MRgFUS ablation of a recurrent tenosynovial giant cell tumor in the foot using ExAblate 2100 system in combination with patient immobilization device.

INTRODUCTION: Magnetic Resonance-guided Focused Ultrasound (MRgFUS) treatment for certain anatomy locations can be extremely challenging due to patient positioning and potential motion. This present study describes the treatment of a recurrent tenosynovial giant cell tumor of the plantar forefoot using the ExAblate 2100 system in combination with patient immobilization device. METHODS: Prior to the treatment, several patient immobilization devices were investigated. Vacuum cushions were selected and tested for safety and compatibility with the treatment task and the MR environment. RESULTS: During the treatment, one vacuum cushion immobilized the patient's right leg in knee flexion and allowed the bottom of the foot to be securely positioned on the treatment window. Another vacuum cushion supported the patient upper body extended outside the scanner bore. 19 sonications were successfully executed. The treatment was judged to be successful. No immediate complications were observed. CONCLUSIONS: MRgFUS treatment of a recurrent tenosynovial giant cell tumor of the right plantar forefoot was successful with the use of patient immobilization vacuum cushions. IMPLICATIONS FOR PRACTICE: The immobilization system could be utilized to aid future MRgFUS treatment of lesions in challenging anatomic locations. Various sizes of the vacuum cushions are available to potentially better accommodate other body parts and treatment configurations.

[Literature data mining on the current research status of uveitis in China].

Objective: To analyze the current research status of uveitis in China. Methods: It was a bibliometric analysis study. Using search formulas covering uveitis and its multiple subtypes, uveitis-related literature in English with publication dates from 2013 to 2022 was retrieved in Web of Science core databases through certain search strategies. This study used the latent Dirichlet allocation (LDA) algorithm to build topic models and analyzed the trends of research topics in recent years. Bibliometric analysis was used to analyze and visualize the bibliometric indicators (e.g., number of publications, citations, and H-index) of the included literature using tools such as VOSviewer software. Results: Over the past decade, China has published 1 657 papers on uveitis, ranking second globally. However, there is still room for improvement in terms of the H-index (58) and citation (12.28 per publication). Countries such as the USA (43.04%) and the United Kingdom (62.54%) were engaged in more international collaboration. We identified ten optimal LDA topics for uveitis literature in China such as immunotherapy, Behçet's disease, and Vogt-Koyanagi-Harada syndrome. Research on uveitis in China was mostly published in Ocular Immunology and Inflammation (92). Conclusions: China has made remarkable progress in uveitis research. Nonetheless, there is still untapped potential to enhance our global academic influence. It is encouraged to promote international collaborations, harness our expertise in areas like Behçet's disease and VKH syndrome, and publish our scientific achievements in high-impact journals.

Uncertainties and opportunities in delivering environmentally sustainable surgery: the surgeons' view.

Surgery is a carbon-heavy activity and creates a high volume of waste. Surgical teams around the world want to deliver more environmentally sustainable surgery but are unsure what to do and how to create change. There are many interventions available, but resources and time are limited. Capital investment into healthcare and engagement of senior management are challenging. However, frontline teams can change behaviours and drive wider change. Patients have a voice here too, as they would like to ensure their surgery does not harm their local community but are concerned about the effects on them when changes are made. Environmentally sustainable surgery is at the start of its journey. Surgeons need to rapidly upskill their generic knowledge base, identify which measures they can implement locally and take part in national research programmes. Surgical teams in the NHS have the chance to create a world-leading programme that can bring change to hospitals around the world. This article provides an overview of how surgeons see the surgical team being involved in environmentally sustainable surgery.

Multi-Stage Adaptive Spline Autofocus (MASA) with a Learned Metric for Deformable Motion Compensation in Interventional Cone-Beam CT.

Purpose: Cone-beam CT (CBCT) is widespread in abdominal interventional imaging, but its long acquisition time makes it susceptible to patient motion. Image-based autofocus has shown success in CBCT deformable motion compensation, via deep autofocus metrics and multi-region optimization, but it is challenged by the large parameter dimensionality required to capture intricate motion trajectories. This work leverages the differentiable nature of deep autofocus metrics to build a novel optimization strategy, Multi-Stage Adaptive Spine Autofocus (MASA), for compensation of complex deformable motion in abdominal CBCT. Methods: MASA poses the autofocus problem as a multi-stage adaptive sampling strategy of the motion trajectory, sampled with Hermite spline basis with variable amplitude and knot temporal positioning. The adaptive method permits simultaneous optimization of the sampling phase, local temporal sampling density, and time-dependent amplitude of the motion trajectory. The optimization is performed in a multi-stage schedule with increasing number of knots that progressively accommodates complex trajectories in late stages, preconditioned by coarser components from early stages, and with minimal increase in dimensionality. MASA was evaluated in controlled simulation experiments with two types of motion trajectories: i) combinations of slow drifts with sudden jerk (sigmoid) motion; and ii) combinations of periodic motion sources of varying frequency into multi-frequency trajectories. Further validation was obtained in clinical data from liver CBCT featuring motion of contrast-enhanced vessels, and soft-tissue structures. Results: The adaptive sampling strategy provided successful motion compensation in sigmoid trajectories, compared to fixed sampling strategies (mean SSIM increase of 0.026 compared to 0.011). Inspection of the estimated motion showed the capability of MASA to automatically allocate larger sampling density to parts of the scan timeline featuring sudden motion, effectively accommodating complex motion without increasing the problem dimension. Experiments on multi-frequency trajectories with 3-stage MASA (5, 10, and 15 knots) yielded a twofold SSIM increase compared to single-stage autofocus with 15 knots (0.076 vs 0.040, respectively). Application of MASA to clinical datasets resulted in simultaneous improvement on the delineation of both contrast-enhanced vessels and soft-tissue structures in the liver. Conclusion: A new autofocus framework, MASA, was developed including a novel multi-stage technique for adaptive temporal sampling of the motion trajectory in combination with fully differentiable deep autofocus metrics. This novel adaptive sampling approach is a crucial step for application of deformable motion compensation to complex temporal motion trajectories.

[Genome sequence analysis of two SARS-CoV-2 virus infections in Inner Mongolia, 2022].

The target gene sequences of the novel coronaviruses obtained by sequencing were compared with the reference sequences to analyze the genetic variation of the two cases of the novel coronaviruses from Inner Mongolia Autonomous Region in 2022 and to explore the sources of infection. The results showed that the two sequences belonged to different evolutionary branches, Delta (AY.122) and Omicron (BA.1.1), respectively. hCoV-19/Inner Mongolia/IVDC-591/2022 had 48 single nucleotide polymorphisms on the genome sequences, sharing 40 nucleotide mutation sites with a Mongolian strain; hCoV-19/Inner Mongolia/IVDC-592/2022 genome shared 57 nucleotide mutation sites with a UK strain, and the nucleotide mutation site identity was 100% (57/57). Phylogenetic analysis showed that the target gene sequences were not directly related to domestic novel coronavirus sequences during the same period, but were related to isolates from Europe and Mongolia.

A pilot study to assess the impact of aboriginal and torres strait islander cultural humility webinars on australian medical school students.

BACKGROUND: The Aboriginal and Torres Strait Islander Health Curriculum Framework helps higher education providers to deliver safe and well-informed cultural humility education. However, there is currently a scarcity of evidence surrounding the efficacy and impact of cultural humility education. This study will use qualitative and quantitative research methods to evaluate learning outcomes from an Indigenous health educational webinar aimed at Australian medical students. METHODS: A pilot study was conducted following a group of Australian medical students who attended an educational Indigenous health (IH) culturally responsive webinar. Recruitment was conducted via the webinar hosts' social media pages. Quantitative methods involved sending one pre- and two post-webinar questionnaires to attendees. To assess participants' retention of information, one post-webinar survey was sent out immediately after the webinar and another three months after the webinar. These questionnaires were designed to reflect pre-determined learning objectives for the webinar. Qualitative methods involved a focus group discussion to identify common themes from participant feedback. RESULTS: Twenty-six participants were included in the final quantitative analysis. Most of the participants were clinical students between 18 and 24 years old who did not identify as Aboriginal and/or Torres Strait Islander. There was a significant increase (p = 0.007) between pre-intervention (M = 0.35, SD = 0.26) and post-webinar knowledge for the learning outcome exploring the links between health and education (M = 047, SD = 0.25). No results were obtained from the three months post-intervention questionnaire. The qualitative analysis synthesized feedback from three participants and identified presenter delivery style as an important mediator of webinar effectiveness. CONCLUSIONS: There was a significant increase in knowledge and understanding for the learning outcome that explored the links between health and education. We attribute this partly to the engaging and conversational delivery style of the webinar presenters. The importance of Indigenous facilitators that encourage reflective teaching should not be understated. Our results suggest that cultural humility webinars can have a positive impact on medical students' understanding of the Aboriginal and/or Torres Strait Islander health landscape. This pilot study warrants further research on a larger population.

[Impact of VA-ECMO combined with IABP and timing on outcome of patients with acute myocardial infarction complicated with cardiogenic shock].

Objective: To investigate the impact of combined use and timing of arterial-venous extracorporeal membrane oxygenation (VA-ECMO) with intra-aortic balloon pump (IABP) on the prognosis of patients with acute myocardial infarction complicated with cardiogenic shock (AMICS). Methods: This was a prospective cohort study, patients with acute myocardial infarction and cardiogenic shock who received VA-ECMO support from the Heart Center of Lanzhou University First Hospital from March 2019 to March 2022 in the registration database of the Chinese Society for Extracorporeal Life Support were enrolled. According to combination with IABP and time point, patients were divided into VA-ECMO alone group, VA-ECMO+IABP concurrent group and VA-ECMO+IABP non-concurrent group. Data from 3 groups of patients were collected, including the demographic characteristics, risk factors, ECG and echocardiographic examination results, critical illness characteristics, coronary intervention results, VA-ECMO related parameters and complications were compared among the three groups. The primary clinical endpoint was all-cause death, and the safety indicators of mechanical circulatory support included a decrease in hemoglobin greater than 50 g/L, gastrointestinal bleeding, bacteremia, lower extremity ischemia, lower extremity thrombosis, acute kidney injury, pulmonary edema and stroke. Kaplan-Meier survival curves were used to analyze the survival outcomes of patients within 30 days of follow-up. Using VA-ECMO+IABP concurrent group as reference, multivariate Cox regression model was used to evaluate the effect of the combination of VA-ECMO+IABP at different time points on the prognosis of AMICS patients within 30 days. Results: The study included 68 AMICS patients who were supported by VA-ECMO, average age was (59.8±10.8) years, there were 12 female patients (17.6%), 19 cases were in VA-ECMO alone group, 34 cases in VA-ECMO+IABP concurrent group and 15 cases in VA-ECMO+IABP non-concurrent group. The success rate of ECMO weaning in the VA-ECMO+IABP concurrent group was significantly higher than that in the VA-ECMO alone group and the VA-ECMO+IABP non-concurrent group (all P<0.05). Compared with the ECMO+IABP non-concurrent group, the other two groups had shorter ECMO support time, lower rates of acute kidney injury complications (all P<0.05), and lower rates of pulmonary edema complications in the ECMO alone group (P<0.05). In-hospital survival rate was significantly higher in the VA-ECMO+IABP concurrent group (28 patients (82.4%)) than in the VA-ECMO alone group (9 patients) and VA-ECMO+IABP non-concurrent group (7 patients) (all P<0.05). The survival rate up to 30 days of follow-up was also significantly higher surviving patients within were in the ECMO+IABP concurrent group (26 cases) than in VA-ECMO alone group (9 patients) and VA-ECMO+IABP non-concurrent group (4 patients) (all P<0.05). Multivariate Cox regression analysis showed that compared with the concurrent use of VA-ECMO+IABP, the use of VA-ECMO alone and non-concurrent use of VA-ECMO+IABP were associated with increased 30-day mortality in AMICS patients (HR=2.801, P=0.036; HR=2.985, P=0.033, respectively). Conclusions: When VA-ECMO is indicated for AMICS patients, combined use with IABP at the same time can improve the ECMO weaning rate, in-hospital survival and survival at 30 days post discharge, and which does not increase additional complications.

Universal DNA methylation age across mammalian tissues.

Aging, often considered a result of random cellular damage, can be accurately estimated using DNA methylation profiles, the foundation of pan-tissue epigenetic clocks. Here, we demonstrate the development of universal pan-mammalian clocks, using 11,754 methylation arrays from our Mammalian Methylation Consortium, which encompass 59 tissue types across 185 mammalian species. These predictive models estimate mammalian tissue age with high accuracy (r > 0.96). Age deviations correlate with human mortality risk, mouse somatotropic axis mutations and caloric restriction. We identified specific cytosines with methylation levels that change with age across numerous species. These sites, highly enriched in polycomb repressive complex 2-binding locations, are near genes implicated in mammalian development, cancer, obesity and longevity. Our findings offer new evidence suggesting that aging is evolutionarily conserved and intertwined with developmental processes across all mammals.

Medical Imaging Compatibility of Magnesium- and Iron-Based Bioresorbable Flow Diverters.

BACKGROUND AND PURPOSE: Bioresorbable flow diverters are under development to mitigate complications associated with conventional flow-diverter technology. One proposed advantage is the ability to reduce metal-induced artifacts in follow-up medical imaging. In the current work, the medical imaging compatibility of magnesium- and iron-based bioresorbable flow diverters is assessed relative to an FDA-approved control in phantom models. MATERIALS AND METHODS: Bioresorbable flow diverters, primarily composed of braided magnesium or antiferromagnetic iron alloy wires, were compared with an FDA-approved control flow diverter. The devices were assessed for MR imaging safety in terms of magnetically induced force and radiofrequency heating using 1.5T, 3T, and 7T field strength clinical scanners. The devices were deployed in phantom models, and metal-induced image artifacts were assessed in the 3 MR imaging scanners and a clinical CT scanner following clinical scan protocols; device visibility was assessed under fluoroscopy. RESULTS: The magnesium-based bioresorbable flow diverter, iron-based bioresorbable flow diverter, and the control device all demonstrated MR imaging safety in terms of magnetically induced force and radiofrequency heating at all 3 field strengths. The bioresorbable flow diverters did not elicit excessive MR imaging artifacts at any field strength relative to the control. Furthermore, the bioresorbable flow diverters appeared to reduce blooming artifacts in CT relative to the control. The iron-based bioresorbable flow diverter and control device were visible under standard fluoroscopy. CONCLUSIONS: We have demonstrated the baseline medical imaging compatibility of magnesium and antiferromagnetic iron alloy bioresorbable flow diverters. Future work will evaluate the medical imaging characteristics of the bioresorbable flow diverters in large-animal models.

Quercetin downregulates the expression of IL15 in cancer cells through DNA methylation.

OBJECTIVE: This study aimed to investigate the effect of quercetin on cellular immunity (via IL15 expression) against cancer and to elucidate its regulatory mechanism. MATERIALS AND METHODS: HeLa cells and A549 cells were cultured in vitro and were divided into control (DMSO treated) and experimental groups (treated with different concentrations of quercetin). Transcript levels of IL15 and DNA methyltransferase (DNMTS) were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Genomic DNA was extracted, treated with bisulfite, and the promoter region of IL15 was cloned. Finally, Sanger sequencing was used to detect the degree of promoter methylation. RESULTS: Following quercetin treatment, the expression of IL15 was significantly downregulated in HeLa and A549 cells. The methylation level of IL15 promoter in HeLa cells was about twice that of the control group, and the methylation level of IL15 promoter in A549 cells was about three times that of the control group. CONCLUSIONS: Quercetin inhibits cancer cell proliferation while downregulating IL15 expression, and this regulation is achieved by increasing the methylation of the IL15 promoter.

The SPEAK study rationale and design: A linguistic corpus-based approach to understanding thought disorder.

AIM: Psychotic symptoms are typically measured using clinical ratings, but more objective and sensitive metrics are needed. Hence, we will assess thought disorder using the Research Domain Criteria (RDoC) heuristic for language production, and its recommended paradigm of "linguistic corpus-based analyses of language output". Positive thought disorder (e.g., tangentiality and derailment) can be assessed using word-embedding approaches that assess semantic coherence, whereas negative thought disorder (e.g., concreteness, poverty of speech) can be assessed using part-of-speech (POS) tagging to assess syntactic complexity. We aim to establish convergent validity of automated linguistic metrics with clinical ratings, assess normative demographic variance, determine cognitive and functional correlates, and replicate their predictive power for psychosis transition among at-risk youths. METHODS: This study will assess language production in 450 English-speaking individuals in Australia and Canada, who have recent onset psychosis, are at clinical high risk (CHR) for psychosis, or who are healthy volunteers, all well-characterized for cognition, function and symptoms. Speech will be elicited using open-ended interviews. Audio files will be transcribed and preprocessed for automated natural language processing (NLP) analyses of coherence and complexity. Data analyses include canonical correlation, multivariate linear regression with regularization, and machine-learning classification of group status and psychosis outcome. CONCLUSIONS: This prospective study aims to characterize language disturbance across stages of psychosis using computational approaches, including psychometric properties, normative variance and clinical correlates, important for biomarker development. SPEAK will create a large archive of language data available to other investigators, a rich resource for the field.

3D-2D image registration in the presence of soft-tissue deformation in image-guided transbronchial interventions.

Purpose. Target localization in pulmonary interventions (e.g. transbronchial biopsy of a lung nodule) is challenged by deformable motion and may benefit from fluoroscopic overlay of the target to provide accurate guidance. We present and evaluate a 3D-2D image registration method for fluoroscopic overlay in the presence of tissue deformation using a multi-resolution/multi-scale (MRMS) framework with an objective function that drives registration primarily by soft-tissue image gradients.Methods. The MRMS method registers 3D cone-beam CT to 2D fluoroscopy without gating of respiratory phase by coarse-to-fine resampling and global-to-local rescaling about target regions-of-interest. A variation of the gradient orientation (GO) similarity metric (denotedGO') was developed to downweight bone gradients and drive registration via soft-tissue gradients. Performance was evaluated in terms of projection distance error at isocenter (PDEiso). Phantom studies determined nominal algorithm parameters and capture range. Preclinical studies used a freshly deceased, ventilated porcine specimen to evaluate performance in the presence of real tissue deformation and a broad range of 3D-2D image mismatch.Results. Nominal algorithm parameters were identified that provided robust performance over a broad range of motion (0-20 mm), including an adaptive parameter selection technique to accommodate unknown mismatch in respiratory phase. TheGO'metric yielded median PDEiso= 1.2 mm, compared to 6.2 mm for conventionalGO.Preclinical studies with real lung deformation demonstrated median PDEiso= 1.3 mm with MRMS +GO'registration, compared to 2.2 mm with a conventional transform. Runtime was 26 s and can be reduced to 2.5 s given a prior registration within ∼5 mm as initialization.Conclusions. MRMS registration via soft-tissue gradients achieved accurate fluoroscopic overlay in the presence of deformable lung motion. By driving registration via soft-tissue image gradients, the method avoided false local minima presented by bones and was robust to a wide range of motion magnitude.

Targeted Deformable Motion Compensation for Vascular Interventional Cone-Beam CT Imaging.

Purpose: Cone-beam CT has become commonplace for 3D guidance in interventional radiology (IR), especially for vascular procedures in which identification of small vascular structures is crucial. However, its long image acquisition time poses a limit to image quality due to soft-tissue deformable motion that hampers visibility of small vessels. Autofocus motion compensation has shown promising potential for soft-tissue deformable motion compensation, but it lacks specific target to the imaging task. This work presents an approach for deformable motion compensation targeted at imaging of vascular structures. Methods: The proposed method consists on a two-stage framework for: i) identification of contrast-enhanced blood vessels in 2D projection data and delineation of an approximate region covering the vascular target in the volume space, and, ii) a novel autofocus approach including a metric designed to promote the presence of vascular structures acting solely in the region of interest. The vesselness of the image is quantified via evaluation of the properties of the 3D image Hessian, yielding a vesselness filter that gives larger values to voxels candidate to be part of a tubular structure. A cost metric is designed to promote large vesselness values and spatial sparsity, as expected in regions of fine vascularity. A targeted autofocus method was designed by combining the presented metric with a conventional autofocus term acting outside of the region of interest. The resulting method was evaluated on simulated data including synthetic vascularity merged with real anatomical features obtained from MDCT data. Further evaluation was obtained in two clinical datasets obtained during TACE procedures with a robotic C-arm (Artis Zeego, Siemens Healthineers). Results: The targeted vascular autofocus effectively restored the shape and contrast of the contrast-enhanced vascularity in the simulation cases, resulting in improved visibility and reduced artifacts. Segmentations performed with a single threshold value on the target vascular regions yielded a net increase of up to 42% in DICE coefficient computed against the static reference. Motion compensation in clinical datasets resulted in improved visibility of vascular structures, observed in maximum intensity projections of the contrast-enhanced liver vessel tree. Conclusion: Targeted motion compensation for vascular imaging showed promising performance for increased identification of small vascular structures in presence of motion. The development of autofocus metrics and methods tailored to vascular imaging opens the way for reliable compensation of deformable motion while preserving the integrity of anatomical structures in the image.

[Clinical characteristics and prognosis of seizures in 75 children with acute lymphoblastic leukemia].

OBJECTIVE: To investigate the clinical characteristics, treatment, and prognosis of seizures in children with acute lymphoblastic leukemia (ALL) during chemotherapy. METHODS: Children with ALL with seizures during chemotherapy admitted to the Department of Pediatrics, Peking University People's Hospital from January 2010 to March 2022 were retrospectively analyzed. Clinical data including the incidence of seizure, time at seizure onset, causes, management, and prognosis were collected retrospectively. RESULTS: A total of 932 children with ALL were admitted during the study period, of whom, 75 (8%) were complicated with seizures during the period of chemotherapy. There were 40 males and 35 females, with a median age of 7.5 (1-17) years, and 43 cases (57.3%) occurred within the first 2 months of chemotherapy. The underlying diseases were reversible posterior encephalopathy syndrome (n=15), cerebral hemorrhage (n=10, one of whom was complicated with venous sinus thrombosis), intrathecal or systemic methotrexate administration (n=11), brain abscess (n=7, fungal infection in 3 cases, and bacterial in 4), viral encephalitis (n=2), febrile seizure (n=7), hyponatremia (n=7), hypocalcemia (n=2), and unknown cause (n=14). Sixty-four children underwent neuroimaging examination after seizure occurrence, of whom 37 (57.8%) were abnormal. The electroencephalograhpy (EEG) was performed in 44 cases and was abnormal in 24 (54.4%). Fifty-five patients remained in long-term remission with regular chemotherapy, 8 patients received hematopoietic stem cell transplantation, 9 died and 3 lost to follow-up. Symptomatic epilepsy was diagnosed in 18 cases (24%), and was well controlled in 16 with over 1 year of seizure-free. Whereas 2 cases were refractory to anti-seizure medications. CONCLUSION: Seizures are relatively common in children with ALL, most commonly due to reversible posterior encephalopathy syndrome, methotrexate-related neurotoxicity, and cerebral hemorrhage. Seizures occurred within 2 months of chemotherapy in most cases. Neuroimaging and EEG should be performed as soon as possible after the first seizure onset to identify the etiology and to improve the treatment regimen. Some cases developed symptomatic epilepsy, with a satisfactory outcome of seizure remission mostly after concurrent antiseizure medication therapy.

Space-time analysis of COVID-19 cases and SARS-CoV-2 wastewater loading: A geodemographic perspective.

Severe acute respiratory syndrome - coronavirus 2 (SARS-CoV-2) continues to effect communities across the world. One way to combat these effects is to enhance our collective ability to remotely monitor community spread. Monitoring SARS-CoV-2 in wastewater is one approach that enables researchers to estimate the total number of infected people in a region; however, estimates are often made at the sewershed level which may mask the geographic nuance required for targeted interdiction efforts. In this work, we utilize an apportioning method to compare the spatial and temporal trends of daily case count with the temporal pattern of viral load in the wastewater at smaller units of analysis within Austin, TX. We find different lag-times between wastewater loading and case reports. Daily case reports for some locations follow the temporal trend of viral load more closely than others. These findings are then compared to socio-demographic characteristics across the study area.

DNA binding by the Rad9A subunit of the Rad9-Rad1-Hus1 complex.

The Rad9-Rad1-Hus1 checkpoint clamp activates the DNA damage response and promotes DNA repair. DNA loading on the central channel of the Rad9-Rad1-Hus1 complex is required to execute its biological functions. Because Rad9A has the highest DNA affinity among the three subunits, we determined the domains and functional residues of human Rad9A that are critical for DNA interaction. The N-terminal globular domain (residues 1-133) had 3.7-fold better DNA binding affinity than the C-terminal globular domain (residues 134-266) of Rad9A1-266. Rad9A1-266 binds DNA 16-, 60-, and 30-fold better than Rad9A1-133, Rad9A134-266, and Rad9A94-266, respectively, indicating that different regions cooperatively contribute to DNA binding. We show that basic residues including K11, K15, R22, K78, K220, and R223 are important for DNA binding. The reductions on DNA binding of Ala substituted mutants of these basic residues show synergistic effect and are dependent on their residential Rad9A deletion constructs. Interestingly, deletion of a loop (residues 160-163) of Rad9A94-266 weakens DNA binding activity by 4.1-fold as compared to wild-type (WT) Rad9A94-266. Cellular sensitivity to genotoxin of rad9A knockout cells is restored by expressing WT-Rad9Afull. However, rad9A knockout cells expressing Rad9A mutants defective in DNA binding are more sensitive to H2O2 as compared to cells expressing WT-Rad9Afull. Only the rad9A knockout cells expressing loop-deleted Rad9A mutant are more sensitive to hydroxyurea than cells expressing WT-Rad9A. In addition, Rad9A-DNA interaction is required for DNA damage signaling activation. Our results indicate that DNA association by Rad9A is critical for maintaining cell viability and checkpoint activation under stress.

Crystal nucleation and growth processes in Cu-rich glass-forming Cu-Zr alloys.

The glass formation ability of an alloy depends on two competing processes: glass-transition, on one hand, and crystal nucleation and growth, on the other hand. While these phenomena have been widely studied before in nearly equiatomic Cu-Zr alloys, studies are lacking for solute/solvent-rich ones. In the present work, molecular dynamics simulations show that the addition of a small amount of Zr (1-10 at. %) to Cu drastically increases the incubation time and slows down crystal growth, thus, leading to an improved glass forming ability. The crystal nucleation and growth processes of a competing face-centered cubic (FCC) Cu crystalline phase are analyzed in detail. In particular, the values of the critical cooling rate, incubation period for crystallization, and growth rate of FCC Cu crystals in these Cu-rich alloys are obtained. The growth of a supersaturated FCC Cu solid solution is found to be polymorphic at the interface (except for alloys with 9 and 10 at. % Zr) though a Zr concentration gradient is observed within growing crystals at high enough Zr content. The crystal growth rate before crystal impingement is nearly constant in all alloys, though it decreases exponentially with the Zr content. Crystallization kinetics are also analyzed within the existing theories and compared with the experimental values available in the literature.

Mammalian MutY Homolog (MYH or MUTYH) is Critical for Telomere Integrity under Oxidative Stress.

Telomeres consist of special features and proteins to protect the ends of each chromosome from deterioration and fusion. The telomeric DNA repeats are highly susceptible to oxidative damage that can accelerate telomere shortening and affect telomere integrity. Several DNA repair factors including MYH/MUTYH DNA glycosylase, its interacting partners Rad9/Rad1/Hus1 checkpoint clamp, and SIRT6 aging regulator, are associated with the telomeres. MYH prevents C:G to A:T mutation by removing adenine mispaired with a frequent oxidative DNA lesion, 8-oxoguanine. Here, we show that hMYH knockout (KO) human HEK-293T cells are more sensitive to H2O2 treatment, have higher levels of DNA strand breaks and shorter telomeres than the control hMYH +/+ cells. SIRT6 foci increase at both the global genome and at telomeric regions in H2O2-treated hMYH +/+ cells. However, in untreated hMYH KO HEK-293T cells, SIRT6 foci only increase at the global genome, but not at the telomeric regions. In addition, the hMYH KO HEK-293T cells have increased extra-chromosomal and intra-chromosomal telomeres compared to the control cells, even in the absence of H2O2 treatment. After H2O2 treatment, the frequency of extra-chromosomal telomeres increased in control HEK-293T cells. Remarkably, in H2O2-treated hMYH KO cells, the frequencies of extra-chromosomal telomeres, intra-chromosomal telomeres, and telomere fusions are further increased. We further found that the sensitivity to H2O2 and shortened telomeres of hMYH KO cells, are restored by expressing wild-type hMYH, and partially rescued by expressing hMYHQ324H mutant (defective in Hus1 interaction only), but not by expressing hMYHV315A mutant (defective in both SIRT6 and Hus1 interactions). Thus, MYH interactions with SIRT6 and Hus1 are critical for maintaining cell viability and telomeric stability. Therefore, the failure to coordinate 8-oxoG repair is detrimental to telomere integrity.