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The article considers the key problems of the transition of the national health system to a new platform of personalized medicine and, in particular, pediatrics. In the second part, published in this issue, the main mechanisms for building a new model are analyzed. The main prerequisites (financial and economic, fundamental research and applied research), the emergence and construction in the structure of global trends in the development of health care markets, actualized at the end of the last century, are presented. It is indicated that one of the main incentives for the development of personalized medicine is a noticeable increase in individual and social demand for preventive drugs and the corresponding tools. The development of programs for managing their own health is gaining in importance, and new business-development models (including public and private partnerships) are being developed and implemented. The evidence is examined that a progressive scenario for the development of a model of personalized medicine will provide a significant reduction in the cost of medical care. A large section of the article is devoted to the development of the provision that the understanding and awareness of the importance of the protection and management of one's own health by a modern state, medical audience and individual citizen is the most important aspect of the educational and educational activities of a doctor and a nurse. The perspectives of personalized pediatrics as a global instrument for restructuring the entire healthcare system are considered in detail.

The article considers the key problems of the transition of the national health-care system to a new platform of personalized medicine and, in particular, pediatrics. The first part, published in this issue, analyzes the most important of the necessary aspects of the infrastructure of the new model. Evidence is given of the extreme urgency of introducing a new model of predictive, preventive and personalized medicine (PPPM). The result of implementation should be breakthrough success in solving many epidemiological, diagnostic, curative, preventive, social and economic problems. It is emphasized that neonatology and pediatrics are the most important link in this paradigm. When considering the potential architectonics of the model, important characteristics of its main segments are revealed. Diagnostic principles (genotyping, targeting, and dynamic screening of biomarkers) and arsenal (genomics, proteomics, metabolomics, mathematical modeling tools, etc.) of personalized medicine are presented. Attention is focused on the need to create information (global, regional and target-specific) banks that are necessary for monitoring individual health. The need to create a new social decision-making mechanism for selecting a preventive protocol that minimizes the risks of the disease or prevents its development is discussed. Four categories of basic programs of medical and social support of persons from the risk category are considered. The necessary conditions for translating these programs into practice are presented. The main tasks and problems of developing the principles for the preparation of preventive-prophylactic and protocols of medical rehabilitation for personalized medicine were discussed.

Defect-mediated energy transfer is an energy transfer process between midgap electronic states in a semiconductor nanocrystal (NC) and molecular acceptors, such as fluorescent dye molecules. Super-resolution fluorescence microscopy represents an exciting technique for pinpointing the nanoscale positions of lattice defect sites in, for example, a micrometer-sized particle or thin film sample by spatially resolving the location of the acceptor dye molecules with nanometer resolution. Toward this goal, our group performed ensemble-level, time-resolved fluorescence spectroscopy measurements of ZnO NC/Alexafluor 555 (A555) mixtures and calculated that the emissive defect sites are located, on average, 0.5 nm from the NC surface [Nilsson, Z. N.; J. Chem. Phys. 2021, 154 (5), 054704]. However, ensemble-level measurements cannot spatially resolve the defect sites on single particles, nor can they distinguish between surface-adsorbed dye molecules that participate in the energy transfer (EnT) process from those that do not. In this work, we compared the photoluminescence intensity trajectories of 789 isolated, single ZnO NC donors to those of 73 non-specifically bound and five specifically bound ZnO NC/A555 pairs, where the donor and acceptor centroid positions were separated by a distance that was smaller than our localization precision (40 nm). We observed minor fluorescence intensity fluctuations in the donor and defect channels instead of clear anticorrelated intensity fluctuations, which could be explained by (1) the presence of multiple emissive defect sites per NC, (2) donor–acceptor separation distances slightly larger than the Förster radius (R0 = 3.1 nm; defined as the distance at which EnT is 50% efficient), and/or (3) poor dipole–dipole coupling. The single molecule imaging methodology we developed, an alternating ultraviolet–visible excitation sequence combined with multicolor photon detection, successfully distinguishes specifically bound and non-specifically bound NC/dye pairs and can be applied to study a wide range of hybrid NC/dye energy transfer systems.

Age-related hearing impairment (ARHI), one of the most common sensory disorders, can be mitigated, but not cured or eliminated. To identify genetic influences underlying ARHI, we conducted a genome-wide association study of ARHI in 6,527 cases and 45,882 controls among the non-Hispanic whites from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort. We identified two novel genome-wide significant SNPs: rs4932196 (odds ratio = 1.185, p = 4.0x10-11), 52Kb 3' of ISG20, which replicated in a meta-analysis of the other GERA race/ethnicity groups (1,025 cases, 12,388 controls, p = 0.00094) and in a UK Biobank case-control analysis (30,802 self-reported cases, 78,586 controls, p = 0.015); and rs58389158 (odds ratio = 1.132, p = 1.8x10-9), which replicated in the UK Biobank (p = 0.00021). The latter SNP lies just outside exon 8 and is highly correlated (r2 = 0.96) with the missense SNP rs5756795 in exon 7 of TRIOBP, a gene previously associated with prelingual nonsyndromic hearing loss. We further tested these SNPs in phenotypes from audiologist notes available on a subset of GERA (4,903 individuals), stratified by case/control status, to construct an independent replication test, and found a significant effect of rs58389158 on speech reception threshold (SRT; overall GERA meta-analysis p = 1.9x10-6). We also tested variants within exons of 132 other previously-identified hearing loss genes, and identified two common additional significant SNPs: rs2877561 (synonymous change in ILDR1, p = 6.2x10-5), which replicated in the UK Biobank (p = 0.00057), and had a significant GERA SRT (p = 0.00019) and speech discrimination score (SDS; p = 0.0019); and rs9493627 (missense change in EYA4, p = 0.00011) which replicated in the UK Biobank (p = 0.0095), other GERA groups (p = 0.0080), and had a consistent significant result for SRT (p = 0.041) and suggestive result for SDS (p = 0.081). Large cohorts with GWAS data and electronic health records may be a useful method to characterize the genetic architecture of ARHI.

The structure, function, stability, and many other properties of a protein in a fixed environment are fully specified by its sequence, but in a manner that is difficult to discern. We present a general approach for rapidly mapping sequences directly to their energies on a pre-specified rigid backbone, an important sub-problem in computational protein design and in some methods for protein structure prediction. The cluster expansion (CE) method that we employ can, in principle, be extended to model any computable or measurable protein property directly as a function of sequence. Here we show how CE can be applied to the problem of computational protein design, and use it to derive excellent approximations of physical potentials. The approach provides several attractive advantages. First, following a one-time derivation of a CE expansion, the amount of time necessary to evaluate the energy of a sequence adopting a specified backbone conformation is reduced by a factor of 10(7) compared to standard full-atom methods for the same task. Second, the agreement between two full-atom methods that we tested and their CE sequence-based expressions is very high (root mean square deviation 1.1-4.7 kcal/mol, R2 = 0.7-1.0). Third, the functional form of the CE energy expression is such that individual terms of the expansion have clear physical interpretations. We derived expressions for the energies of three classic protein design targets-a coiled coil, a zinc finger, and a WW domain-as functions of sequence, and examined the most significant terms. Single-residue and residue-pair interactions are sufficient to accurately capture the energetics of the dimeric coiled coil, whereas higher-order contributions are important for the two more globular folds. For the task of designing novel zinc-finger sequences, a CE-derived energy function provides significantly better solutions than a standard design protocol, in comparable computation time. Given these advantages, CE is likely to find many uses in computational structural modeling.

Objective: To evaluate the clinical presentation and outcomes of treatment for patients with chondrosarcomas involving the skull base and temporal bone.Study design: Retrospective review.Setting: Tertiary medical centre.Patients: Cases of histologically confirmed chondrosarcoma involving the skull base and temporal bones.Intervention: Surgery.Main outcome measures: Demographic features of presenting patients; presenting symptoms and signs; surgical approach employed; use of post-operative radiation therapy; histological grade of tumour; and interval of post-operative follow up.Results: Twelve patients were identified with chondrosarcomas involving the skull base, with post-operative follow up ranging from three to 33 years. The average age at presentation was 42 years. The most common presenting symptoms were diplopia, decreased visual acuity and headaches. Five of the 12 patients required multiple surgical procedures.Conclusions: Patients with chondrosarcoma involving the skull base and temporal bone may present in a variety of ways. Surgical resection, even subtotal, in combination with radiation therapy, can often provide good tumour control over many years for these rare tumours. [ABSTRACT FROM AUTHOR]

The efferent cholinergic pathways to the vestibular periphery have yet to be fully characterized. While the nicotinic acetylcholine receptor subunit (nAChR) a 9 is now regarded as the principle receptor for efferent cholinergic signaling to the organ of Corti, there is still uncertainty over how the more complex efferent effects of the labyrinth are produced. Recent experimental work has demonstrated that the nAChR a 9 is present in the vestibular end-organs of the rat and mouse, suggesting that a 9 may be one of the mediators of efferent cholinergic signaling in the vestibular periphery as well. In this experiment, we sought to determine whether a 9 was also present in the vestibular end-organs of the chick. A homologue of a 9 has been cloned recently from the chick cochlea. Using reverse transcription polymerase chain reaction (RT-PCR), individual vestibular end-organ preparations, including posterior ampulla, combined horizontal and superior ampulla, saccule, utricle, and the vestibular ganglion were screened for a 9 messenger RNA expression. In each end-organ and the vestibular ganglion, a cDNA of the expected size was obtained by RT-PCR and was confirmed tobe a 9 by sequence analysis. Further, a 9 mRNA was identified by RT-PCR from individually isolated type I and type II vestibular hair cells (single-cell RT-PCR). Lastly, insitu hybridization using digoxigenin-labeled a 9 riboprobes confirmedthe presence of a 9 in type I and type II hair cells throughout the vestibular periphery. These results demonstrate the expression of a 9 in the vestibular end-organs ofthe chick, and lend further support for the role of a 9 as a mediator of efferent cholinergic signaling in vestibular hair cells. [ABSTRACT FROM AUTHOR]

Linear elastic fracture modeling coupled with empirical material tensile data result in good quantitative agreement with the experimental determination of mode I fracture for both brittle and toughened epoxy nanocomposites. The nanocomposites are comprised of diglycidyl ether of bisphenol A cured with Jeffamine D-230 and some were filled with core-shell rubber nanoparticles of varying concentrations. The quasi-static single-edge notched bending (SENB) test is modeled using both the surface-based cohesive zone (CZS) and extended finite element methods (XFEM) implemented in the Abaqus software. For each material considered, the critical load predicted by the simulated SENB test is used to calculate the mode I fracture toughness. Damage initiates in these models when nodes at the simulated crack tip attain the experimentally measured yield stress. Prediction of fracture processes using a generalized truncated linear traction–separation law (TSL) was significantly improved by considering the case of a linear softening function. There are no adjustable parameters in the XFEM model. The CZS model requires only optimization of the element displacement at the fracture parameter. Thus, these continuum methods describe these materials in mode I fracture with a minimum number of independent parameters.

Normal hearing requires exquisite cooperation between bony and sensorineural structures within the cochlea. For example, the inner ear secretes proteins such as osteoprotegrin (OPG) that can prevent cochlear bone remodeling. Accordingly, diseases that affect bone regulation can also result in hearing loss. Patients with fibrous dysplasia develop trabecular bone overgrowth resulting in hearing loss if the lesions affect the temporal bones. Unfortunately, the mechanisms responsible for this hearing loss, which could be sensorineural and/or conductive, remain unclear. In this study, we used a unique transgenic mouse model of increased Gs G-protein coupled receptor (GPCR) signaling induced by expression of an engineered receptor, Rs1, in osteoblastic cells. These ColI(2.3)+/Rs1+ mice showed dramatic bone lesions that histologically and radiologically resembled fibrous dysplasia. We found that ColI(2.3)+/Rs1+ mice showed progressive and severe conductive hearing loss. Ossicular chain impingement increased with the size and number of dysplastic lesions. While sensorineural structures were unaffected, ColI(2.3)+/Rs1+ cochleae had abnormally high osteoclast activity, together with elevated tartrate resistant acid phosphatase (TRAP) activity and receptor activator of nuclear factor kappa-B ligand (Rankl) mRNA expression. ColI(2.3)+/Rs1+ cochleae also showed decreased expression of Sclerostin (Sost), an antagonist of the Wnt signaling pathway that normally increases bone formation. The osteocyte canalicular networks of ColI(2.3)+/Rs1+ cochleae were disrupted and showed abnormal osteocyte morphology. The osteocytes in the ColI(2.3)+/Rs1+ cochleae showed increased expression of matrix metalloproteinase 13 (MMP-13) and TRAP, both of which can support osteocyte-mediated peri-lacunar remodeling. Thus, while the ossicular chain impingement is sufficient to account for the progressive hearing loss in fibrous dysplasia, the deregulation of bone remodeling extends to the cochlea as well. Our findings suggest that factors regulating bone remodeling, including peri-lacunar remodeling by osteocytes, may be useful targets for treating the bony overgrowths and hearing changes of fibrous dysplasia and other bony pathologies.