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Deep brain stimulation (DBS) for Parkinson's disease (PD) is an established advanced therapy that produces therapeutic effects through high frequency stimulation. Although this therapeutic option leads to improved clinical outcomes, the mechanisms of the underlying efficacy of this treatment are not well understood. Therefore, investigation of DBS and its postoperative effects on brain architecture is of great interest. Diffusion weighted imaging (DWI) is an advanced imaging technique, which has the ability to estimate the structure of white matter fibers; however, clinical application of DWI after DBS implantation is challenging due to the strong susceptibility artifacts caused by implanted devices. This study aims to evaluate the feasibility of generating meaningful white matter reconstructions after DBS implantation; and to subsequently quantify the degree to which these tracts are affected by post-operative device-related artifacts.DWI was safely performed before and after implanting electrodes for DBS in 9 PD patients. Differences within each subject between pre- and post-implantation FA, MD, and RD values for 123 regions of interest (ROIs) were calculated. While differences were noted globally, they were larger in regions directly affected by the artifact. White matter tracts were generated from each ROI with probabilistic tractography, revealing significant differences in the reconstruction of several white matter structures after DBS. Tracts pertinent to PD, such as regions of the substantia nigra and nigrostriatal tracts, were largely unaffected.The aim of this study was to demonstrate the feasibility and clinical applicability of acquiring and processing DWI post-operatively in PD patients after DBS implantation. The presence of global differences provides an impetus for acquiring DWI shortly after implantation to establish a new baseline against which longitudinal changes in brain connectivity in DBS patients can be compared. Understanding that post-operative fiber tracking in patients is feasible on a clinically-relevant scale has significant implications for increasing our current understanding of the pathophysiology of movement disorders, and may provide insights into better defining the pathophysiology and therapeutic effects of DBS. Keywords: Postoperative imaging, Clinical feasibility, Deep brain stimulation, Diffusion weighted imaging, Tractography, Susceptibility artifact, Parkinson's disease

BackgroundHyperbaric oxygen (HBO2) treatment is used across a range of medical specialties for a variety of applications, particularly where hypoxia and inflammation are important contributors. Because of its hypoxia-relieving and anti-inflammatory effects HBO2 may be useful for new indications not currently approved by the Undersea and Hyperbaric Medical Society. Identifying these new applications for HBO2 is difficult because individual centers may only treat a few cases and not track the outcomes consistently. The web-based International Multicenter Registry for Hyperbaric Oxygen Therapy captures prospective outcome data for patients treated with HBO2 therapy. These data can then be used to identify new potential applications for HBO2, which has relevance for a range of medical specialties. ObjectiveAlthough hyperbaric medicine has established indications, new ones continue to emerge. One objective of this registry study was to identify cases where HBO2 has been used for conditions falling outside of current Undersea and Hyperbaric Medical Society–approved indications and present outcome data for them. MethodsThis descriptive study used data from a web-based, multicenter, international registry of patients treated with HBO2. Participating centers agree to collect data on all patients treated using standard outcome measures, and individual centers send deidentified data to the central registry. HBO2 treatment programs in the United States, the United Kingdom, and Australia participate. Demographic, outcome, complication, and treatment data, including pre- and posttreatment quality of life questionnaires (EQ-5D-5L) were collected for individuals referred for HBO2 treatment. ResultsOut of 9726 patient entries, 378 (3.89%) individuals were treated for 45 emerging indications. Post–COVID-19 condition (PCC; also known as postacute sequelae of COVID-19; 149/378, 39.4%), ulcerative colitis (47/378, 12.4%), and Crohn disease (40/378, 10.6%) accounted for 62.4% (n=236) of the total cases. Calciphylaxis (20/378, 5.3%), frostbite (18/378, 4.8%), and peripheral vascular disease–related wounds (12/378, 3.2%) accounted for a further 13.2% (n=50). Patients with PCC reported significant improvement on the Neurobehavioral Symptom Inventory (NSI score: pretreatment=30.6; posttreatment=14.4; P

Abstract Pancreatic acinar cell carcinoma (PACC) is a rare form of pancreatic cancer that commonly harbors targetable alterations, including activating fusions in the MAPK pathway and loss-of-function (LOF) alterations in DNA damage response/homologous recombination DNA repair-related genes. Here, we describe a patient with PACC harboring both somatic biallelic LOF of NBN and an activating NTRK1 fusion. Upon disease progression following 13 months of treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX), genomic analysis of a metastatic liver biopsy revealed the emergence of a novel reversion mutation restoring the reading frame of NBN. To our knowledge, genomic reversion of NBN has not been previously reported as a resistance mechanism in any tumor type. The patient was treated with, but did not respond to, targeted treatment with a selective NTRK inhibitor. This case highlights the complex but highly actionable genomic landscape of PACC and underlines the value of genomic profiling of rare tumor types such as PACC.

To promote collaboration across canine science, address replicability issues, and advance open science practices within animal cognition, we have launched the ManyDogs consortium, modeled on similar ManyX projects in other fields. We aimed to create a collaborative network that (a) uses large, diverse samples to investigate and replicate findings, (b) promotes open science practices of pre-registering hypotheses, methods, and analysis plans, (c) investigates the influence of differences across populations and breeds, and (d) examines how different research methods and testing environments influence the robustness of results. Our first study combines a phenomenon that appears to be highly reliable—dogs’ ability to follow human pointing—with a question that remains controversial: do dogs interpret pointing as a social communicative gesture or as a simple associative cue? We collected data (N = 455) from 20 research sites on two conditions of a 2-alternative object choice task: (1) Ostensive (pointing to a baited cup after making eye-contact and saying the dog’s name); (2) Non-ostensive (pointing without eye-contact, after a throat-clearing auditory control cue). Comparing performance between conditions, while both were significantly above chance, there was no significant difference in dogs’ responses. This result was consistent across sites. Further, we found that dogs followed contralateral, momentary pointing at lower rates than has been reported in prior research, suggesting that there are limits to the robustness of point-following behavior: not all pointing styles are equally likely to elicit a response. Together, these findings underscore the important role of procedural details in study design and the broader need for replication studies in canine science.

Background:. The demonstrated benefits of virtual reality (VR) in orthopaedic surgical training are numerous. However, it is relatively unknown how best to implement VR into an already established orthopaedic resident education curriculum and how trainees will engage and use these technologies longitudinally. Methods:. This was an exploratory, qualitative research study performed in accordance with Consolidated Criteria for Reporting Qualitative Research guidelines. Orthopaedic surgery residents at a single institution were recruited during the 2022 to 2023 academic year. Semistructured interviews were conducted. Data were analyzed through grounded theory methodology, beginning with open coding, followed by axial coding, and concluding with selective coding that describes orthopaedic surgery residents' current perceptions of VR as a training tool. Results:. Six residents participated in interviews before thematic saturation was achieved. Average interview length was 13:27 (±2:59) minutes. Residents felt that currently, VR is most useful for interns and junior residents as an educational adjunct for learning anatomy, surgical exposures, and the steps of a procedure in a risk- and judgment-free arena. There seems to be a “ceiling effect” with VR given current technological limitations, and residents remarked that there is an associated “opportunity cost” with using VR technology. Some residents may find it more time-efficient to study texts, videos, or surgical guides rather than use VR. Cost (limited number of headsets) and technological barriers (i.e., hardware, software, and Wi-Fi issues) were some of the described barriers to VR utilization. Residents felt that there needs to be dedicated technological support to help with these issues. At this time, given these limitations of VR, many preferred VR as an optional educational adjunct rather than as a required curricular tool or assessment of surgical competency. Conclusions:. There is current utility for VR in orthopaedic surgical training. Future technological advances may make VR more central to resident education. This study describes resident perceptions about the technology and best use practices for the technology. Level of Evidence:. Qualitative Study, Level V Evidence

Background:. COVID-19 forced surgical resident training programs to adapt to meet educational requirements within the constraints of various guidelines. Some of the changes implemented during the pandemic have imparted a lasting effect on orthopaedic education. As such, the purpose of this article was to review how orthopaedic training and education were affected during the COVID-19 pandemic. Methods:. The published literature was queried using search strategies devised by a medical librarian, according to the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Studies eligible for inclusion were studies related to COVID-19, orthopaedic surgical training, and medical education. Studies were excluded if they (1) were abstracts, conference proceedings, letters, perspective pieces, reviews, or editorials; (2) evaluated medical student education; (3) included other specialties; or (4) were unrelated to COVID-19 and/or orthopaedic training. Results:. Eighty-three (n = 83) studies were included. Five themes emerged including (I) Fellowship Application, Interview, and Match Processes; (II) Social Media and Websites for Program Information; (III) Changes in Trainee Surgical Volume; (IV) Trainee Mental Health and Well-being; and (V) Innovations in Education. The pandemic decreased opportunities for medical students to gain exposure to orthopaedic surgery. Social media use, particularly Instagram, among orthopaedic residencies increased during the pandemic. Between the cancellation of away rotations and in-person interviews, applicants saved over $6,000; however, both residency applicants and interviewers preferred in-person interviews. The pandemic led to decreased surgical volume and in-person didactics for trainees, thus relying more on virtual learning. Orthopaedic trainees had mixed feelings regarding online virtual education. Although some respondents reported that they preferred the convenience of online learning, others expressed dissatisfaction with the quality of virtual education. Conclusions:. The shift to virtual learning affected how applicants learned about residency programs, with many relying on virtual away rotations and social media to compare different programs. The pandemic also highlighted issues of diversity and accessibility within orthopaedic surgery, with cost savings from virtual interviews and canceled away rotations potentially benefiting applicants from lower socioeconomic backgrounds. Although some innovative approaches and adaptations to orthopaedic education and training have shown promise and may continue to be used in the future after the COVID-19 pandemic, the role of others, such as virtual interviews, is less clear.

Abstract Background Cachexia is frequent, deadly, and untreatable for patients with pancreatic ductal adenocarcinoma (PDAC). The reproductive hormone and cytokine Activin is a mediator of PDAC cachexia, and Activin receptor targeting was clinically tested for cancer cachexia therapy. However, sex‐specific manifestations and mechanisms are poorly understood, constraining development of effective treatments. Methods Cachexia phenotypes, muscle gene/protein expression, and effects of the Activin blocker ACVR2B/Fc were assessed in LSL‐KrasG12D/+, LSL‐Trp53R172H/+, and Pdx‐1‐Cre (KPC) mice with autochthonic PDAC. Effects of PDAC and sex hormones were modelled by treating C2C12 myotubes with KPC‐cell conditioned medium (CM) and estradiol. Muscle gene expression by RNAseq and change in muscle from serial CT scans were measured in patients with PDAC. Results Despite equivalent tumour latency (median 17 weeks) and mortality (24.5 weeks), male KPC mice showed earlier and more severe cachexia than females. In early PDAC, male gastrocnemius, quadriceps, and tibialis anterior muscles were reduced (−21.7%, −18.9%, and −20.8%, respectively, all P

Summary: Genetics have nominated many schizophrenia risk genes and identified convergent signals between schizophrenia and neurodevelopmental disorders. However, functional interpretation of the nominated genes in the relevant brain cell types is often lacking. We executed interaction proteomics for six schizophrenia risk genes that have also been implicated in neurodevelopment in human induced cortical neurons. The resulting protein network is enriched for common variant risk of schizophrenia in Europeans and East Asians, is down-regulated in layer 5/6 cortical neurons of individuals affected by schizophrenia, and can complement fine-mapping and eQTL data to prioritize additional genes in GWAS loci. A sub-network centered on HCN1 is enriched for common variant risk and contains proteins (HCN4 and AKAP11) enriched for rare protein-truncating mutations in individuals with schizophrenia and bipolar disorder. Our findings showcase brain cell-type-specific interactomes as an organizing framework to facilitate interpretation of genetic and transcriptomic data in schizophrenia and its related disorders.

Many postsecondary education institutions in the United States struggle to effectively support high levels of academic achievement and college completion among their students. This is especially true at less selective and online colleges and universities that are understudied but serve an increasing number of students. Psychological factors may play an important role in promoting positive student outcomes during the college years. Two randomized controlled experiments including online university students focused on the potential influence of opportunities for students to reflect upon their future identities or ideas about their lives in the years to come. In Study 1 (N = 1,042), a course activity designed to engage students’ future identities showed positive effects on course grades and persistence in college during the next semester. In Study 2 (N = 2,515), a more rigorous design demonstrated the effects of activating future identities on specific motivational processes with positive consequences for academic outcomes. Together, the experiments suggest that educators and advisors should engage with how students imagine their futures in order to help support student success.

Abstract Background Several lines of evidence suggest that high-density lipoprotein (HDL) reduces Alzheimer’s disease (AD) risk by decreasing vascular beta-amyloid (Aβ) deposition and inflammation, however, the mechanisms by which HDL improve cerebrovascular functions relevant to AD remain poorly understood. Methods Here we use a human bioengineered model of cerebral amyloid angiopathy (CAA) to define several mechanisms by which HDL reduces Aβ deposition within the vasculature and attenuates endothelial inflammation as measured by monocyte binding. Results We demonstrate that HDL reduces vascular Aβ accumulation independently of its principal binding protein, scavenger receptor (SR)-BI, in contrast to the SR-BI-dependent mechanism by which HDL prevents Aβ-induced vascular inflammation. We describe multiple novel mechanisms by which HDL acts to reduce CAA, namely: i) altering Aβ binding to collagen-I, ii) forming a complex with Aβ that maintains its solubility, iii) lowering collagen-I protein levels produced by smooth-muscle cells (SMC), and iv) attenuating Aβ uptake into SMC that associates with reduced low density lipoprotein related protein 1 (LRP1) levels. Furthermore, we show that HDL particles enriched in apolipoprotein (apo)E appear to be the major drivers of these effects, providing new insights into the peripheral role of apoE in AD, in particular, the fraction of HDL that contains apoE. Conclusion The findings in this study identify new mechanisms by which circulating HDL, particularly HDL particles enriched in apoE, may provide vascular resilience to Aβ and shed new light on a potential role of peripherally-acting apoE in AD.

We review observations of solar activity, geomagnetic variation, and auroral visibility for the extreme geomagnetic storm on 1872 February 4. The extreme storm (referred to here as the Chapman–Silverman storm) apparently originated from a complex active region of moderate area (≈ 500 μ sh) that was favorably situated near disk center (S19° E05°). There is circumstantial evidence for an eruption from this region at 9–10 UT on 1872 February 3, based on the location, complexity, and evolution of the region, and on reports of prominence activations, which yields a plausible transit time of ≈29 hr to Earth. Magnetograms show that the storm began with a sudden commencement at ≈14:27 UT and allow a minimum Dst estimate of ≤ −834 nT. Overhead aurorae were credibly reported at Jacobabad (British India) and Shanghai (China), both at 19.°9 in magnetic latitude (MLAT) and 24.°2 in invariant latitude (ILAT). Auroral visibility was reported from 13 locations with MLAT below ∣20∣° for the 1872 storm (ranging from ∣10.°0∣–∣19.°9∣ MLAT) versus one each for the 1859 storm (∣17.°3∣ MLAT) and the 1921 storm (∣16.°2∣ MLAT). The auroral extension and conservative storm intensity indicate a magnetic storm of comparable strength to the extreme storms of 1859 September (25.°1 ± 0.°5 ILAT and −949 ± 31 nT) and 1921 May (27.°1 ILAT and −907 ± 132 nT), which places the 1872 storm among the three largest magnetic storms yet observed.

Abstract Background Polyadenylation plays a key role in producing mature mRNAs in eukaryotes. It is widely believed that the poly(A)-binding proteins (PABs) uniformly bind to poly(A)-tailed mRNAs, regulating their stability and translational efficiency. Results We observe that the homozygous triple mutant of broadly expressed Arabidopsis thaliana PABs, AtPAB2, AtPAB4, and AtPAB8, is embryonic lethal. To understand the molecular basis, we characterize the RNA-binding landscape of these PABs. The AtPAB-binding efficiency varies over one order of magnitude among genes. To identify the sequences accounting for the variation, we perform poly(A)-seq that directly sequences the full-length poly(A) tails. More than 10% of poly(A) tails contain at least one guanosine (G); among them, the G-content varies from 0.8 to 28%. These guanosines frequently divide poly(A) tails into interspersed A-tracts and therefore cause the variation in the AtPAB-binding efficiency among genes. Ribo-seq and genome-wide RNA stability assays show that AtPAB-binding efficiency of a gene is positively correlated with translational efficiency rather than mRNA stability. Consistently, genes with stronger AtPAB binding exhibit a greater reduction in translational efficiency when AtPAB is depleted. Conclusions Our study provides a new mechanism that translational efficiency of a gene can be regulated through the G-content-dependent PAB binding, paving the way for a better understanding of poly(A) tail-associated regulation of gene expression.

How cellular noise impacts metabolic trade-offs remains unknown. Here, the authors use a quantitative single-cell mass imaging strategy to reveal that cellular noise impacts cellular biomass and triacylglycerol accumulation, as well as protein and fatty-acid recycling under starvation, differently.

Oligomeric amyloid β (Aβ) is currently considered the most neurotoxic form of the Aβ peptide implicated in Alzheimer's disease (AD). The molecular structures of the oligomers have remained mostly unknown due to their transient nature. As a result, the molecular mechanisms of interactions between conformation-specific antibodies and their Aβ oligomer (AβO) cognates are not well understood. A monoclonal conformation-specific antibody, m5E3, was raised against a structural epitope of Aβ oligomers. m5E3 binds to AβOs with high affinity, but not to Aβ monomers or fibrils. In this study, a computational model of the variable fragment (Fv) of the m5E3 antibody (Fv5E3) is introduced. We further employ docking and molecular dynamics simulations to determine the molecular details of the antibody-oligomer interactions, and to classify the AβOs as Fv5E3-positives and negatives, and to provide a rationale for the low affinity of Fv5E3 for fibrils. This information will help us to perform site-directed mutagenesis on the m5E3 antibody to improve its specificity and affinity toward oligomeric Aβ species. We also provide evidence for the possible capability of the m5E3 antibody to disaggregate AβOs and to fragment protofilaments.

Recently emerging evidence indicates accelerated age-related changes in the structure and function of the brain in schizophrenia, raising a question about its potential consequences on cognitive function. Using a large sample of schizophrenia patients and controls and a battery of tasks across multiple cognitive domains, we examined whether patients show accelerated age-related decline in cognition and whether an age-related effect differ between females and males. We utilized data of 1,415 schizophrenia patients and 1,062 healthy community collected by the second phase of the Consortium on the Genetics of Schizophrenia (COGS-2). A battery of cognitive tasks included the Letter-Number Span Task, two forms of the Continuous Performance Test, the California Verbal Learning Test, Second Edition, the Penn Emotion Identification Test and the Penn Facial Memory Test. The effect of age and gender on cognitive performance was examined with a general linear model. We observed age-related changes on most cognitive measures, which was similar between males and females. Compared to controls, patients showed greater deterioration in performance on attention/vigilance and greater slowness of processing social information with increasing age. However, controls showed greater age-related changes in working memory and verbal memory compared to patients. Age-related changes (η2p of 0.001 to .008) were much smaller than between-group differences (η2p of 0.005 to .037). This study found that patients showed continued decline of cognition on some domains but stable impairment or even less decline on other domains with increasing age. These findings indicate that age-related changes in cognition in schizophrenia are subtle and not uniform across multiple cognitive domains.

Aim: Depression is highly prevalent in type 2 diabetes and is associated with lower adherence to medical treatments, worse glycemic control, and increased risk for diabetes-related complications. The mechanisms underlying depression in type 2 diabetes are unclear. The haptoglobin (Hp) genotype is associated with type 2 diabetes related complications including increased risk for cerebrovascular pathology and worse cognitive performance. Its relationship with depression is unknown. We investigated the role of Hp genotype on the association of depression with brain and white matter hyperintensities (WMH) volumes.Methods: Depressive symptoms (measured with the 15-item Geriatric Depression Scale), brain MRI, and Hp genotypes, were examined in elderly subjects with type 2 diabetes [29 (13.8%) Hp 1–1 carriers and 181 (86.2%) non-carriers]. The interaction of Hp genotype with number of depressive symptoms on regional brain measures was assessed using regression analyses.Results: The significant interactions were such that in Hp 1–1 carriers but not in non-carriers, number of depressive symptoms was associated with overall frontal cortex (p = 0.01) and WMH (p = 0.04) volumes but not with middle temporal gyrus volume (p = 0.43).Conclusions: These results suggest that subjects with type 2 diabetes carrying the Hp 1–1 genotype may have higher susceptibility to depression in the context of white matter damage and frontal lobe atrophy. The mechanisms underlying depression in diabetes may differ by Hp genotype.

OBJECTIVES/GOALS: Neuroblastoma (NB) is the most common extra-cranial solid tumor with outcomes varying from spontaneous regression to metastatic with high mortality rates. The tumor immune microenvironment (TIME) may play a significant role in this disease. In this study we analyze the TIME comparing high-risk (HR) and low-risk (LR) NBs using multiplex platforms. METHODS/STUDY POPULATION: Two tissue microarrays (TMAs) with 2mm cores were created from 41 patients treated at Columbia University Irving Medical Center. Five micron TMA slides were stained for Digital Spatial Profiling (DSP, nanoString) and multiplex immunofluorescence (mIF). For DSP, a 24-patient subset including 11 HR, 8 LR and 4 intermediate risk patients was analyzed for 34 proteins. Protein expression among risk groups was compared using Mann-Whitney t-test. For mIF, TMA FFPE slides were stained for DAPI, CD3, CD8, CD68, HLA-DR, PDL1 and Chromogranin A. Whole TMA cores were captured as 9 -20X multispectral images (MSIs) stitched into a 3x3 MSI using Vectra (Akoya). MSIs were processed with inForm and qualitative analysis performed comparing HR and LR tumors. RESULTS/ANTICIPATED RESULTS: With DSP, we find significantly more HLA-DR in HR compared to LR tumors (p = 0.016). When controlling for immune cells with CD45 we find HLA-DR/CD45 to be higher in HR than LR tumors (p = 0.026). We found increased PD1 and PDL1 expression in all groups without significant difference between LR and HR (p = 0.778 and p = 0.310, respectively). Preliminary analysis of mIF on 9 patients (4 HR and 5 LR) finds HR tumors appear to have more immune cells than LR tumors, specifically more CD3+CD8- T cells while total CD8+ cells may be similar. There may be less macrophages in the HR compared to LR tumors. Completion of image processing and quantitative analysis of mIF data is underway. DISCUSSION/SIGNIFICANCE OF IMPACT: Increased expression of immune markers in NB TIME correlates with higher risk, which is unlike many other tumors. We compared TIME in HR and LR NB using multiplex platforms, DSP and mIF. We find that HLA-DR is more expressed in HR NB while PD1 and PDL1 expression is consistently high and not different between risk groups. Further analysis is underway. CONFLICT OF INTEREST DESCRIPTION: Robyn D. Gartrell-Corrado received grant support from nanoString for Digital Spatial Profiling and received honoraria and travel support from Northwest Biotherapeutics and PerkinElmer, respectively.

Constitutive TGFβ signaling is important in maintaining retinal neurons and blood vessels and is a factor contributing to the risk for age-related macular degeneration (AMD), a retinal disease involving neurodegeneration and microglial activation. How TGFβ signaling to microglia influences pathological retinal neuroinflammation is unclear. We discovered that ablation of the TGFβ receptor, TGFBR2, in retinal microglia of adult mice induced abnormal microglial numbers, distribution, morphology, and activation status, and promoted a pathological microglial gene expression profile. TGFBR2-deficient retinal microglia induced secondary gliotic changes in Müller cells, neuronal apoptosis, and decreased light-evoked retinal function reflecting abnormal synaptic transmission. While retinal vasculature was unaffected, TGFBR2-deficient microglia demonstrated exaggerated responses to laser-induced injury that was associated with increased choroidal neovascularization, a hallmark of advanced exudative AMD. These findings demonstrate that deficiencies in TGFβ-mediated microglial regulation can drive neuroinflammatory contributions to AMD-related neurodegeneration and neovascularization, highlighting TGFβ signaling as a potential therapeutic target.

Abstract A central aim of cell biology was to understand the strategy of gene expression in response to the environment. Here, we study gene expression response to metabolic challenges in exponentially growing Escherichia coli using mass spectrometry. Despite enormous complexity in the details of the underlying regulatory network, we find that the proteome partitions into several coarse‐grained sectors, with each sector's total mass abundance exhibiting positive or negative linear relations with the growth rate. The growth rate‐dependent components of the proteome fractions comprise about half of the proteome by mass, and their mutual dependencies can be characterized by a simple flux model involving only two effective parameters. The success and apparent generality of this model arises from tight coordination between proteome partition and metabolism, suggesting a principle for resource allocation in proteome economy of the cell. This strategy of global gene regulation should serve as a basis for future studies on gene expression and constructing synthetic biological circuits. Coarse graining may be an effective approach to derive predictive phenomenological models for other ‘omics’ studies.

To study the relationships of long-term trajectories of glycemic control with cognitive performance in cognitively normal elderly with type 2 diabetes (T2D).Subjects (n = 835) pertain to a diabetes registry (DR) established in 1998 with an average of 18 HbA1c measurements per subject, permitting identification of distinctive trajectory groups of HbA1c and examining their association with cognitive function in five domains: episodic memory, semantic categorization, attention/working memory, executive function, and overall cognition. Analyses of covariance compared cognitive function among the trajectory groups adjusting for sociodemographic, cardiovascular, diabetes-related covariates and depression.Subjects averaged 72.8 years of age. Six trajectories of HbA1c were identified, characterized by HbA1c level at entry into the DR (Higher/Lower), and trend over time (Stable/Decreasing/Increasing). Both groups with a trajectory of decreasing HbA1c levels had high HbA1c levels at entry into the DR (9.2%, 10.7%), and high, though decreasing, HbA1c levels over time. They had the worst cognitive performance, particularly in overall cognition (p

This article argues the Satan in Zech 3 was modeled on Achaemenid imperial structure. First, the term in the Hebrew Bible is discussed. Second, a brief overview of Achaemenid offices and loyalty ceremonies is given. These are applied to Zech 3 and the Satan, arguing that the vision is a heavenly version of satrapal confirmation of priests. The article concludes by discussing imperial and theological hubris, arguing that Zech 3 is an instance of political Persian, rather than “Zoroastrian,” influence.

The interaction between the expanding supernova (SN) ejecta with the circumstellar material (CSM) that was expelled from the progenitor prior to explosion is a long-sought phenomenon, yet observational evidence is scarce. Here we confirm a new example: SN 2004dk, originally a hydrogen-poor, helium-rich Type Ib SN that reappeared as a strong -emitting point source on narrowband images. We present follow-up optical spectroscopy that reveals the presence of a broad component with full width at half maximum of ∼ 290 in addition to the narrow +[N ii] emission features from the host galaxy. Such a broad component is a clear sign of an ejecta–CSM interaction. We also present observations with the XMM-Newton Observatory, the Swift satellite, and the Chandra X-ray Observatory that span 10 days to 15 years after discovery. The detection of strong radio, X-ray, and emission years after explosion allows various constraints to be put on pre-SN mass-loss processes. We present a wind-bubble model in which the CSM is "pre-prepared" by a fast wind interacting with a slow wind. Much of the outer density profile into which the SN explodes corresponds to no steady-state mass-loss process. We estimate that the shell of compressed slow wind material was ejected ∼1400 yr prior to explosion, perhaps during carbon burning, and that the SN shock had swept up about 0.04 of material. The region emitting the has a density of order . [ABSTRACT FROM AUTHOR]

The study of historical great geomagnetic storms is crucial for assessing the possible risks to the technological infrastructure of a modern society, caused by extreme space–weather events. The normal benchmark has been the great geomagnetic storm of 1859 September, the so-called “Carrington Event.” However, there are numerous records of another great geomagnetic storm in 1872 February. This storm, which occurred about 12 years after the Carrington Event, resulted in comparable magnetic disturbances and auroral displays over large areas of the Earth. We have revisited this great geomagnetic storm in terms of the auroral and sunspot records in historical documents from East Asia. In particular, we have surveyed the auroral records from East Asia and estimated the equatorward boundary of the auroral oval to be near 24.°2 invariant latitude, on the basis that the aurora was seen near the zenith at Shanghai (20° magnetic latitude, MLAT). These results confirm that this geomagnetic storm of 1872 February was as extreme as the Carrington Event, at least in terms of the equatorward motion of the auroral oval. Indeed, our results support the interpretation of the simultaneous auroral observations made at Bombay (10° MLAT). The East Asian auroral records have indicated extreme brightness, suggesting unusual precipitation of high-intensity, low-energy electrons during this geomagnetic storm. We have compared the duration of the East Asian auroral displays with magnetic observations in Bombay and found that the auroral displays occurred in the initial phase, main phase, and early recovery phase of the magnetic storm. [ABSTRACT FROM AUTHOR]

We present a comparative study of absolute distances to a sample of very nearby, bright Type Ia supernovae (SNe) derived from high cadence, high signal-to-noise, multi-band photometric data. Our sample consists of four SNe: 2012cg, 2012ht, 2013dy and 2014J. We present new homogeneous, high-cadence photometric data in Johnson–Cousins BVRI and Sloan g′r′i′z′ bands taken from two sites (Piszkesteto and Baja, Hungary), and the light curves are analyzed with publicly available light curve fitters (MLCS2k2, SNooPy2 and SALT2.4). When comparing the best-fit parameters provided by the different codes, it is found that the distance moduli of moderately reddened SNe Ia agree within ≲0.2 mag, and the agreement is even better (≲0.1 mag) for the highest signal-to-noise BVRI data. For the highly reddened SN 2014J the dispersion of the inferred distance moduli is slightly higher. These SN-based distances are in good agreement with the Cepheid distances to their host galaxies. We conclude that the current state-of-the-art light curve fitters for Type Ia SNe can provide consistent absolute distance moduli having less than ∼0.1–0.2 mag uncertainty for nearby SNe. Still, there is room for future improvements to reach the desired ∼0.05 mag accuracy in the absolute distance modulus. [ABSTRACT FROM AUTHOR]

Most Type I superluminous supernovae (SLSNe-I) reported to date have been identified by their high peak luminosities and spectra lacking obvious signs of hydrogen. We demonstrate that these events can be distinguished from normal-luminosity SNe (including Type Ic events) solely from their spectra over a wide range of light-curve phases. We use this distinction to select 19 SLSNe-I and four possible SLSNe-I from the Palomar Transient Factory archive (including seven previously published objects). We present 127 new spectra of these objects and combine these with 39 previously published spectra, and we use these to discuss the average spectral properties of SLSNe-I at different spectral phases. We find that Mn ii most probably contributes to the ultraviolet spectral features after maximum light, and we give a detailed study of the O ii features that often characterize the early-time optical spectra of SLSNe-I. We discuss the velocity distribution of O ii, finding that for some SLSNe-I this can be confined to a narrow range compared to relatively large systematic velocity shifts. Mg ii and Fe ii favor higher velocities than O ii and C ii, and we briefly discuss how this may constrain power-source models. We tentatively group objects by how well they match either SN 2011ke or PTF12dam and discuss the possibility that physically distinct events may have been previously grouped together under the SLSN-I label. [ABSTRACT FROM AUTHOR]

The optical transient PTF11kx exhibited both the characteristic spectral features of Type Ia supernovae (SNe Ia) and the signature of ejecta interacting with circumstellar material (CSM) containing hydrogen, indicating the presence of a nondegenerate companion. We present an optical spectrum at 1342 days after peak from Keck Observatory, in which the broad component of Hα emission persists with a similar profile as in early-time observations. We also present Spitzer IRAC detections obtained 1237 and 1818 days after peak, and an upper limit from Hubble Space Telescope ultraviolet imaging at 2133 days. We interpret our late-time observations in the context of published results—and reinterpret the early-time observations—in order to constrain the CSM’s physical parameters and to compare to theoretical predictions for recurrent-nova systems. We find that the CSM’s radial extent may be several times the distance between the star and the CSM’s inner edge, and that the CSM column density may be two orders of magnitude lower than previous estimates. We show that the Hα luminosity decline is similar to other SNe with CSM interaction and demonstrate how our infrared photometry is evidence for newly formed, collisionally heated dust. We create a model for PTF11kx’s late-time CSM interaction and find that X-ray reprocessing by photoionization and recombination cannot reproduce the observed Hα luminosity, suggesting that the X-rays are thermalized and that Hα radiates from collisional excitation. Finally, we discuss the implications of our results regarding the progenitor scenario and the geometric properties of the CSM for the PTF11kx system. [ABSTRACT FROM AUTHOR]

The Type Ia supernova (SN Ia) 2016coj in NGC 4125 (redshift z = 0.00452 ± 0.00006) was discovered by the Lick Observatory Supernova Search 4.9 days after the fitted first-light time (FFLT; 11.1 days before B-band maximum). Our first detection (prediscovery) is merely 0.6 ± 0.5 days after the FFLT, making SN 2016coj one of the earliest known detections of an SN Ia. A spectrum was taken only 3.7 hr after discovery (5.0 days after the FFLT) and classified as a normal SN Ia. We performed high-quality photometry, low- and high-resolution spectroscopy, and spectropolarimetry, finding that SN 2016coj is a spectroscopically normal SN Ia, but the velocity of Si ii λ6355 around peak brightness (∼12,600 ) is a bit higher than that of typical normal SNe. The Si ii λ6355 velocity evolution can be well fit by a broken-power-law function for up to a month after the FFLT. SN 2016coj has a normal peak luminosity ( mag), and it reaches a B-band maximum ∼16.0 days after the FFLT. We estimate there to be low host-galaxy extinction based on the absence of Na i D absorption lines in our low- and high-resolution spectra. The spectropolarimetric data exhibit weak polarization in the continuum, but the Si ii line polarization is quite strong (∼0.9% ± 0.1%) at peak brightness. [ABSTRACT FROM AUTHOR]

We re-examine the classifications of supernovae (SNe) presented in the Lick Observatory Supernova Search (LOSS) volume-limited sample with a focus on the stripped-envelope SNe. The LOSS volume-limited sample, presented by Leaman et al. and Li et al., was calibrated to provide meaningful measurements of SN rates in the local universe; the results presented therein continue to be used for comparisons to theoretical and modeling efforts. Many of the objects from the LOSS sample were originally classified based upon only a small subset of the data now available, however, and recent studies have both updated some subtype distinctions and improved our ability to perform robust classifications, especially for stripped-envelope SNe. We re-examine the spectroscopic classifications of all events in the LOSS volume-limited sample (180 SNe and SN impostors) and update them if necessary. We discuss the populations of rare objects in our sample including broad-lined SNe Ic, Ca-rich SNe, SN 1987A-like events (we identify SN 2005io as SN 1987A-like here for the first time), and peculiar subtypes. The relative fractions of SNe Ia, SNe II, and stripped-envelope SNe in the local universe are not affected, but those of some subtypes are. Most significantly, after discussing the often unclear boundary between SNe Ib and Ic when only noisy spectra are available, we find a higher SN Ib fraction and a lower SN Ic fraction than calculated by Li et al.: spectroscopically normal SNe Ib occur in the local universe 1.7 ± 0.9 times more often than do normal SNe Ic. [ABSTRACT FROM AUTHOR]