Search

This paper presents a study on the dynamics of a thin liquid film flowing down a vertical cylindrical fibre under a streamwise thermal gradient. Previous works on isothermal flows have shown that the inlet flow and fibre geometry are the main factors that determine a transition from the absolute to the convective instability flow regimes. Our experiments demonstrate that an irregular wavy pattern and bead coalescence, which are commonly seen in the convective regime, can also be triggered by applying a thermal gradient along the fibre. We develop a lubrication model that accounts for gravity, temperature-dependent viscosity and surface tension to describe the thermal effects on downstream bead dynamics. Numerical simulations of the model show good agreement between the predicted droplet coalescence dynamics and the experimental data.

We study the effects of nozzle geometry on the dynamics of thin fluid films flowing down a vertical cylindrical fibre. Recent experiments show that varying the nozzle diameter can lead to different flow regimes and droplet characteristics in the film. Using a weighted residual modelling approach, we develop a system of coupled equations that account for inertia, surface tension effects, gravity and a film stabilization mechanism to describe both near-nozzle fluid structures and downstream bead dynamics. We report good agreement between the predicted droplet properties and the experimental data.

Recent experiments on thin films flowing down a vertical fibre with varying nozzle diameters present a wealth of new dynamics that illustrate the need for more advanced theory. We present a detailed analysis using a full lubrication model that includes slip boundary conditions, nonlinear curvature terms and a film stabilization term. This study brings to focus the presence of a stable liquid layer playing an important role in the full dynamics. We propose a combination of these physical effects to explain the observed velocity and stability of travelling droplets in the experiments and their transition to isolated droplets. This is also supported by stability analysis of the travelling wave solution of the model.

Growing concern over the scarcity of freshwater motivates the development of compact and economic vapor capture methods for distributed thermal desalination or harvesting of water. We report a study of water vapor condensation on cold liquid beads traveling down a massive array of vertical cotton threads that act as pseudo-superhydrophilic surfaces. These liquid beads form through intrinsic flow instability and offer localized high-curvature surfaces that enhance vapor diffusion toward the liquid surface, a critical rate-limiting step. As the liquid flow rate increases, the bead spacing decreases, whereas the bead size and speed stay nearly constant. The resulting increase in the spatial bead density leads to mass transfer conductances and hence condensation rates per volume that are almost three times higher than the best reported values. Parallel and contiguous gas flow paths also result in a substantial reduction in gas pressure drop and hence electric fan power consumption.

The humidification-dehumidification (HDH) process is appealing for small-scale distributed desalination of high-salinity water. We report a new design of compact light-weight humidifiers with high effectiveness and low electric energy consumption for HDH systems. The new design consists of a dense array of vertically aligned strings, along which thin films of a heated liquid feed are allowed to flow under gravity. A counterflowing gas stream makes direct contact with liquid films carrying the generated water vapor to a dehumidifier. The unique geometric configuration of our design affords high interface-to-volume ratios necessary for high heat/mass exchange effectiveness and straight contiguous gas flow paths for reduced gas-phase pressure drops. We constructed a 0.4 m-tall prototype and examined the effects of the liquid flow rate, air velocity and feed liquid salinity on the heat/mass transfer performance and the gas stream axial pressure drop. Compared with previously reported pad humidifiers and spray columns, the present multi-string humidifier achieves almost 5 times the evaporation rate per humidifier volume at comparable gas stream pressure drops or an order of magnitude reduction in the gas stream pressure drop at comparable total evaporate rates. Our work demonstrates a highly-effective but compact and light-weight multi-string humidifier with a small gas stream axial pressure drop for HDH and related applications.

Jet flows induced by oscillating cantilever plates enable power-efficient cooling enhancement and fluid acceleration. We report a combined experimental and numerical study of the vortex regimes present in the wake of a harmonically oscillating thin cantilever plate in a quiescent fluid and analyze their effect on the flow generation downstream. We use Particle Image Velocimetry (PIV) in conjunction with two-dimensional numerical simulations to investigate the vortex evolution around the trailing edge of the plates with different geometries and vibrational properties. Our observations suggest the existence of three distinct regimes in the wake: non-propagating, intermediate and propagating. Comparing the temporal decay of the vortex circulation in different regimes shows that different mechanisms are involved in the formation of these vortical patterns. A regime map is proposed next, denoting the incident of each vortex regime as a function of relevant dimensionless parameters. Our analysis of the mean jet on the normal mid-plane, as quantified by the momentum-averaged Reynolds number Rejet, shows that the induced jet downstream the trailing edge is tightly correlated with the identified vortex regimes. The present study improves our understanding of vortex generation and propagation in oscillating cantilevers and facilitates optimized design and operation of piezoelectric fans and similar devices.

Metal-filled polymers containing micro-powders of highly conductive metals can serve as a starting material to fabricate complex metal structures using economic filament extrusion-based 3D printing and molding methods. We report our measurements of the thermal conductivity of copper samples prepared using these methods before and after a thermal treatment process. Sintering the samples at 980 ℃ leads to an order of magnitude improvement in thermal conductivity when compared with as-printed or as-molded samples. Thermal conductivity values of approximately 30 W/mK are achieved using commercially available polymer-copper composite filaments with a copper volume fraction of 0.4. Over-sintering the samples at 1080 ℃ further enhances the thermal conductivity by more than two folds, but it leads to uncontrolled shrinkage of the samples. The measured thermal conductivities show a modest decrease with increasing temperatures due to increased electron-phonon scattering rates. The experimental data agree well with the thermal conductivity models previously reported for sintered porous metal samples. The measured electrical conductivity, Young's modulus and yield strength of the present sintered samples are also reported.

Direct-contact heat exchangers that involve energy exchange between gas and liquid streams have a variety of applications, including waste heat recovery, thermoelectric power plant cooling, and thermal desalination. Direct-contact heat exchangers are appealing as they may help mitigate potential corrosion, fouling, and scaling of solid surfaces and enhance heat transfer effectiveness. In this study, we experimentally investigate the thermohydraulic characteristics of an economic light-weight direct-contact heat exchanger that incorporates an array of strings of diameter of the order of 0.1–1 mm to sustain flows of thin liquid films. We constructed a 1.6 m-tall prototype heat exchanger with an array of as many as 112 vertically aligned strings. Thin films of a non-evaporating liquid are flown down the strings by gravity and exchange thermal energy with a counterflowing gas stream. We obtained axial liquid temperature profiles and frictional loss in the gas stream for different combinations of liquid and gas flow rates and two different string pitches. Numerical simulation is also performed to help interpret and indirectly validate our experimental results. The overall, gas-side, and liquid-side heat transfer coefficients extracted from the experimentally measured temperature profiles are examined to evaluate the impact of instability in liquid film flows and inter-bead spacing. The applicability of the Reynolds analogy is also assessed using the measured gas-stream pressure drops and air-side heat transfer coefficients. The present study helps improve our understanding of heat transfer and gas-stream pressure drop in string-based direct-contact heat exchangers and provides an experimental database to help systematically optimize their design.

Piezoelectric fans offer an intriguing alternative to conventional rotary fans for thermal management of portable and wearable electronics due to their scalability, low power consumption and simple mechanical construct. We report a combined experimental and modeling study to help elucidate power dissipation mechanisms in piezoelectric fans. To analyze contributions from these different mechanisms, mathematical models that account for mechanical hysteresis, dielectric loss and viscous damping from generated air flows are used in conjunction with vibration amplitudes and power consumption data obtained experimentally from piezoelectric fans of different blade lengths, thicknesses and mass distributions. In parallel, we perform experiments on convective heat transfer coefficients and aerodynamic forces acting on surfaces that are oriented perpendicular with respect to fan-induced air flows. These experiments establish that the portion of power dissipation ascribed to air flows correlates well with the heat transfer performance and aerodynamic force. A power ratio, defined as the fraction of the air flow power to the total power dissipation, is then proposed as a useful indicator of the power efficiency of the piezoelectric fans. We show that the power efficiency exhibits a peak at a particular bias voltage amplitude, and provide a guideline to determine this optimum voltage. Lastly, we relate the air flow power to the blade's geometrical parameters to facilitate systematic optimization of the blades for both cooling performance and power efficiency.

Direct contact heat exchangers based on wetted string columns offer an intriguing alternative to packed beds and spray columns. We experimentally examine the flow and heat transfer characteristics of thin liquid films flowing down strings of a diameter approximately 1 mm against a counterflowing air stream. Numerical simulations are also performed to help interpret and validate our experimental results. The Rayleigh-Plateau instability caused by interplay among surface tension, gravity, and viscous forces leads to the formation of uniformly spaced drop-like liquid beads traveling down a string. The liquid mass flow rate and also the nozzle radius influence the radius and spatial/temporal frequency of liquid beads. Aerodynamic drag exerted by the counterflowing air stream deforms liquid beads. The relationship between flow characteristics and heat transfer effectiveness are examined experimentally for different combinations of the air velocities, liquid mass flow rates, and nozzle radii. We show that the liquid mass flow rate and the air velocity are two primary factors influencing heat transfer effectiveness whereas details of the liquid flow instability affect local bead-to-air heat transfer coefficients. We also compare the heat transfer effectiveness and the pressure drop between a wetted string column that consists of an array of vertical strings and a well-established structured packing that consists of vertical plates. The wetted string column is shown to deliver comparable heat transfer performance but at a lower air pressure drop than the structured packing. The present work helps improve our understanding of the flow and heat transfer performance of string-based direct-contact heat exchangers and helps build a foundation for their systematic design and optimization.

Thermal conductance switches enable active and reconfigurable thermal control and management for a wide variety of applications. We demonstrate a thermal conductance switch based on the actuation of liquid droplets in a co-planar electro-wetting-on-dielectric (EWOD) configuration. By eliminating the need for relative motions of two heat transfer surfaces, the device provides a significant advantage in the mechanical design of adaptive thermal control systems. Proof-of-concept devices are constructed and characterized to confirm the mechanism of droplet detachment and attachment for thermal switching. Numerical simulation is performed to elucidate the experimentally measured thermal performance and identify thermocapillary flows as an important contributor to heat transfer for certain dielectric liquids. The present work provides a proof-of-concept demonstration of novel thermal conductance switches and offers physical insights to help systematically design the switches for practical applications.

We report characterization and analysis of the frequency-dependent temperature responses in thin films exhibiting the electrocaloric (EC) effect under AC bias fields using a high-precision lock-in technique. The temperature response detected by an embedded thin-film resistance thermometer is analyzed using the steady-periodic solutions of a 3D heat conduction model to extract the equivalent volumetric heat sources/sinks, which represent the combined effects of cleclrocaloric cooling/heating and hysteresis loss. The dependence of the measured heat source strengths on the bias field frequency and amplitude is consistent with our model prediction and independently measured dielectric properties. The volumetric heating rate due to hysteresis loss is estimated to be as much as 15% of the EC heating/cooling rates for solution-cast relaxor ferroelectric polymer films studied here. Our experimental approach enables a systematic study of the electrocaloric performance of thin films and deleterious impact of hysteresis loss.

We report a design concept for a deployable planar microdevice and the modeling and experimental validation of its mechanical behavior. The device consists of foldable membranes that are suspended between flexible stems and actuated by push-pull wires. Such a deployable device can be introduced into a region of interest in its compact "collapsed" state and then deployed to conformally cover a large two-dimensional surface area for minimally invasive biomedical operations and other engineering applications. We develop and experimentally validate theoretical models based on the energy minimization approach to examine the conformality and figures of merit of the device. The experimental results obtained using model contact surfaces agree well with the prediction and quantitatively highlight the importance of the membrane bending modulus in controlling surface conformality. The present study establishes an early foundation for the mechanical design of this and related deployable planar microdevice concepts. © 2014 by the authors.

A comparative study of oxidation methods to create Cu surfaces with controlled wettability is reported. Micro/nanostructures of Cu oxides are formed on Cu substrates using different chemical and thermal oxidation methods. The morphology and wetting characteristics of the resulting surfaces are characterized using atomic force microscopy, scanning electron microscopy, X-ray diffraction, and contact angle measurements. Chemical oxidation in alkali solutions can form uniform copper oxide layers with high roughness factors without causing thermal stress problems that often hamper thermal oxidation. By combining chemical oxidation with a hydrophobic coating, a wide range of wettability control is demonstrated from superhydrophilic (< 10°) to superhydrophobic (> 170°). Superhydrophilic CuO layers uniformly formed on Cu powder and Cu micropost wick surfaces lead to significant improvement in the capillary and heat transfer performance compared with comparable unoxidized Cu wicks. The present work motivates further studies to exploit the benefits of nanostructured Cu surfaces in various phase change heat transfer applications. © 2013 Taylor and Francis Group, LLC.

Jwa-Kyung Kim,1 Young Rim Song,1 Young-Jun Kwon,2 Hyung Jik Kim,1 Sung Gyun Kim,1 Young-Su Ju21Department of Internal Medicine, Kidney Research Institute, 2Department of Occupational and Environmental Medicine, Hallym University Sacred Heart Hospital, Anyang-si, South KoreaBackground: With increasing age, body fat increases and muscle mass reduces. Even people with a normal weight may have a higher percentage of body fat. The aim of this study is to investigate the association between increased body fat and renal function decline (RFD) in the general elderly population with normal or mildly impaired renal function.Method: We conducted a prospective study of 615 healthy individuals in the general Korean population aged ≥60 years who participated in two health screening check-ups separated by a 4-year period. Obesity was defined as the highest sex-specific tertiles of the percentage body fat (PBF). The main outcome was changes of estimated glomerular filtration rate (eGFR) during the 4 years. Significant RFD was defined as a decrease of eGFR over the upper quartile (≤-2.1% per year). Results: The mean age was 67.2±6.6 years. The median value of the absolute decline in the eGFR and the percent change was -3.0 mL/minute/1.73 m2 and -0.87%/year in men and -3.1 mL/minute/1.73 m2 and -0.89%/year in women, respectively. When stratified by sex-specific PBF tertiles, pronounced differences were observed in both sexes; those at the highest tertile of PBF showed the greatest decline in eGFR. Even after adjustments for traditional risk factors of RFD, PBF was independently associated with eGFR changes (ß=-0.181; P

The genetic clock is a well-established tool used in evolutionary biology for estimating divergence times between species, individuals, or cells based on DNA sequence changes. Yu et al. have revisited the clock to make it applicable to clonal multicellular organisms that expand through asexual reproduction mechanisms, enabling more comprehensive evolutionary tracking., Competing Interests: Declaration of interests Y.S.J. is a genomics co-founder and shareholder of Inocras Inc. Y.K. and J.R. do not declare any conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Objectives: Idiopathic/isolated REM sleep behavior disorder (iRBD) has been strongly linked to neurodegenerative synucleinopathies such as Parkinson disease, dementia with Lewy bodies, and multiple system atrophy. However, there have been increasing reports of RBD as a presenting feature of serious and treatable autoimmune syndromes, particularly IGLON5. This study's objective was to investigate the frequency of autoantibodies in a large cohort of participants with iRBD., Methods: Participants were enrolled in the North American Prodromal Synucleinopathy cohort with polysomnography-confirmed iRBD, free of parkinsonism and dementia. Plasma samples were systematically screened for the autoantibodies IGLON5, DPPX, LGI1, and CASPR2 using plasma IgG cell-based assay. Positive or equivocal results were confirmed by repeat testing, plus tissue-based indirect immunofluorescence assay for IGLON5., Results: Of 339 samples analyzed, 3 participants (0.9%) had confirmed positive IGLON5 autoantibodies in the cell-based assay, which were confirmed by the tissue-based assay. An additional participant was positive for CASPR2 with low titer by cell-based assay only (of lower clinical certainty). These cases exhibited a variety of symptoms including dream enactment, cognitive decline, autonomic dysfunction, and motor symptoms. In 1 IGLON5 case and the CASPR2 case, evolution was suggestive of typical synucleinopathy, suggesting the possibility that findings were incidental. However, 2 participants with IGLON5 died before diagnosis was clinically suspected, with a final clinical picture highly suggestive of autoimmune disease., Discussion: Our finding that nearly 1% of a large iRBD cohort may have a serious but potentially treatable autoantibody syndrome has important clinical implications. In particular, it raises the question of whether autoantibody testing for IGLON-5-IgG should be widely implemented for participants with iRBD, considering the difficulty in diagnosis of autoimmune diseases, their response to treatment, and the potential for rapid disease progression. However, any routine testing protocol will also have to consider costs and potential adverse effects of false-positive findings., Trial Registration Information: NCT03623672.

Purpose: Cancer poses a significant global health challenge, demanding precise genomic testing for individualized treatment strategies. Targeted-panel sequencing (TPS) has improved personalized oncology but often lacks comprehensive coverage of crucial cancer alterations. Whole-genome sequencing (WGS) addresses this gap, offering extensive genomic testing. This study demonstrates the medical potential of WGS., Materials and Methods: This study evaluates target-enhanced WGS (TE-WGS), a clinical-grade WGS method sequencing both cancer and matched normal tissues. Forty-nine patients with various solid cancer types underwent both TE-WGS and TruSight Oncology 500 (TSO500), one of the mainstream TPS approaches., Results: TE-WGS detected all variants reported by TSO500 (100%, 498/498). A high correlation in variant allele fractions (VAF) was observed between TE-WGS and TSO500 (r=0.978). Notably, 223 variants (44.8%) within the common set were discerned exclusively by TE-WGS in peripheral blood, suggesting their germline origin. Conversely, the remaining subset of 275 variants (55.2%) were not detected in peripheral blood using the TE-WGS, signifying them as bona fide somatic variants. Further, TE-WGS provided accurate copy number profiles, fusion genes, microsatellite instability (MSI), and homologous-recombination deficiency (HRD) scores, which were essential for clinical decision-making., Conclusion: TE-WGS is a comprehensive approach in personalized oncology, matching TSO500's key biomarker detection capabilities. It uniquely identifies germline variants and genomic instability markers, offering additional clinical actions. Its adaptability and cost-effectiveness underscore its clinical utility, making TE-WGS a valuable tool in personalized cancer treatment.

Introduction: Kabuki syndrome (KS) is a rare disorder characterized by typical facial features, skeletal anomalies, fetal fingertip pad persistence, postnatal growth retardation, and intellectual disabilities. Heterozygous variants of the KMT2D and KDM6A genes are major genetic causes of KS. This study aimed to report the clinical and genetic characteristics of KS., Methods: This study included 28 Korean patients (14 boys and 14 girls) with KS through molecular genetic testing, including direct Sanger sequencing, whole-exome sequencing, or whole-genome sequencing., Results: The median age at clinical diagnosis was 18.5 months (IQR 7-58 months), and the median follow-up duration was 80.5 months (IQR 48-112 months). Molecular genetic testing identified different pathogenic variants of the KMT2D (n = 23) and KDM6A (n = 3) genes, including 15 novel variants. Patients showed typical facial features (100%), such as long palpebral fissure and eversion of the lower eyelid; intellectual disability/developmental delay (96%); short stature (79%); and congenital cardiac anomalies (75%). Although 71% experienced failure to thrive in infancy, 54% of patients showed a tendency toward overweight/obesity in early childhood. Patients with KDM6A variants demonstrated severe genotype-phenotype correlation., Conclusion: This study enhances the understanding of the clinical and genetic characteristics of KS., (© 2024. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Background: Mobocertinib, an EGFR exon 20 insertion (Ex20ins)-specific tyrosine kinase inhibitor has been used for treatment of advanced/metastatic EGFR Ex20ins-mutant non-small cell lung cancer (NSCLC). However, resistance mechanisms to EGFR Ex20ins-specific inhibitors and the efficacy of subsequent amivantamab treatment is unknown., Methods: To investigate resistance mechanisms, tissue and cfDNA samples were collected before treatment initiation and upon development of resistance from NSCLC patients with EGFR Ex20ins mutations received mobocertinib, poziotinib, and amivantamab treatments. Genetic alterations were analyzed using whole-genome and targeted sequencing, and in vitro resistant cell lines were generated for validation., Results: EGFR amplification (n = 6, including 2 broad copy number gain) and EGFR secondary mutation (n = 3) were observed at the resistance of mobocertinib. One patient had both EGFR secondary mutation and high EGFR focal amplification. In vitro models harboring EGFR alterations were constructed to validate resistance mechanisms and identify overcoming strategies to resistance. Acquired EGFR-dependent alterations were found to mediate resistance to mobocertinib in patients and in vitro models. Furthermore, two of six patients who received sequential amivantamab followed by an EGFR tyrosine kinase inhibitor had MET amplification and showed partial response., Conclusions: Our study revealed EGFR-dependent and -independent mechanisms of mobocertinib resistance in patients with advanced EGFR Ex20ins-mutant NSCLC., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: T.M. Kim reports consulting or advisory roles at Amgen, AstraZeneca/MedImmune, BeiGene, Borung, Daiichi Sankyo, Hanmi, HK inno.N, IMBdx. Inc., Janssen, Novartis, Regeneron, Roche/Genentech, Samsung Bioepis, and Takeda. Y.S. Ju is a founder of Inocras Inc. Se. Park, J. Lim, K. Yi, B. Yi, and Y.S. Ju have stock or stock option of Inocras Inc. D.W Kim reports research funding from Alpha Biopharma, Amgen, AstraZeneca/Medimmune, Boehringer-Ingelheim, Daiichi, -Sankyo, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, ONO Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Chong Keun Dang, Bridge BioTherapeutics, and GSK and travel and accommodation support for advisory board-meeting attendance from Amgen and Daiichi-Sankyo. No disclosures were reported by the other authors., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Methane pyrolysis is known to produce hydrogen and solid carbon in a variety of thermal processes. However, the generated carbon product typically belongs to a low-value amorphous type. Here, we elucidate the thermochemical mechanisms of a reaction that produces high-quality graphite via direct solar methane pyrolysis on a porous substrate. By comparing graphite deposition rates and local reaction zone temperatures of exposed and shadowed regions from the same experiment, we clarify the effects of thermolysis and photolysis in this emission-free process that both decarbonizes a fuel and produces a critical material for the sustainable energy transition., Competing Interests: The authors declare the following competing financial interest(s): Timothy S. Fisher and R. Mitchell Spearrin are co-founders of SolGrapH, Inc., a company specializing in solar-thermal material synthesis. This submitted work is an independent academic study and is not associated with commercial endeavors or intended as a promotion. The other authors have no competing interests to disclose., (© 2024 The Authors. Published by American Chemical Society.)

The lack of an appropriate preclinical model of metabolic dysfunction-associated steatotic liver disease (MASLD) that recapitulates the whole disease spectrum impedes exploration of disease pathophysiology and the development of effective treatment strategies. Here, we develop a mouse model (Streptozotocin with high-fat diet, STZ + HFD) that gradually develops fatty liver, metabolic dysfunction-associated steatohepatitis (MASH), hepatic fibrosis, and hepatocellular carcinoma (HCC) in the context of metabolic dysfunction. The hepatic transcriptomic features of STZ + HFD mice closely reflect those of patients with obesity accompanying type 2 diabetes mellitus, MASH, and MASLD-related HCC. Dietary changes and tirzepatide administration alleviate MASH, hepatic fibrosis, and hepatic tumorigenesis in STZ + HFD mice. In conclusion, a murine model recapitulating the main histopathologic, transcriptomic, and metabolic alterations observed in MASLD patients is successfully established., (© 2024. The Author(s).)

Genomic alterations in tumors play a pivotal role in determining their clinical trajectory and responsiveness to treatment. Targeted panel sequencing (TPS) has served as a key clinical tool over the past decade, but advancements in sequencing costs and bioinformatics have now made whole-genome sequencing (WGS) a feasible single-assay approach for almost all cancer genomes in clinical settings. This paper reports on the findings of a prospective, single-center study exploring the real-world clinical utility of WGS (tumor and matched normal tissues) and has two primary objectives: (1) assessing actionability for therapeutic options and (2) providing clarity for clinical questions. Of the 120 patients with various solid cancers who were enrolled, 95 (79%) successfully received genomic reports within a median of 11 working days from sampling to reporting. Analysis of these 95 WGS reports revealed that 72% (68/95) yielded clinically relevant insights, with 69% (55/79) pertaining to therapeutic actionability and 81% (13/16) pertaining to clinical clarity. These benefits include the selection of informed therapeutics and/or active clinical trials based on the identification of driver mutations, tumor mutational burden (TMB) and mutational signatures, pathogenic germline variants that warrant genetic counseling, and information helpful for inferring cancer origin. Our findings highlight the potential of WGS as a comprehensive tool in precision oncology and suggests that it should be integrated into routine clinical practice to provide a complete image of the genomic landscape to enable tailored cancer management., (© 2024. The Author(s).)

Somatic cells accumulate genomic alterations with age; however, our understanding of mitochondrial DNA (mtDNA) mosaicism remains limited. Here we investigated the genomes of 2,096 clones derived from three cell types across 31 donors, identifying 6,451 mtDNA variants with heteroplasmy levels of ≳0.3%. While the majority of these variants were unique to individual clones, suggesting stochastic acquisition with age, 409 variants (6%) were shared across multiple embryonic lineages, indicating their origin from heteroplasmy in fertilized eggs. The mutational spectrum exhibited replication-strand bias, implicating mtDNA replication as a major mutational process. We evaluated the mtDNA mutation rate (5.0 × 10 -8 per base pair) and a turnover frequency of 10-20 per year, which are fundamental components shaping the landscape of mtDNA mosaicism over a lifetime. The expansion of mtDNA-truncating mutations toward homoplasmy was substantially suppressed. Our findings provide comprehensive insights into the origins, dynamics and functional consequences of mtDNA mosaicism in human somatic cells., (© 2024. The Author(s).)

Low-level somatic mutations in the human brain are implicated in various neurological disorders. The contribution of low-level brain somatic mutations to autism spectrum disorder (ASD), however, remains poorly understood. Here, we performed high-depth exome sequencing with an average read depth of 559.3x in 181 cortical, cerebellar, and peripheral tissue samples to identify brain somatic single nucleotide variants (SNVs) in 24 ASD subjects and 31 controls. We detected ~2.4 brain somatic SNVs per exome per single brain region, with a variant allele frequency (VAF) as low as 0.3%. The mutational profiles, including the number, signature, and type, were not significantly different between the ASD patients and controls. Intriguingly, when considering genes with low-level brain somatic SNVs and ASD risk genes with damaging germline SNVs together, the merged set of genes carrying either somatic or germline SNVs in ASD patients was significantly involved in ASD-associated pathophysiology, including dendrite spine morphogenesis (p = 0.025), mental retardation (p = 0.012), and intrauterine growth retardation (p = 0.012). Additionally, the merged gene set showed ASD-associated spatiotemporal expression in the early and mid-fetal cortex, striatum, and thalamus (all p < 0.05). Patients with damaging mutations in the merged gene set had a greater ASD risk than did controls (odds ratio = 3.92, p = 0.025, 95% confidence interval = 1.12-14.79). The findings of this study suggest that brain somatic SNVs and germline SNVs may collectively contribute to ASD-associated pathophysiology., (© 2024. The Author(s).)

While most dizygotic twins have a dichorionic placenta, rare cases of dizygotic twins with a monochorionic placenta have been reported. The monochorionic placenta in dizygotic twins allows in utero exchange of embryonic cells, resulting in chimerism in the twins. In practice, this chimerism is incidentally identified in mixed ABO blood types or in the presence of cells with a discordant sex chromosome. Here, we applied whole-genome sequencing to one triplet and one twin family to precisely understand their zygotic compositions, using millions of genomic variants as barcodes of zygotic origins. Peripheral blood showed asymmetrical contributions from two sister zygotes, where one of the zygotes was the major clone in both twins. Single-cell RNA sequencing of peripheral blood tissues further showed differential contributions from the two sister zygotes across blood cell types. In contrast, buccal tissues were pure in genetic composition, suggesting that in utero cellular exchanges were confined to the blood tissues. Our study illustrates the cellular history of twinning during human development, which is critical for managing the health of chimeric individuals in the era of genomic medicine., Competing Interests: Declaration of interests Y.S.J. is the co-founder and chief genomics officer of Inocras, Inc. J.S.L. is the co-founder and chief innovation officer of Inocras, Inc., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Sleep spindles are distinct electroencephalogram (EEG) patterns of brain activity that have been posited to play a critical role in development, learning, and neurological disorders. Manual scoring for sleep spindles is labor-intensive and tedious but could supplement automated algorithms to resolve challenges posed with either approaches alone., New Methods: A Personalized Semi-Automatic Sleep Spindle Detection (PSASD) framework was developed to combine the strength of automated detection algorithms and visual expertise of human scorers. The underlying model in the PSASD framework assumes a generative model for EEG sleep spindles as oscillatory components, optimized to EEG amplitude, with remaining signals distributed into transient and low-frequency components., Results: A single graphical user interface (GUI) allows both manual scoring of sleep spindles (model training data) and verification of automatically detected spindles. A grid search approach allows optimization of parameters to balance tradeoffs between precision and recall measures., Comparison With Existing Methods: PSASD outperformed DETOKS in F1-score by 19% and 4% on the DREAMS and P-DROWS-E datasets, respectively. It also outperformed YASA in F1-score by 25% in the P-DROWS-E dataset. Further benchmarking analysis showed that PSASD outperformed four additional widely used sleep spindle detectors in F1-score in the P-DROWS-E dataset. Titration analysis revealed that four 30-second epochs are sufficient to fine-tune the model parameters of PSASD. Associations of frequency, duration, and amplitude of detected sleep spindles matched those previously reported with automated approaches., Conclusions: Overall, PSASD improves detection of sleep spindles in EEG data acquired from both younger healthy and older adult patient populations., Competing Interests: Declaration of Competing Interest The authors do not have any conflicts of interest to disclose. This work was supported by the National Institute on Aging (BJAP; R01AG057901), the McDonnell Center for Systems Neuroscience (MK, BJAP), the National Institute of Mental Health K01MH128663 (MK), and the National Institute of Neurological Diseases and Stroke (Y-ESJ; K23NS089922)., (Copyright © 2024. Published by Elsevier B.V.)

Background: We investigated the potential association between pathogenic BRCA1/2 variants and retinoblastoma pathogenicity., Methods: In this single-centre, retrospective case series, we performed hereditary cancer panel tests using blood samples for patients with retinoblastoma diagnosed between March 2017 and October 2021. Bioinformatics prediction tools were then used to conduct in silico pathogenicity assessments for patients with BRCA1/2 family variants, in addition to the American College of Medical Genetics and Genomics (ACMG) variant classification. One patient with a germline BRCA1 variant was analysed with whole-genome sequencing (WGS), mutational signature analysis and methylation analysis for RB1 and BRCA using the patient's tumour and blood samples., Results: Of 30 retinoblastoma patients who underwent panel sequencing, six (20%) were found to carry germline variants in the BRCA1/2 or BRIP1 genes. Among these six patients, two had pathogenic or likely pathogenic variants as per the ACMG variant classification. Additionally, three patients showed potential pathogenic BRCA1/2 family variants through further analysis with alternative bioinformatics prediction tools. In the WGS analysis of a tumour from a patient with a germline likely pathogenic BRCA1 variant in one allele, we observed the loss of one RB1 allele due to a large deletion. No somatic non-synonymous mutations or frameshift indels were detected in the RB1 locus of the remaining allele. This sample also showed BRCA1 gene promoter hypermethylation in the tumour, indicating additional epigenetic silencing., Conclusion: This study demonstrated that some retinoblastoma patients harboured germline BRCA1/2 family variants, which may be associated with the development of retinoblastoma along with RB1 mutations., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Study Objectives: Rapid eye movement sleep behavior disorder (RBD) is strongly associated with phenoconversion to an overt synucleinopathy, e.g. Parkinson's disease (PD), Lewy body dementia, and related disorders. Comorbid traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD)-henceforth "neurotrauma" (NT)-increase the odds of RBD by ~2.5-fold and are associated with an increased rate of service-connected PD in Veterans. Thus, RBD and NT are both independently associated with PD; however, it is unclear how NT influences neurological function in patients with RBD., Methods: Participants ≥18 years with overnight polysomnogram-confirmed RBD were enrolled between 8/2018 to 4/2021 through the North American Prodromal Synucleinopathy Consortium. Standardized assessments for RBD, TBI, and PTSD history, as well as cognitive, motor, sensory, and autonomic function, were completed. This cross-sectional analysis compared cases (n = 24; RBD + NT) to controls (n = 96; RBD), matched for age (~60 years), sex (15% female), and years of education (~15 years)., Results: RBD + NT reported earlier RBD symptom onset (37.5 ± 11.9 vs. 52.2 ± 15.1 years of age) and a more severe RBD phenotype. Similarly, RBD + NT reported more severe anxiety and depression, greater frequency of hypertension, and significantly worse cognitive, motor, and autonomic function compared to RBD. No differences in olfaction or color vision were observed., Conclusions: This cross-sectional, matched case:control study shows individuals with RBD + NT have significantly worse neurological measures related to common features of an overt synucleinopathy. Confirmatory longitudinal studies are ongoing; however, these results suggest RBD + NT may be associated with more advanced neurological symptoms related to an evolving neurodegenerative process., (Published by Oxford University Press on behalf of Sleep Research Society (SRS) 2024.)

Background: Congenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder caused by loss-of-function mutations of the NTRK1 gene, affecting the autonomic and sensory nervous system. Clinical manifestation is varied and includes recurrent fever, pain insensitivity, anhidrosis, self-mutilating behavior, and intellectual disability., Methods: Clinical and genetic features were assessed in two males and one female with genetically confirmed CIPA using exome or genome sequencing., Results: CIPA symptoms including recurrent fever, pain insensitivity, and anhidrosis manifested at the age of 1 year (age range: 0.3-8 years). Two patients exhibited self-mutilation tendencies, intellectual disability, and developmental delay. Four NTRK1 (NM&#95;002529.3) mutations, c.851-33T>A (p.?), c.2020G>T (p.Asp674Tyr), c.2303C>T (p.Pro768Leu), and c.574-156&#95;850+1113del (exons 5-7 del) were identified. Two patients exhibited early onset and severe phenotype, being homozygous for c.851-33T>A (p.?) mutations and compound heterozygous for c.851-33T>A (p.?) and c.2020G>T (p.Asp674Tyr) mutation of NTRK1. The third patient with compound heterozygous mutations of c.2303C>T (p.Pro768Leu) and c.574-156&#95;850+1113del (exons 5-7 del) displayed a late onset and milder clinical manifestation., Conclusion: All three patients exhibited variable phenotypes and disease severity. This research enriches our understanding of clinical and genetic aspects of CIPA, highlighting variable phenotypes and disease severity., (© 2024 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

Introduction: Breast cancer exhibits vast genomic diversity, leading to varied clinical manifestations. Integrating molecular subtyping with in-depth genomic profiling is pivotal for informed treatment choices and prognostic insights. Whole-genome clinical analysis provides a holistic view of genome-wide variations, capturing structural changes and affirming tumor suppressor gene loss of heterozygosity., Case Presentation: Here we detail four unique breast cancer cases from Seoul St. Mary's Hospital, highlighting the actionable benefits and clinical value of whole-genome sequencing (WGS). As an all-in-one test, WGS demonstrates significant clinical utility in these cases, including: (1) detecting homologous recombination deficiency with underlying somatic causal variants (case 1), (2) distinguishing double primary cancer from metastasis (case 2), (3) uncovering microsatellite instability (case 3), and (4) identifying rare germline pathogenic variants in TP53 gene (case 4). Our observations underscore the enhanced clinical relevance of WGS-based testing beyond pinpointing a few driver mutations in conventional targeted panel sequencing platforms., Conclusion: With genomic advancements and decreasing sequencing costs, WGS stands out as a transformative tool in oncology, paving the way for personalized treatment plans rooted in individual genetic blueprints., Competing Interests: The authors have no conflicts of interest to declare except author information on the cover page., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

The comprehensive genomic impact of ionizing radiation (IR), a carcinogen, on healthy somatic cells remains unclear. Using large-scale whole-genome sequencing (WGS) of clones expanded from irradiated murine and human single cells, we revealed that IR induces a characteristic spectrum of short insertions or deletions (indels) and structural variations (SVs), including balanced inversions, translocations, composite SVs (deletion-insertion, deletion-inversion, and deletion-translocation composites), and complex genomic rearrangements (CGRs), including chromoplexy, chromothripsis, and SV by breakage-fusion-bridge cycles. Our findings suggest that 1 Gy IR exposure causes an average of 2.33 mutational events per Gb genome, comprising 2.15 indels, 0.17 SVs, and 0.01 CGRs, despite a high level of inter-cellular stochasticity. The mutational burden was dependent on total irradiation dose, regardless of dose rate or cell type. The findings were further validated in IR-induced secondary cancers and single cells without clonalization. Overall, our study highlights a comprehensive and clear picture of IR effects on normal mammalian genomes., Competing Interests: Declaration of interests Y.S.J. is a genomic co-founder and chairman of Genome Insight., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)