A massive galaxy that formed its stars at z ≈ 11.

The formation of galaxies by gradual hierarchical co-assembly of baryons and cold dark matter halos is a fundamental paradigm underpinning modern astrophysics1,2 and predicts a strong decline in the number of massive galaxies at early cosmic times3-5. Extremely massive quiescent galaxies (stellar masses of more than 1011 M⊙) have now been observed as early as 1-2 billion years after the Big Bang6-13. These galaxies are extremely constraining on theoretical models, as they had formed 300-500 Myr earlier, and only some models can form massive galaxies this early12,14. Here we report on the spectroscopic observations with the JWST of a massive quiescent galaxy ZF-UDS-7329 at redshift 3.205 ± 0.005. It has eluded deep ground-based spectroscopy8, it is significantly redder than is typical and its spectrum reveals features typical of much older stellar populations. Detailed modelling shows that its stellar population formed around 1.5 billion years earlier in time (z ≈ 11) at an epoch when dark matter halos of sufficient hosting mass had not yet assembled in the standard scenario4,5. This observation may indicate the presence of undetected populations of early galaxies and the possibility of significant gaps in our understanding of early stellar populations, galaxy formation and the nature of dark matter.

The Functional Proximal Proteome of Oncogenic Ras Includes mTORC2.

Proximity-dependent biotin labeling (BioID) may identify new targets for cancers driven by difficult-to-drug oncogenes such as Ras. Therefore, BioID was used with wild-type (WT) and oncogenic mutant (MT) H-, K-, and N-Ras, identifying known interactors, including Raf and PI3K, as well as a common set of 130 novel proteins proximal to all Ras isoforms. A CRISPR screen of these proteins for Ras dependence identified mTOR, which was also found proximal to MT Ras in human tumors. Oncogenic Ras directly bound two mTOR complex 2 (mTORC2) components, mTOR and MAPKAP1, to promote mTORC2 kinase activity at the plasma membrane. mTORC2 enabled the Ras pro-proliferative cell cycle transcriptional program, and perturbing the Ras-mTORC2 interaction impaired Ras-dependent neoplasia in vivo. Combining proximity-dependent proteomics with CRISPR screening identified a new set of functional Ras-associated proteins, defined mTORC2 as a new direct Ras effector, and offers a strategy for finding new proteins that cooperate with dominant oncogenes.

Breast Magnetic Resonance Imaging for Preoperative Evaluation of Breast Cancer: A Systematic Review and Meta-Analysis.

Purpose: Preoperative breast magnetic resonance imaging (MRI) is known to detect additional cancers that are occult on mammography and ultrasound. There is debate as to whether these additional lesions affect clinical outcomes. The objective of this systematic review was to summarize the evidence on whether additional information on disease extent obtained with preoperative breast MRI in patients with newly diagnosed breast cancer affects surgical management, rates of recurrence, survival, re-excision, and early detection of bilateral cancer. Methods: Embase, MEDLINE, and Cochrane Central Register of Controlled Trials were searched until January 2021 (partial update July 2022) for studies comparing outcomes with versus without pre-operative MRI. Included were both randomized controlled trials and other comparative studies provided MRI and control groups had equivalent disease and patient characteristics or methods such as multivariable analysis or propensity score matching were used to control potential confounders. Results: The search resulted in 26,399 citations, of which 8 randomized control trials, 1 prospective cohort study, and 42 retrospective studies met the inclusion criteria. Use of MRI resulted in decreased rates of reoperations (OR = 0.73, 95% CI = 0.63 to 0.85), re-excisions (OR = 0.63, 95% CI = 0.45 to 0.89), and recurrence (HR = 0.77, 95% CI = 0.65 to 0.90). Increased detection of synchronous contralateral breast cancers led to a reduction in metachronous contralateral breast cancer (HR = 0.71, 95% CI = 0.59 to 0.85). Hazard ratios for recurrence-free and overall survival were 0.77 (95% CI = 0.53 to 1.12) and 0.89 (95% CI = 0.74 to 1.07). Conclusion: This systematic review indicates substantial benefits of pre-operative breast MRI in decreasing reoperations and recurrence.

Lateralizing calcaneal osteotomy performed with a percutaneous burr results in a significantly lower increase in tarsal tunnel pressure.

PURPOSE: Tarsal tunnel syndrome is well documented following lateralizing calcaneal osteotomy to manage varus hindfoot deformity. Traditionally, calcaneal osteotomy is performed with an oscillating saw. No studies have investigated the effect of alternative surgical techniques on postoperative tarsal tunnel pressure. The purpose of this study was to investigate the difference in tarsal tunnel pressures following lateralizing calcaneal osteotomy performed using a high-torque, low-speed "minimally invasive surgery" (MIS) Shannon burr versus an oscillating saw. METHODS: Lateralizing calcaneal osteotomy was performed on 10 below-knee cadaveric specimens. This was conducted on 5 specimens each using an oscillating saw (Saw group) or MIS burr (Burr group). The calcaneal tuberosity was translated 1 cm laterally and transfixed using 2 Kirschner wires. Tarsal tunnel pressure was measured before and after osteotomy via ultrasound-guided percutaneous needle barometer. Mean pre/post-osteotomy pressures were compared between groups. Differences were analyzed using Student's t test. RESULTS: The mean pre-procedure tarsal tunnel pressure was 25.8 ± 5.1 mm Hg in the Saw group and 26.4 ± 4.3 mm Hg in the Burr group (p = 0.85). The mean post-procedure pressure was 63.4 ± 5.1 in the Saw group and 47.8 ± 4.3 in the Burr group (p = 0.01). Change in tarsal tunnel pressure was significantly lower in the Burr group (21.4 ± 4.5) compared to the Saw group (37.6 ± 12.5) (p = 0.03). The increase in tarsal tunnel pressure was 43% lower in the Burr group. CONCLUSION: In this cadaveric study, tarsal tunnel pressure increase after lateralizing calcaneal osteotomy was significantly lower when using a burr versus a saw. This is likely because the increased width ("kerf") of the 3 mm MIS burr, compared to the submillimeter saw blade width, causes calcaneal shortening. Given the smaller increase in tarsal tunnel pressure, using the MIS burr for lateralizing calcaneal osteotomy may decrease the risk of postoperative tarsal tunnel syndrome. Future research in vivo should explore this.

A massive, quiescent galaxy at a redshift of 3.717.

Finding massive galaxies that stopped forming stars in the early Universe presents an observational challenge because their rest-frame ultraviolet emission is negligible and they can only be reliably identified by extremely deep near-infrared surveys. These surveys have revealed the presence of massive, quiescent early-type galaxies appearing as early as redshift z ≈ 2, an epoch three billion years after the Big Bang. Their age and formation processes have now been explained by an improved generation of galaxy-formation models, in which they form rapidly at z ≈ 3-4, consistent with the typical masses and ages derived from their observations. Deeper surveys have reported evidence for populations of massive, quiescent galaxies at even higher redshifts and earlier times, using coarsely sampled photometry. However, these early, massive, quiescent galaxies are not predicted by the latest generation of theoretical models. Here we report the spectroscopic confirmation of one such galaxy at redshift z = 3.717, with a stellar mass of 1.7 × 1011 solar masses. We derive its age to be nearly half the age of the Universe at this redshift and the absorption line spectrum shows no current star formation. These observations demonstrate that the galaxy must have formed the majority of its stars quickly, within the first billion years of cosmic history in a short, extreme starburst. This ancestral starburst appears similar to those being found by submillimetre-wavelength surveys. The early formation of such massive systems implies that our picture of early galaxy assembly requires substantial revision.

Association of Taf14 with acetylated histone H3 directs gene transcription and the DNA damage response.

The YEATS domain, found in a number of chromatin-associated proteins, has recently been shown to have the capacity to bind histone lysine acetylation. Here, we show that the YEATS domain of Taf14, a member of key transcriptional and chromatin-modifying complexes in yeast, is a selective reader of histone H3 Lys9 acetylation (H3K9ac). Structural analysis reveals that acetylated Lys9 is sandwiched in an aromatic cage formed by F62 and W81. Disruption of this binding in cells impairs gene transcription and the DNA damage response. Our findings establish a highly conserved acetyllysine reader function for the YEATS domain protein family and highlight the significance of this interaction for Taf14.

Revisiting metal fluorides as lithium-ion battery cathodes.

Metal fluorides, promising lithium-ion battery cathode materials, have been classified as conversion materials due to the reconstructive phase transitions widely presumed to occur upon lithiation. We challenge this view by studying FeF3 using X-ray total scattering and electron diffraction techniques that measure structure over multiple length scales coupled with density functional theory calculations, and by revisiting prior experimental studies of FeF2 and CuF2. Metal fluoride lithiation is instead dominated by diffusion-controlled displacement mechanisms, and a clear topological relationship between the metal fluoride F- sublattices and that of LiF is established. Initial lithiation of FeF3 forms FeF2 on the particle's surface, along with a cation-ordered and stacking-disordered phase, A-LixFeyF3, which is structurally related to α-/ß-LiMn2+Fe3+F6 and which topotactically transforms to B- and then C-LixFeyF3, before forming LiF and Fe. Lithiation of FeF2 and CuF2 results in a buffer phase between FeF2/CuF2 and LiF. The resulting principles will aid future developments of a wider range of isomorphic metal fluorides.

Catalysis-dependent stabilization of Bre1 fine-tunes histone H2B ubiquitylation to regulate gene transcription.

Monoubiquitylation of histone H2B on Lys123 (H2BK123ub1) plays a multifaceted role in diverse DNA-templated processes, yet the mechanistic details by which this modification is regulated are not fully elucidated. Here we show in yeast that H2BK123ub1 is regulated in part through the protein stability of the E3 ubiquitin ligase Bre1. We found that Bre1 stability is controlled by the Rtf1 subunit of the polymerase-associated factor (PAF) complex and through the ability of Bre1 to catalyze H2BK123ub1. Using a domain in Rtf1 that stabilizes Bre1, we show that inappropriate Bre1 levels lead to defects in gene regulation. Collectively, these data uncover a novel quality control mechanism used by the cell to maintain proper Bre1 and H2BK123ub1 levels, thereby ensuring proper control of gene expression.

Intertrochanteric fracture fixation in solid organ transplant patients: outcomes and survivorship.

BACKGROUND: Solid organ transplantation (SOT) recipients have complex medical and surgical risk factors; however, the outcomes of these patients undergoing surgical fixation of hip fractures are unknown. This study sought to evaluate SOT patients' outcomes and survivorship after intertrochanteric (IT) fracture fixation. METHODS: A retrospective review identified 12 SOT patients who underwent cephalomedullary (CMN) nail fixation for IT fractures and were matched (1:2) to a cohort of 24 non-SOT IT fracture patients. Perioperative results and complications, mortality/patient survivorship, and clinical outcomes were compared between the cohorts. RESULTS: The time from presentation to surgical fixation was within 48 h of presentation for the non-SOT patients, while only 75% of SOT patients underwent surgery within 48 h of presentation (p = 0.034). The 90-day readmission rate for SOT patients was 25% versus 13% in the non-SOT group (p = 0.38). Similarly, the SOT cohort experienced a higher rate of major medical complication (25% vs. 13%, p = 0.38). There were two (16%) reoperations in the SOT group and three (13%) in the non-SOT matched group (p = 0.99). Respectively, the 90-day and 1-year estimated patient survivorship was similar between the two cohorts: SOT patients with 92% (95% CI 54-99%) and 73% (95% CI 24-93%) versus 86% (95% CI 62-95%) and 72% (95% CI 47-86%, HR 0.92, 95% CI 0.18-4.62, p = 0.92) in non-SOT patients. CONCLUSION: SOT patients who underwent CMN fixation for IT fractures required more time from hospital presentation to surgical management than non-SOT patients. Although not statistically significant, SOT patients demonstrated more acute complications and readmissions, but similar mortality compared to those without transplant.

Using informatics to engage patients.

As a specialty, radiology has spent much of the last two decades implementing information systems that improve departmental efficiency and the ordering provider's access to information. While our patients have realized benefits such as improved access to care and reduced turnaround times, there has been little focus on using these information systems to improve patient engagement. In the last decade, society has shifted. Now, consumers in every industry expect to be able to use technology to help them accomplish different tasks from scheduling to communicating. Medicine, in general, has been slow to respond to the concept of the patient as a consumer. In this manuscript we describe some of the informatics efforts we have employed in our department to improve patient engagement. We present these initiatives, corresponding to each aspect of the radiology value stream, from the patient's point of view.

Optimization of data acquisition and analysis for fiber ball imaging.

The inverse Funk transform of high angular resolution diffusion imaging (HARDI) data provides an estimate for the fiber orientation density function (fODF) in white matter (WM). Since the inverse Funk transform is a straightforward linear transformation, this technique, referred to as fiber ball imaging (FBI), offers a practical means of calculating the fODF that avoids the need for a response function or nonlinear numerical fitting. Nevertheless, the accuracy of FBI depends on both the choice of b-value and the number of diffusion-encoding directions used to acquire the HARDI data. To inform the design of optimal scan protocols for its implementation, FBI predictions are investigated here with in vivo data from healthy adult volunteers acquired at 3 T for b-values spanning 1000 to 10,000 s/mm2, for diffusion-encoding directions varying in number from 30 to 256 and for TE ranging from 90 to 120 ms. Our results suggest b-values above 4000 s/mm2 with at least 64 diffusion-encoding directions are adequate to achieve reasonable accuracy with FBI for calculating axon-specific diffusion measures and for performing WM fiber tractography (WMFT).

Early In-Hospital Pain Control Is a Stronger Predictor for Patients Requiring a Refill of Narcotic Pain Medication Compared to the Amount of Narcotics Given at Discharge.

BACKGROUND: The United States is combating an opioid epidemic. Orthopedic surgeons are the third highest opioid prescribers and therefore have an opportunity and obligation to assist in the efforts to reduce opioid use and abuse. In this article, we evaluate risk factors for patients requiring an opioid refill after primary total knee arthroplasty, with the goal to reduce opioid prescriptions for those patients at low risk of requiring a refill in order to reduce the amount of unused medication. METHODS: We retrospectively reviewed narcotic-naïve patients who underwent total knee arthroplasty from December 2017 to May 2018. We performed multivariable analysis on demographics and preoperative, operative, and postoperative characteristics to determine risk factors for requiring a prescription refill following hospital discharge. RESULTS: One-hundred fifty-seven patients were included in the analysis. Sixty percent of patients required a prescription refill. Risk factors included younger age (P = .003) and increased pain on postoperative day one (P < .001). The amount of narcotic medication given at discharge did not independently affect the refill rate (P = .21). CONCLUSION: There is strong evidence that elderly patients and those with good pain control on postoperative day 1 are at a lower risk of requiring a narcotic refill postoperatively. With this information, physicians may begin to tailor narcotic prescriptions based on patient risk factors for requiring a prescription refill rather than provide patients with the same number of pills for a given surgery in an effort to reduce unused narcotic medication.

The Evolving Role of MicroRNAs in Endothelial Cell Dysfunction in Response to Infection.

The microRNAs are short noncoding RNA molecules responsible for translational repression and silencing of target genes via binding to the mRNA. They are found in all eukaryotic cells and play a critical role in virtually all physiological processes, including within the cardiovascular system where they influence cellular development, differentiation, cardiovascular function, hemostasis, and programmed cell death. Dysregulated microRNA expression is associated with several conditions ranging from cancer and autoimmune disease to infection. Progressively, it has become increasingly clear that microRNAs are important components of the host response to microbes. The cardiovascular system, coupled with cells of the innate immune system, provide the initial interaction and first response to microbial infection, respectively. This review presents the current state of knowledge regarding the role of microRNAs with emphasis on their role in controlling endothelial cell function.

Structural plasticity of the ventral stream and aphasia recovery.

Restrengthening of the residual language network is likely to be crucial for speech recovery in poststroke aphasia. Eight participants with chronic aphasia received intensive speech therapy for 3 weeks, with standardized naming tests and brain magnetic resonance imaging before and after therapy. Kurtosis-based diffusion tensor tractography was used to measure mean kurtosis (MK) along a segment of the inferior longitudinal fasciculus (ILF). Therapy-related reduction in the number of semantic but not phonemic errors was associated with strengthening (renormalization) of ILF MK (r = -0.90, p < 0.05 corrected), suggesting that speech recovery is related to structural plasticity of language-specific components of the residual language network. Ann Neurol 2017;82:147-151.

Preoperative automated fibre quantification predicts postoperative seizure outcome in temporal lobe epilepsy.

Approximately one in every two patients with pharmacoresistant temporal lobe epilepsy will not be rendered completely seizure-free after temporal lobe surgery. The reasons for this are unknown and are likely to be multifactorial. Quantitative volumetric magnetic resonance imaging techniques have provided limited insight into the causes of persistent postoperative seizures in patients with temporal lobe epilepsy. The relationship between postoperative outcome and preoperative pathology of white matter tracts, which constitute crucial components of epileptogenic networks, is unknown. We investigated regional tissue characteristics of preoperative temporal lobe white matter tracts known to be important in the generation and propagation of temporal lobe seizures in temporal lobe epilepsy, using diffusion tensor imaging and automated fibre quantification. We studied 43 patients with mesial temporal lobe epilepsy associated with hippocampal sclerosis and 44 healthy controls. Patients underwent preoperative imaging, amygdalohippocampectomy and postoperative assessment using the International League Against Epilepsy seizure outcome scale. From preoperative imaging, the fimbria-fornix, parahippocampal white matter bundle and uncinate fasciculus were reconstructed, and scalar diffusion metrics were calculated along the length of each tract. Altogether, 51.2% of patients were rendered completely seizure-free and 48.8% continued to experience postoperative seizure symptoms. Relative to controls, both patient groups exhibited strong and significant diffusion abnormalities along the length of the uncinate bilaterally, the ipsilateral parahippocampal white matter bundle, and the ipsilateral fimbria-fornix in regions located within the medial temporal lobe. However, only patients with persistent postoperative seizures showed evidence of significant pathology of tract sections located in the ipsilateral dorsal fornix and in the contralateral parahippocampal white matter bundle. Using receiver operating characteristic curves, diffusion characteristics of these regions could classify individual patients according to outcome with 84% sensitivity and 89% specificity. Pathological changes in the dorsal fornix were beyond the margins of resection, and contralateral parahippocampal changes may suggest a bitemporal disorder in some patients. Furthermore, diffusion characteristics of the ipsilateral uncinate could classify patients from controls with a sensitivity of 98%; importantly, by co-registering the preoperative fibre maps to postoperative surgical lacuna maps, we observed that the extent of uncinate resection was significantly greater in patients who were rendered seizure-free, suggesting that a smaller resection of the uncinate may represent insufficient disconnection of an anterior temporal epileptogenic network. These results may have the potential to be developed into imaging prognostic markers of postoperative outcome and provide new insights for why some patients with temporal lobe epilepsy continue to experience postoperative seizures.

Evaluating kurtosis-based diffusion MRI tissue models for white matter with fiber ball imaging.

In order to quantify well-defined microstructural properties of brain tissue from diffusion MRI (dMRI) data, tissue models are typically employed that relate biological features, such as cell morphology and cell membrane permeability, to the diffusion dynamics. A variety of such models have been proposed for white matter, and their validation is a topic of active interest. In this paper, three different tissue models are tested by comparing their predictions for a specific microstructural parameter to a value measured independently with a recently proposed dMRI method known as fiber ball imaging (FBI). The three tissue models are all constructed with the diffusion and kurtosis tensors, and they are hence compatible with diffusional kurtosis imaging. Nevertheless, the models differ significantly in their details and predictions. For voxels with fractional anisotropies (FAs) exceeding 0.5, all three are reasonably consistent with FBI. However, for lower FA values, one of these, called the white matter tract integrity (WMTI) model, is found to be in much better accord with FBI than the other two, suggesting that the WMTI model has a broader range of applicability.

Electrolyte-Induced Surface Transformation and Transition-Metal Dissolution of Fully Delithiated LiNi0.8Co0.15Al0.05O2.

Enabling practical utilization of layered R3̅m positive electrodes near full delithiation requires an enhanced understanding of the complex electrode-electrolyte interactions that often induce failure. Using Li[Ni0.8Co0.15Al0.05]O2 (NCA) as a model layered compound, the chemical and structural stability in a strenuous thermal and electrochemical environment was explored. Operando microcalorimetry and electrochemical impedance spectroscopy identified a fingerprint for a structural decomposition and transition-metal dissolution reaction that occurs on the positive electrode at full delithiation. Surface-sensitive characterization techniques, including X-ray absorption spectroscopy and high-resolution transmission electron microscopy, measured a structural and morphological transformation of the surface and subsurface regions of NCA. Despite the bulk structural integrity being maintained, NCA surface degradation at a high state of charge induces excessive transition-metal dissolution and significant positive electrode impedance development, resulting in a rapid decrease in electrochemical performance. Additionally, the impact of electrolyte salt, positive electrode surface area, and surface Li2CO3 content on the magnitude and character of the dissolution reaction was studied.

Communicating breast cancer risk information to young adult women: A pilot study.

OBJECTIVE: To examine the effectiveness of a health promotion flyer to increase awareness of breast cancer risk and physical activity as a risk reduction strategy in young adult women. METHODS: Young adult women (N = 123) viewed one of five health promotion flyers online and then completed measures of perceived breast cancer risk (PR) and perceived informativeness (PI) and a qualitative thought-listing activity. RESULTS: Differences were observed in PI such that the control and low risk/low information messages were significantly less informative than the others. Qualitative analyses revealed two general themes: message content and flyer design. Additional analyses of the flyer design comments revealed four sub-themes: negative thoughts about the image, positive thoughts about the image, misunderstanding breast cancer risk information, and social comparison. Exploratory analyses controlling for message type indicated that image appraisal predicted PI such that those who commented on the image found the flyer to be less informative. DISCUSSION: Results suggest that the flyer was informative but did not impact young women's breast cancer risk perceptions. Additionally, the image may have distracted young women from the intended message. Evaluating the acceptability of images used in health promotion materials is recommended before testing the effectiveness of the intervention.

Fiber ball imaging.

By modeling axons as thin cylinders, it is shown that the inverse Funk transform of the diffusion MRI (dMRI) signal intensity obtained on a spherical shell in q-space gives an estimate for a fiber orientation density function (fODF), where the accuracy improves with increasing b-value provided the signal-to-noise ratio is sufficient. The method is similar to q-ball imaging, except that the Funk transform of q-ball imaging is replaced by its inverse. We call this new approach fiber ball imaging. The fiber ball method is demonstrated for healthy human brain, and fODF estimates are compared to diffusion orientation distribution function (dODF) approximations obtained with q-ball imaging. The fODFs are seen to have sharper features than the dODFs, reflecting an enhancement of the higher degree angular frequencies. The inverse Funk transform of the dMRI signal intensity data provides a simple and direct method of estimating a fODF. In addition, fiber ball imaging leads to an estimate for the ratio of the fraction of MRI visible water confined to the intra-axonal space divided by the square root of the intra-axonal diffusivity. This technique may be useful for white matter fiber tractography, as well as other types of microstructural modeling of brain tissue.

Epilepsy-related cytoarchitectonic abnormalities along white matter pathways.

OBJECTIVE: Temporal lobe epilepsy (TLE) is one of the most common forms of epilepsy. Unfortunately, the clinical outcomes of TLE cannot be determined based only on current diagnostic modalities. A better understanding of white matter (WM) connectivity changes in TLE may aid the identification of network abnormalities associated with TLE and the phenotypic characterisation of the disease. METHODS: We implemented a novel approach for characterising microstructural changes along WM pathways using diffusional kurtosis imaging (DKI). Along-the-tract measures were compared for 32 subjects with left TLE and 36 age-matched and gender-matched controls along the left and right fimbria-fornix (FF), parahippocampal WM bundle (PWMB), arcuate fasciculus (AF), inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF) and cingulum bundle (CB). Limbic pathways were investigated in relation to seizure burden and control with antiepileptic drugs. RESULTS: By evaluating measures along each tract, it was possible to identify abnormalities localised to specific tract subregions. Compared with healthy controls, subjects with TLE demonstrated pathological changes in circumscribed regions of the FF, PWMB, UF, AF and ILF. Several of these abnormalities were detected only by kurtosis-based and not by diffusivity-based measures. Structural WM changes correlated with seizure burden in the bilateral PWMB and cingulum. CONCLUSIONS: DKI improves the characterisation of network abnormalities associated with TLE by revealing connectivity abnormalities that are not disclosed by other modalities. Since TLE is a neuronal network disorder, DKI may be well suited to fully assess structural network abnormalities related to epilepsy and thus serve as a tool for phenotypic characterisation of epilepsy.