107 patients with either sporadic multigland or suspected/confirmed familial parathyroid tumors. Results GCM2 variants were observed in 9 of 107 cases (8.4%): Y282D in 4 patients (6.3%) with sporadic multigland disease; Y394S in 2 patients (11.1%) with familial PHPT and three (4.8%) with sporadic multigland disease. Compared with the general population, Y282D was enriched 5.9-fold in multigland disease but its penetrance was very low (0.02%). Y394S was enriched 79-fold in sporadic multigland disease and 93-fold in familial PHPT, but its penetrance was low (1.33%, 1.04% respectively). Conclusions Observed in vitro activating GCM2 variant alleles are significantly overrepresented in PHPT patients with multiglandular or familial disease compared with the general population, yet penetrance values are very low i.e. most individuals with these variants in the population have a very low risk of developing PHPT. The potential clinical utility of detecting these GCM2 variants requires further investigation, including assessing their possible role as pathogenic/low-penetrance alleles.

New features of the pulsar B0950+08 radiation at the frequency of 111 MHz

Results of long time observations of the pulsar B0950+08 are given. These observations were carried out at the LPA radio telescope at the frequency of 111 MHz from January of 2016 to May of 2019 (450 days). A strong variability in emission of this pulsar has been detected with changes of signal to noise ratios hundreds of times. Part of long-time flux density variability can be explained by the refractive scintillations in the interstellar medium. The existence of radiation between the interpulse (IP) and main pulse (MP) was confirmed. It was more powerful than at high frequencies. We detected the unusual interpulse and precursor (Pr) radiation on August 1, 2017. On the base of strong 65 interpulses we found the correlations between energies of IP and Pr and between the phase of IP and the distance Pr-IP. It is shown that the observed peculiarities of this pulsar can be explained in the frame of the aligned rotator model. We estimated distances of radiation levels from the center of the neutron star. The calculated value of the initial period of 0.2 sec means that not all pulsars are born with millisecond periods. The large age of the pulsar (6.8 millions of years) and the small angle between its magnetic moment and the rotation axis (less than 20°) confirm the suggestion on the pulsar evolution to an alignment.

Treating Agitation in Patients with Dementia with a Therapy Dog in a Milieu Therapy Setting on a Geropsychiatric Ward

<b><i>Background:</i></b> Animal-assisted intervention has become a common therapeutic practice used for patients with dementia in home-dwelling and institutions. The most established procedure is a visiting service by specially trained dogs and their owners to improve social interactions and reduce symptoms of agitation. <b><i>Objectives:</i></b> The study aims to investigate the effects of a therapy dog on agitation of inpatients with dementia in a gerontopsychiatric ward. <b><i>Materials and Methods:</i></b> The severity of agitation was assessed by a rater blinded for the presence of the dog via the Overt Agitation Severity Scale (OASS). The scale was conducted on 1 day with the dog and his handler present (resident doctor on the ward) and on another day with only the handler present. Each patient was his/her own control. Heart rate variability (HRV) and serum level of brain-derived neurotrophic factor (BDNF) of the patients were measured on both days. 26 patients with the Mini-Mental Status Examination (MMSE) score &#x3c;21 and the diagnosis of dementia were included in the study. <b><i>Results:</i></b> A significant reduction of agitation in the OASS could be shown when the dog was present (<i>p</i> = 0.006). The data neither demonstrated a difference in the HRV for the parameters mean heart rate (<i>p</i> = 0.65), root mean square of successive differences (<i>p</i> = 0.63), and high frequencies (<i>p</i> = 0.27) nor in serum BDNF concentrations (<i>p</i> = 0.42). <b><i>Discussion:</i></b> Therapy dogs can be implemented as a therapeutic tool in a gerontopsychiatric ward to reduce symptoms of agitation in patients with dementia. The study was registered in the German Clinical Trials Register (DRKS00024093).