Miracle-dz/UniFAR-FTUs huggingface dataset:
Cytosine, but not adenine, base editors induce genome-wide off-target mutations in rice

Spotting off-targets from gene editing Unintended genomic modifications limit the potential therapeutic use of gene-editing tools. Available methods to find off-targets generally do not work in vivo or detect single-nucleotide changes. Three papers in this issue report new methods for monitoring gene-editing tools in vivo (see the Perspective by Kempton and Qi). Wienert et al. followed the recruitment of a DNA repair protein to DNA breaks induced by CRISPR-Cas9, enabling unbiased detection of off-target editing in cellular and animal models. Zuo et al. identified off-targets without the interference of natural genetic heterogeneity by injecting base editors into one blastomere of a two-cell mouse embryo and leaving the other genetically identical blastomere unedited. Jin et al. performed whole-genome sequencing on individual, genome-edited rice plants to identify unintended mutations. Cytosine, but not adenine, base editors induced numerous single-nucleotide variants in both mouse and rice. Science, this issue p. 286, p. 289, p. 292; see also p. 234 Whole-genome sequencing analyses reveal substantial off-target mutations induced by cytosine base editors in rice. Cytosine and adenine base editors (CBEs and ABEs) are promising new tools for achieving the precise genetic changes required for disease treatment and trait improvement. However, genome-wide and unbiased analyses of their off-target effects in vivo are still lacking. Our whole-genome sequencing analysis of rice plants treated with the third-generation base editor (BE3), high-fidelity BE3 (HF1-BE3), or ABE revealed that BE3 and HF1-BE3, but not ABE, induce substantial genome-wide off-target mutations, which are mostly the C→T type of single-nucleotide variants (SNVs) and appear to be enriched in genic regions. Notably, treatment of rice with BE3 or HF1-BE3 in the absence of single-guide RNA also results in the rise of genome-wide SNVs. Thus, the base-editing unit of BE3 or HF1-BE3 needs to be optimized in order to attain high fidelity.
Visual Object Perception in Premanifest and Early Manifest Huntington’s Disease

Abstract Objective In Huntington’s disease (HD), a hereditary neurodegenerative disorder, cognitive impairment in early disease stages mainly involves executive dysfunction. However, visual cognitive deficits have additionally been reported and are of clinical relevance given their influence on daily life and overall cognitive performance. This study aimed to assess visual perceptual skills in HD gene carriers. Methods Subtasks of the Visual Object and Space Perception battery and Groningen Intelligence Test were administered in 62 participants (18 healthy controls, 22 participants with a genetic confirmation of HD without symptoms, i.e., premanifest HD, and 22 participants with a genetic confirmation of HD with symptoms, i.e., manifest HD). Group differences in task performance were measured using analysis of covariance with and without correction for age. Receiver Operating Characteristics (ROC) analysis was performed to examine which task best discriminated between groups and cut-off scores were provided. Results Manifest HD performed significantly worse compared to both controls and premanifest HD on all visual perceptional tasks. Premanifest HD did not differ in task performance from controls. Besides the Shape Detection, all tasks were robust in discriminating between groups. The Animal Silhouettes test was most accurate in discriminating manifest HD from premanifest HD (AUC = 0.90, SE = 0.048, p < .001). Conclusion Visual perceptual deficits are present in early manifest HD, especially an impaired recognition of animals and objects from sketched silhouettes, and not in premanifest HD. This suggests that decline in visual processing only occurs in clinical disease stages. The visual cognitive battery, especially the Silhouettes tasks used in this study is sensitive in discriminating manifest HD from premanifest HD and controls.
Compensatory behaviors among racial and ethnic minority undergraduate women

ABSTRACT Limited research has examined prevalence rates of disordered eating across racial and ethnic groups. The current study aimed to assess the prevalence of compensatory behaviors across minority undergraduate women. Self-report responses (N = 3,430) on the Eating Disorder Examination Questionnaire were analyzed from 2,094 White (55.9%), 684 Hispanic/Latina (18.3%), 508 Asian (13.6%), 235 Black (6.3%), and 65 Native American/Alaskan Native (1.7%) women attending college within the United States. Racial and ethnic differences were significant across all compensatory behaviors. Most notably, Asian and Native American women engage in compensatory behaviors comparable to or more than their White peers, and Black women consistently reported the lowest prevalence rate of any behavior. Findings were compared to the existing literature, noting general trends across studies that may help inform screening, assessment, and treatment of eating pathology as well as suggest future directions for intervention science.
Double autoinhibition mechanism of signal transduction ATPases with numerous domains (STAND) with a tetratricopeptide repeat sensor

Abstract Upon triggering by their inducer, signal transduction ATPases with numerous domains (STANDs), initially in monomeric resting forms, multimerize into large hubs that activate target macromolecules. This process requires conversion of the STAND conserved core (the NOD) from a closed form encasing an ADP molecule to an ATP-bound open form prone to multimerize. In the absence of inducer, autoinhibitory interactions maintain the NOD closed. In particular, in resting STAND proteins with an LRR- or WD40-type sensor domain, the latter establishes interactions with the NOD that are disrupted in the multimerization-competent forms. Here, we solved the first crystal structure of a STAND with a tetratricopeptide repeat sensor domain, PH0952 from Pyrococcus horikoshii, revealing analogous NOD-sensor contacts. We use this structural information to experimentally demonstrate that similar interactions also exist in a PH0952 homolog, the MalT STAND archetype, and actually contribute to the MalT autoinhibition in vitro and in vivo. We propose that STAND activation occurs by stepwise release of autoinhibitory contacts coupled to the unmasking of inducer-binding determinants. The MalT example suggests that STAND weak autoinhibitory interactions could assist the binding of inhibitory proteins by placing in register inhibitor recognition elements born by two domains.
Associations of homocysteine status and homocysteine metabolism enzyme polymorphisms with hypertension and dyslipidemia in a Chinese hypertensive population

ABSTRACT Background: Hypertension (HTN), dyslipidemia and hyperhomocysteinemia (HHcy) are risk factors for cardiovascular disease (CVD). Methods: Hypertensive Chinese subjects (n = 228) were enrolled. MTHFR C667T, MTHFR A1298C, MTR A2756G, and MTRR A66G genotypes were determined. Unconditional logistic regression was performed to determine the associations of serum Hcy status and genotypes with HTN and dyslipidemia. Results: The mean age of hypertensive adults was 65.53 ± 9.94 years, including 88 (38.6%) men and 140 (61.4%) women. Patients with MTHFR 667TT and MTRR GG carriers showed higher serum Hcy levels (P = 0.019 and 0.018, respectively), which is associated with higher serum triacylglycerols (TAG) and total cholesterol (TC) levels (P = 0.014 and 0.044, respectively) and a higher risk for hypertriglyceridemia (OR = 1.889, 95% CI: 1.105–3.229, P = 0.020). Compared with low Hcy and MTRR 66AA, those with high Hcy and 66AA or 66AG+GG showed higher odd\s of hypertriglyceridemia (MTRR 66AA+ high Hcy: OR: 2.692, 95% CI: 1.189–6.096, Pcombined = 0.018; MTRR 66AG/GG+ high Hcy: OR: 3.433, 95% CI: 1.517–7.772, Pcombined = 0.003, respectively). Patients with high Hcy and MTHFR 667CC, as well as those with low Hcy and 667CT+TT, showed lower odds of uncontrolled SBP (MTHFR 667CC+ high Hcy: OR: 0.338, 95% CI: 0.115–0.996, Pcombined = 0.049; MTHFR 667CT/TT+ low Hcy: OR: 0.421, 95% CI: 0.193–0.921, Pcombined = 0.030) compared to patients with low Hcy and MTHFR 667CC. Conclusions: Serum Hcy status and Hcy metabolism gene polymorphisms (MTHFR C667T and MTRR A66G) may have synergistic effects on the prevalence of HTN and dyslipidemia.
Integrative Oncology: International Perspectives

Interest in integrative oncology (IO) is growing globally. Patients with cancer are actively using traditional complementary and integrative medicine (TCIM) as part of their cancer and survivorship care. Published studies from around the world report increasing use of TCIM by people living with cancer. This article summarizes the presentations that took place during a symposium titled, “Integrative Oncology: International Perspectives” at the International Research Congress on Integrative Medicine and Health in Baltimore, 2018. The purpose of the presentations was to examine whether cancer services across a variety of geographical regions, including Australia, Canada, the United States, and the European Union, were actively responding to cancer survivors’ demand for TCIM. The presenters highlighted utilization rates and both facilitators and barriers to the provision of IO services in their respective countries and regions. The audience discussion following the presentations drew out many noteworthy perspectives.
Patterns of MMPI-2-Restructured Form (MMPI-2-RF) validity scale scores observed across Veteran Affairs settings.

The purpose of this investigation is to provide descriptive information on veteran response styles for a variety of VA referral types using the Minnesota Multiphasic Personality Inventory (MMPI)-2-Restructured Form (MMPI-2-RF), which has well-supported protocol validity scales. The sample included 17,640 veterans who were administered the MMPI-2-RF between when it was introduced to the VA system in 2013 until May 31, 2015 at any VA in the United States. This study examines frequencies of protocol invalidity based on the MMPI-2-RF's validity scales and provides comprehensive descriptive findings on validity scale scores within the VA. Three distinct trends can be seen. First, a majority of the sample did not elevate any of the validity scales beyond their recommended interpretive cut-scores, indicating that scores on the substantive scales would be deemed valid and interpretable in those cases. Second, elevation rates are higher for the overreporting scales in comparison to the underreporting and non-content-based invalid responding scales. Lastly, a majority of those with an elevation on one overreporting validity indicator also had an elevation on at least one other overreporting scale. Implications for practice and the utility of the MMPI-2-RF within the VA are discussed. (PsycINFO Database Record (c) 2019 APA, all rights reserved).
The epidemiology and incidence of cytomegalovirus retinitis in the HIV population in Singapore over 6 years.

PURPOSE We report the epidemiologic trend of cytomegalovirus (CMV) retinitis among human immunodeficiency virus (HIV) patients in Singapore. METHODS Our study included a retrospective case series of HIV patients with newly diagnosed CMV retinitis (CMVR) at the Singapore CDC between 2005 and 2010. Demographics, symptoms, signs, and laboratory results, including CD4 counts, were collected. Prevalence and disease trends over time were measured. RESULTS Of 224 new patients, 92.9% were male and 96.0% were on antiretroviral therapy (ART). Median age was 43.0 years, with a median CD4 count of 38.0 cells/μL at HIV diagnosis. There was a decline in CD4 counts at diagnosis, and median duration of ART initiation from HIV diagnosis generally was earlier. Overall incidence rate was 10.4 cases per 1000 person-years (PY) and the mortality rate was 19.4 per 1000 PY. Mean survival time was 160.2 months (95% confidence interval [CI] 150.3-170.2). The 25 patients who died during the study period were older at the time of CMVR diagnosis (P = 0.003) and had lower CD4 counts (P = 0.030). Worse prognoses were associated with older age (hazard ratio [HR] 1.06, 95% CI 1.02-1.10) and shorter time lag from HIV to CMVR diagnosis (HR 0.97, 95% CI 0.95-0.99). Patients who did not receive highly active antiretroviral treatment (HAART) had a higher mortality risk (HR 4.70, 95% CI 1.54-14.33). CONCLUSIONS The incidence rate of CMVR was decreasing with earlier initiation of ART and lower CD4 counts at HIV diagnosis. Poor prognostic factors included older age, shorter time lag from HIV to CMVR diagnosis, and the absence of HAART. Constant ophthalmologic surveillance until immune reconstitution is recommended.
A Brain Model of Disturbed Self-Appraisal in Depression.

OBJECTIVE A disturbed sense of self is a core feature of depression. The medial prefrontal cortex, which has a central role in self-appraisal processes, is often implicated in the illness, although it remains unclear how functional alterations of the region contribute to the observed disturbances. The aim of this study was to clarify the role of the medial prefrontal cortex in self-appraisal processes in depression. METHOD The authors applied a recently developed dynamic network model of self-directed cognition to functional MRI data from 71 adolescents and young adults with moderate to severe major depressive disorder, none of whom were being treated with medication, and 88 healthy control participants. Bayesian model averaging was used to determine parameter estimates for the dynamic causal models, which were compared between groups. RESULTS While self-directed cognitive processes in the depression group were shown to rely on the same dynamic network as in the healthy control group, the medial prefrontal cortex had a "hyperregulatory" effect on the posterior cingulate cortex in the depressed group, with self-appraisal causing significantly more negative modulation of connectivity between the medial prefrontal cortex and the posterior cingulate cortex than in the control group (odds ratio=0.54, 95% CI=0.38, 0.77). This parameter was significantly inversely related with a depression factor related to poor concentration and inner tension (r=-0.32; 95% CI=-0.51, -0.08). CONCLUSIONS The exaggerated influence of the medial prefrontal cortex on the posterior cingulate cortex in depression is a neural correlate of the disturbed self-appraisal that is characteristic of the illness.
Adult Lumbar Scoliosis: Underreported on Lumbar MR Scans

BACKGROUND AND PURPOSE: Adult lumbar scoliosis is an increasingly recognized entity that may contribute to back pain. We investigated the epidemiology of lumbar scoliosis and the rate at which it is unreported on lumbar MR images. MATERIALS AND METHODS: The coronal and sagittal sequences of lumbar spine MR imaging scans of 1299 adult patients, seeking care for low back pain, were reviewed to assess for and measure the degree of scoliosis and spondylolisthesis. Findings were compared with previously transcribed reports by subspecialty trained neuroradiologists. Inter- and intraobserver reliability was calculated. RESULTS: The prevalence of adult lumbar scoliosis on MR imaging was 19.9%, with higher rates in ages >60 years (38.9%, P < .001) and in females (22.6%, P = .002). Of scoliotic cases, 66.9% went unreported, particularly when the scoliotic angle was <20° (73.9%, P < .001); 10.5% of moderate to severe cases were not reported. Spondylolisthesis was present in 15.3% (199/1299) of cases, demonstrating increased rates in scoliotic patients (32.4%, P < .001), and it was reported in 99.5% of cases. CONCLUSIONS: Adult lumbar scoliosis is a prevalent condition with particularly higher rates among older individuals and females but is underreported on spine MR images. This can possibly result in delayed 1) identification of a potential cause of low back pain, 2) referral to specialized professionals for targeted evaluation and management, and 3) provision of health care. The coronal “scout images” should be reviewed as part of the complete lumbar spine evaluation if dedicated coronal sequences are not already part of the spine protocol.
Statistics of noisy growth with mechanical feedback in elastic tissues

Significance Tissue growth is often a noisy process, and control of this noise is vital to the integrity of growth and development. However, a basic theoretical understanding of how noise affects growth, especially in tissues with mechanical feedback, is lacking. Here, we consider the simplest model of stochastic tissue growth and show that it predicts nontrivial behavior for observable quantities like density correlations and the sizes of marked clones. The former, in particular, exhibits power laws analogous to those seen in models of the early universe, hinting at a hitherto unexplored richness in the physics of “inflationary embryology. ” Tissue growth is a fundamental aspect of development and is intrinsically noisy. Stochasticity has important implications for morphogenesis, precise control of organ size, and regulation of tissue composition and heterogeneity. However, the basic statistical properties of growing tissues, particularly when growth induces mechanical stresses that can in turn affect growth rates, have received little attention. Here, we study the noisy growth of elastic sheets subject to mechanical feedback. Considering both isotropic and anisotropic growth, we find that the density–density correlation function shows power law scaling. We also consider the dynamics of marked, neutral clones of cells. We find that the areas (but not the shapes) of two clones are always statistically independent, even when they are adjacent. For anisotropic growth, we show that clone size variance scales like the average area squared and that the mode amplitudes characterizing clone shape show a slow 1/n decay, where n is the mode index. This is in stark contrast to the isotropic case, where relative variations in clone size and shape vanish at long times. The high variability in clone statistics observed in anisotropic growth is due to the presence of two soft modes—growth modes that generate no stress. Our results lay the groundwork for more in-depth explorations of the properties of noisy tissue growth in specific biological contexts.
Challenging Dogma: Optimal Treatment of the “Fight Bite”

Background: The optimal treatment of human bites to the dorsal metacarpophalangeal region (ie, “fight bite”) in the absence of gross purulence is controversial. Few studies have compared the outcomes of operative debridement with expectant wound care and oral antibiotics. Methods: We performed a retrospective chart review of all patients evaluated at a Level 1 trauma center over a 10-year period. We compared demographic and clinical characteristics of patients across treatment and outcome groups using the Fisher exact test. Logistic regression models were used to describe the relationships between the outcome and treatment variables. Results: We identified 115 patients with a mean age of 29 years. The mean follow-up was 51.8 days. Seventy-two (63%) patients were treated with antibiotics only. Thirty-two (28%) patients were treated with irrigation in the emergency department (ED) and expectant wound care. Eleven (9%) patients were treated with irrigation and debridement in the operating room. No demographic variables were found to correlate with the treatment selected. A 12% complication rate (major and minor) was observed. After adjusting for duration of follow-up and days to presentation, neither the treatment rendered nor the antibiotics selected influenced the rate of complications. Time to presentation >24 hours was the only variable associated with higher complication rate (P = .003). Conclusions: Not all fight bites require operative intervention. Irrigation in the ED with expectant wound care and oral antibiotics can be sufficient for patients presenting within 24 hours of injury in the absence of gross purulence.
Anaesthesia maintenance with propofol versus sevoflurane to reduce postoperative pain: Still too early for recommendations?

In this issue you will find a paper by Sau Ching Wong et al. entitled "The effect of total intravenous anaesthesia with propofol on postoperative pain after third molar surgery: a double blind randomized controlled trial"(Wong, Leung, and Cheung 2018 ##in press, will be assigned to an 2019-issue##). This paper reports results of a trial conducted in a standard surgical model of pain: the bilateral third molar extraction surgery. This article is protected by copyright. All rights reserved.
Iris varix: 10-year experience with 28 eyes

Purpose: The purpose of this study is to describe the clinical characteristics, multimodality imaging findings, and clinical course of iris varices. Methods: Retrospective, noncomparative, observational case series of 28 eyes of 26 patients with iris varices, diagnosed between 2007 and 2017, has been used. Results: The mean (±SD) age was 58.3 ± 12.5 years (median 57.5, range 37–81). Patients were 57.7% male and 27% hypertensive. Varices were bilateral in two patients. The mean and median visual acuities were both 20/20 (range 20/16–20/40). Intraocular pressures were 16 mmHg (10–23 mmHg). Secondary glaucoma did not occur. The inferotemporal iris quadrant was affected in 75%. A single varix was seen in 64% and 36% appeared multiple. Varix orientation was radial in 57% and circumferential in 21%. Combined radial and circumferential varix orientation was noted in 18%. One had independent radial and circumferential varices in separate quadrants. A single episcleral sentinel blood vessel directed to the varix was present in 36%. Ultrasound biomicroscopy (UBM) showed a slightly increased mean iris thickness of 0.8 mm and multiple echolucent iris stromal vascular channels. Iris angiography showed no leakage of dye. Managed by observation over a mean follow-up of 37.7 months (range, 3–129), 96.4% eyes were stable and one (3.6%) regressed. No corectopia, ectropion uveae, hyphema, or metachronous anterior segment benign or malignant tumors occurred. Conclusion: Iris varix is primarily located in the inferotemporal quadrant and not associated with dysmorphic pupillary findings, progression, secondary glaucoma, or malignancy. Iris varices were benign vasculopathies with no associated ocular or vision-related morbidity.