Ionized gas extends over 40 kpc in an odd radio circle host galaxy.

A new class of extragalactic astronomical sources discovered in 2021, named odd radio circles (ORCs)1, are large rings of faint, diffuse radio continuum emission spanning approximately 1 arcminute on the sky. Galaxies at the centres of several ORCs have photometric redshifts of z ≃ 0.3-0.6, implying physical scales of several 100 kpc in diameter for the radio emission, the origin of which is unknown. Here we report spectroscopic data on an ORC including strong [O II] emission tracing ionized gas in the central galaxy of ORC4 at z = 0.4512. The physical extent of the [O II] emission is approximately 40 kpc in diameter, larger than expected for a typical early-type galaxy2 but an order of magnitude smaller than the large-scale radio continuum emission. We detect an approximately 200 km s-1 velocity gradient across the [O II] nebula, as well as a high velocity dispersion of approximately 180 km s-1. The [O II] equivalent width (approximately 50 Å) is extremely high for a quiescent galaxy. The morphology, kinematics and strength of the [O II] emission are consistent with the infall of shock ionized gas near the galaxy, following a larger, outward-moving shock. Both the extended optical and radio emission, although observed on very different scales, may therefore result from the same dramatic event.

Bioengineering methods for analysis of cells in vitro.

Efforts in the interdisciplinary field of bioengineering have led to innovative methods for investigating the complexities of cell responses in vitro. These approaches have emphasized the reduction of complex multicomponent cellular microenvironments into distinct individual signals as a means to both (a) better construct mimics of in vivo microenvironments and (b) better deconstruct microenvironments to study them. Microtechnology tools, together with advances in biomaterials, have been fundamental to this progress by enabling the tightly controlled presentation of environmental cues and the improved systematic analysis of cellular perturbations. In this review, we describe bioengineering approaches for controlling and measuring cell-environmental interactions in vitro, including strategies for high-throughput analysis. We also describe the mechanistic insights gained by the use of these novel tools, with associated applications ranging from fundamental biological studies, in vitro modeling of in vivo processes, and cell-based therapies.

Dynamic Regulation of Long-Chain Fatty Acid Oxidation by a Noncanonical Interaction between the MCL-1 BH3 Helix and VLCAD.

MCL-1 is a BCL-2 family protein implicated in the development and chemoresistance of human cancer. Unlike its anti-apoptotic homologs, Mcl-1 deletion has profound physiologic consequences, indicative of a broader role in homeostasis. We report that the BCL-2 homology 3 (BH3) α helix of MCL-1 can directly engage very long-chain acyl-CoA dehydrogenase (VLCAD), a key enzyme of the mitochondrial fatty acid ß-oxidation (FAO) pathway. Proteomic analysis confirmed that the mitochondrial matrix isoform of MCL-1 (MCL-1Matrix) interacts with VLCAD. Mcl-1 deletion, or eliminating MCL-1Matrix alone, selectively deregulated long-chain FAO, causing increased flux through the pathway in response to nutrient deprivation. Transient elevation in MCL-1 upon serum withdrawal, a striking increase in MCL-1 BH3/VLCAD interaction upon palmitic acid titration, and direct modulation of enzymatic activity by the MCL-1 BH3 α helix are consistent with dynamic regulation. Thus, the MCL-1 BH3 interaction with VLCAD revealed a separable, gain-of-function role for MCL-1 in the regulation of lipid metabolism.

Inhibition of FOXP3 by stapled alpha-helical peptides dampens regulatory T cell function.

Despite continuing advances in the development of novel cellular-, antibody-, and chemotherapeutic-based strategies to enhance immune reactivity, the presence of regulatory T cells (Treg cells) remains a complicating factor for their clinical efficacy. To overcome dosing limitations and off-target effects from antibody-based Treg cell deletional strategies or small molecule drugging, we investigated the ability of hydrocarbon stapled alpha-helical (SAH) peptides to target FOXP3, the master transcription factor regulator of Treg cell development, maintenance, and suppressive function. Using the crystal structure of the FOXP3 homodimer as a guide, we developed SAHs in the likeness of a portion of the native FOXP3 antiparallel coiled-coil homodimerization domain (SAH-FOXP3) to block this key FOXP3 protein-protein interaction (PPI) through molecular mimicry. We describe the design, synthesis, and biochemical evaluation of single- and double-stapled SAHs covering the entire coiled-coil expanse. We show that lead SAH-FOXP3s bind FOXP3, are cell permeable and nontoxic to T cells, induce dose-dependent transcript and protein level alterations of FOXP3 target genes, impede Treg cell function, and lead to Treg cell gene expression changes in vivo consistent with FOXP3 dysfunction. These results demonstrate a proof of concept for rationally designed FOXP3-directed peptide therapeutics that could be used as approaches to amplify endogenous immune responsiveness.

A Stable Aluminum Tris(dithiolene) Triradical.

A stable aluminum tris(dithiolene) triradical (3) was experimentally realized through a low-temperature reaction of the sterically demanding lithium dithiolene radical (2) with aluminum iodide. Compound 3 was characterized by single-crystal X-ray diffraction, UV-vis and EPR spectroscopy, SQUID magnetometry, and theoretical computations. The quartet ground state of triradical 3 has been unambiguously confirmed by variable-temperature continuous wave EPR experiments and SQUID magnetometry. Both SQUID magnetometry and broken-symmetry DFT computations reveal a small doublet-quartet energy gap [ΔEDQ = 0.18 kcal mol-1 (SQUID); ΔEDQ = 0.14 kcal mol-1 (DFT)]. The pulsed EPR experiment (electron spin echo envelop modulation) provides further evidence for the interaction of these dithiolene-based radicals with the central aluminum nucleus of 3.

The Role of the Gut Microbiome in Bipolar Disorder and its Common Medical Comorbidities.

Bipolar disorder is a decidedly heterogeneous and multifactorial disease, with significant psychosocial and medical disease burden. Much difficulty has been encountered in developing novel therapeutics and objective biomarkers for clinical use in this population. In that regard, gut-microbial homeostasis appears to modulate several key pathways relevant to a variety of psychiatric, metabolic, and inflammatory disorders. Microbial impact on immune, endocrine, endocannabinoid, kynurenine, and other pathways are discussed throughout this review. Emphasis is placed on this system's relevance to current pharmacology, diet, and comorbid illness in bipolar disorder. Despite the high level of optimism promoted in many reviews on this topic, substantial obstacles exist before any microbiome-related findings can provide meaningful clinical utility. Beyond a comprehensive overview of pathophysiology, this review hopes to highlight several key areas where progress is needed. As well, novel microbiome-associated suggestions are presented for future research.

Intervention treatment reducing cellular senescence inhibits tubulointerstitial fibrosis in diabetic mice following acute kidney injury.

Senescence of kidney tubules leads to tubulointerstitial fibrosis (TIF). Proximal tubular epithelial cells undergo stress-induced senescence during diabetes and episodes of acute kidney injury (AKI), and combining these injuries promotes the progression of diabetic kidney disease (DKD). Since TIF is crucial to progression of DKD, we examined the therapeutic potential of targeting senescence with a senolytic drug (HSP90 inhibitor) and/or a senostatic drug (ASK1 inhibitor) in a model of TIF in which AKI is superimposed on diabetes. After 8 weeks of streptozotocin-induced diabetes, mice underwent bilateral clamping of renal pedicles to induce mild AKI, followed by 28 days of reperfusion. Groups of mice (n=10-12) received either vehicle, HSP90 inhibitor (alvespimycin), ASK1 inhibitor (GS-444217), or both treatments. Vehicle-treated mice displayed tubular injury at day 3 and extensive tubular cell senescence at day 10, which remained unresolved at day 28. Markers of senescence (Cdkn1a and Cdkn2a), inflammation (Cd68, Tnf, and Ccl2), and TIF (Col1a1, Col4a3, α-Sma/Acta2, and Tgfb1) were elevated at day 28, coinciding with renal function impairment. Treatment with alvespimycin alone reduced kidney senescence and levels of Col1a1, Acta2, Tgfb1, and Cd68; however, further treatment with GS-444217 also reduced Col4a3, Tnf, Ccl2, and renal function impairment. Senolytic therapy can inhibit TIF during DKD, but its effectiveness can be improved by follow-up treatment with a senostatic inhibitor, which has important implications for treating progressive DKD.

Active narcotic use and post-peroral endoscopic myotomy outcomes in esophageal motility disorders.

BACKGROUND AND AIMS: Peroral endoscopic myotomy (POEM) is a minimally invasive technique used to treat esophageal motility disorders. Opioid use has been demonstrated to adversely affect esophageal dysmotility and is associated with an increased prevalence of esophageal motility disorders. Our aim was to investigate the effect of narcotic use on success rates in patients undergoing POEM. METHODS: This was a single-center, retrospective study of patients undergoing POEM between February 2017 and September 2021. Primary outcomes were post-POEM Eckardt score (ES), distensibility index, and length of procedure. Secondary outcomes included technical success, myotomy length, length of stay, adverse events, reintervention rates, and postprocedure GERD. RESULTS: During the study period, 90 patients underwent POEM for treatment of esophageal dysmotility disorders. Age, sex, race, indications for POEM, and body mass index were not significant between those with or without narcotic use. There were no differences in procedure time, preprocedure ESs, or length of stay. Postprocedure ESs were higher in the group with active narcotic use compared to the group with no prior history (2.73 vs 1.2, P = .004). Distensibility indexes measured with EndoFLIP (Medtronic, Minneapolis, Minn, USA) were not different in patients using narcotics compared with opioid-naïve patients. CONCLUSION: Active narcotic use negatively affects symptom improvement after POEM for the treatment of esophageal motility disorders.

Childhood cancer data initiative: Status report.

In March 2023, over 800 researchers, clinicians, patients, survivors, and advocates from the pediatric oncology community met to discuss the progress of the National Cancer Institute's Childhood Cancer Data Initiative. We present here the status of the initiative's efforts in building its data ecosystem and updates on key programs, especially the Molecular Characterization Initiative and the planned Coordinated National Initiative for Rare Cancers in Children and Young Adults. These activities aim to improve access to childhood cancer data, foster collaborations, facilitate integrative data analysis, and expand access to molecular characterization, ultimately leading to the development of innovative therapeutic approaches.

Black Carbon Impacts on Paraburkholderia xenovorans Strain LB400 Cell Enrichment and Activity: Implications toward Lower-Chlorinated Polychlorinated Biphenyls Biodegradation Potential.

Volatilization of lower-chlorinated polychlorinated biphenyls (LC-PCBs) from sediment poses health threats to nearby communities and ecosystems. Biodegradation combined with black carbon (BC) materials is an emerging bioaugmentation approach to remove PCBs from sediment, but development of aerobic biofilms on BC for long-term, sustained LC-PCBs remediation is poorly understood. This work aimed to characterize the cell enrichment and activity of biphenyl- and benzoate-grown Paraburkholderia xenovorans strain LB400 on various BCs. Biphenyl dioxygenase gene (bphA) abundance on four BC types demonstrated corn kernel biochar hosted at least 4 orders of magnitude more attached cells per gram than other feedstocks, and microscopic imaging revealed the attached live cell fraction was >1.5× more on corn kernel biochar than GAC. BC characteristics (i.e., sorption potential, pore size, pH) appear to contribute to cell attachment differences. Reverse transcription qPCR indicated that BC feedstocks significantly influenced bphA expression in attached cells. The bphA transcript-per-gene ratio of attached cells was >10-fold more than suspended cells, confirmed by transcriptomics. RNA-seq also demonstrated significant upregulation of biphenyl and benzoate degradation pathways on attached cells, as well as revealing biofilm formation potential/cell-cell communication pathways. These novel findings demonstrate aerobic PCB-degrading cell abundance and activity could be tuned by adjusting BC feedstocks/attributes to improve LC-PCBs biodegradation potential.

A wealth of structures for the Ge2H2+ radical cation: comparison of theory and experiment.

Five structures of Ge2H2 and Ge2H2+ are investigated in this study. Optimized geometries at the CCSD(T)/cc-pwCVQZ-PP level of theory were obtained. Focal point analyses were performed on these optimized geometries to determine relative energies using the CCSD(T) method with polarized basis sets up to quintuple-zeta. Energy corrections include full T and pertubative (Q) coupled-cluster effects plus anharmonic corrections to the zero-point vibrational energy. Relative ordering in energy from lowest to highest of the five Ge2H2+ structures is butterfly, germylidene, monobridged, trans, then linear. In neutral Ge2H2, the monobridged structure lies lower in energy than the germylidene structure. Fundamental vibrational frequencies and IR intensities were computed for the minima at the CCSD(T)/cc-pwCVTZ-PP level of theory to compare with experimental research. Partial atomic charges and natural bonding orbital analyses indicated that the positive charge of Ge2H2+ is contained in the region of the Ge-Ge bond.

Structures and Energetics of E2H3+ (E = As, Sb, and Bi) Cations.

E2H2 (E = As, Sb, Bi) structures involving multiple bonds have attracted much attention recently. The E2H3+ cations (protonated E2H2) are predicted to be viable with substantial proton affinities (>180 kcal/mol). Herein, the bonding characters and energetics of a number of E2H3+ isomers are explored through CCSD(T) and DFT methods. For the As2H3+ system, the CCSD(T)/cc-pVQZ-PP method predicts that the vinylidene-like structure lies lowest in energy, with the trans and cis isomers higher by 6.7 and 9.3 kcal/mol, respectively. However, for Sb2H3+ and Bi2H3+ systems, the trans isomer is the global minimum, while the energies of the cis and vinylidene-like structures are higher, respectively, by 2.0 and 2.4 kcal/mol for Sb2H3+ and 1.6 and 15.0 kcal/mol for Bi2H3+. Thus, the vinyledene-like structure is the lowest energy for the arsenic system but only a transition state of the bismuth system. With permanent dipole moments, all minima may be observable in microwave experiments. Besides, we have also obtained transition states and planar-cis structures with higher energies. The current results should provide new insights into the various isomers and provide a number of predictions for future experiments.

Plant functional trait change across a warming tundra biome.

The tundra is warming more rapidly than any other biome on Earth, and the potential ramifications are far-reaching because of global feedback effects between vegetation and climate. A better understanding of how environmental factors shape plant structure and function is crucial for predicting the consequences of environmental change for ecosystem functioning. Here we explore the biome-wide relationships between temperature, moisture and seven key plant functional traits both across space and over three decades of warming at 117 tundra locations. Spatial temperature-trait relationships were generally strong but soil moisture had a marked influence on the strength and direction of these relationships, highlighting the potentially important influence of changes in water availability on future trait shifts in tundra plant communities. Community height increased with warming across all sites over the past three decades, but other traits lagged far behind predicted rates of change. Our findings highlight the challenge of using space-for-time substitution to predict the functional consequences of future warming and suggest that functions that are tied closely to plant height will experience the most rapid change. They also reveal the strength with which environmental factors shape biotic communities at the coldest extremes of the planet and will help to improve projections of functional changes in tundra ecosystems with climate warming.

Angiolipoma associated with antiretroviral switch therapy: a case report.

BACKGROUND: Angiolipomas have been well described in patients with HIV exposed to protease inhibitors with possible resolution after switching to non-nucleoside reverse transcriptase inhibitor-based regimens. Resolution of symptoms have occurred with switches to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens; however, little is known regarding the development of angiolipomas when switching from NNRTI- to modern, integrase strand transfer inhibitor-based regimens. We describe a patient who underwent switch therapy from tenofovir disoproxil fumarate/emtricitabine/efavirenz (TDF/FTC/EFV) to tenofovir alafenamide/FTC/bictegravir (TAF/FTC/BIC) who later developed angiolipomas. CASE PRESENTATION: A 55-year-old male had been on TDF/FTC/EFV for 8 years before switching to TAF/FTC/BIC. Nineteen months after antiretroviral switch, the patient presented with multiple lesions in the upper extremities and abdomen. Diagnostic biopsies revealed non-encapsulated angiolipomas and HHV-8 and non-alcoholic fatty liver disease was ruled out. New lesions continued to appear 29 months after ART switch, after which now lesions appeared and prior lesions remained stable with no increase in size noted. No surgical intervention or change in antiretroviral therapy was needed. CONCLUSIONS: Angiogenesis may have been suppressed with TDF/FTC/EFV treatment, however when switched to TAF/FTC/BIC, promoted the growth of angiolipomas. Clinicians should be aware of the impact of switching to modern ART therapies resulting in possible adipogenesis.

Pandemic stressors and mental health indicators in eight countries.

PURPOSE: The Covid-19 pandemic has exacted a significant physical, financial, social, and emotional toll on populations throughout the world. This study aimed to document the association between pandemic stressors and mental health during the pandemic across countries that differ in cultural, geographic, economic, and demographic factors. METHODS: We administered an online survey randomly in Brazil, China, Germany, Egypt, India, Indonesia, Nigeria, and the United States from September 2020 to November 2020. This survey included questions on Covid-19-related stressors as well as the Patient Health Questionnaire-2 and the Primary Care PTSD Checklist to screen for depression and post-traumatic stress disorder (PTSD) symptoms, respectively. We performed bivariable and multivariable regression analyses to assess the prevalence and odds ratios of overall depression symptoms and probable PTSD and in relation to stressors across countries. RESULTS: Among 8754 respondents, 28.9% (95% CI 27.5-30.0%) experienced depression symptoms, and 5.1% (95% CI 4.5-6.0%) experienced probable PTSD. The highest prevalence of depression symptoms was in Egypt (41.3%, 95% CI 37.6-45.0%) and lowest in the United States (24.9%, 95% CI 22.3-27.7%). The highest prevalence of probable PTSD was in Brazil (7.3%, 95% CI 5.6-9.4%) and the lowest in China (1.2%, 95% CI 0.7-2.0%). Overall, experiencing six or more Covid-19-related stressors was associated with both depression symptoms (OR 1.90, 95% CI 1.46-2.48) and probable PTSD (OR 13.8, 95% CI 9.66-19.6). CONCLUSION: The association between pandemic related stressors and the burden of adverse mental health indicators early in the Covid-19 pandemic transcended geographic, economic, cultural, and demographic differences between countries. The short-term and long-term impacts of the pandemic on mental health should be incorporated in efforts to tackle the consequences of Covid-19.

Corneal Neurotization: Essentials for The Facial Paralysis Surgeon.

Deficits in corneal innervation lead to neurotrophic keratopathy (NK). NK is frequently associated with facial palsy, and corneal damage can be accelerated by facial palsy deficits. Corneal nerves are important regulators of limbal stem cells, which play a critical role in epithelial maintenance and healing. Nonsurgical treatments of NK have undergone recent innovation, and growth factors implicated in corneal epithelial renewal are a promising therapeutic avenue. However, surgical intervention with corneal neurotization (CN) remains the only definitive treatment of NK. CN involves the transfer of unaffected sensory donor nerve branches to the affected cornea, and a variety of donor nerves and approaches have been described. CN can be performed in a direct or indirect manner; employ the supraorbital, supratrochlear, infraorbital, or great auricular nerves; and utilize autograft, allograft, or nerve transfer alone. Unfortunately, comparative studies of these factors are limited due to the procedure's novelty and varied recovery timelines after CN. Regardless of the chosen approach, CN has been shown to be a safe and effective procedure to restore corneal sensation and improve visual acuity in patients with NK.

Counterintuitive Chemistry: Carbene Stabilization of Zero-Oxidation State Main Group Species.

Carbenes have evolved from transient laboratory curiosities to a robust, diverse, and surprisingly impactful ligand class. A variety of different carbenes have significantly contributed to the development of low-oxidation state main group chemistry. This Perspective focuses upon advances in the chemistry of carbene complexes containing main group element cores in the formal oxidation state of zero, including their diverse synthetic strategies, unusual bonding and structural motifs, and utility in transition metal coordination chemistry and activation of small molecules.

Novel computational biology modeling system can accurately forecast response to neoadjuvant therapy in early breast cancer.

BACKGROUND: Generalizable population-based studies are unable to account for individual tumor heterogeneity that contributes to variability in a patient's response to physician-chosen therapy. Although molecular characterization of tumors has advanced precision medicine, in early-stage and locally advanced breast cancer patients, predicting a patient's response to neoadjuvant therapy (NAT) remains a gap in current clinical practice. Here, we perform a study in an independent cohort of early-stage and locally advanced breast cancer patients to forecast tumor response to NAT and assess the stability of a previously validated biophysical simulation platform. METHODS: A single-blinded study was performed using a retrospective database from a single institution (9/2014-12/2020). Patients included: ≥ 18 years with breast cancer who completed NAT, with pre-treatment dynamic contrast enhanced magnetic resonance imaging. Demographics, chemotherapy, baseline (pre-treatment) MRI and pathologic data were input into the TumorScope Predict (TS) biophysical simulation platform to generate predictions. Primary outcomes included predictions of pathological complete response (pCR) versus residual disease (RD) and final volume for each tumor. For validation, post-NAT predicted pCR and tumor volumes were compared to actual pathological assessment and MRI-assessed volumes. Predicted pCR was pre-defined as residual tumor volume ≤ 0.01 cm3 (≥ 99.9% reduction). RESULTS: The cohort consisted of eighty patients; 36 Caucasian and 40 African American. Most tumors were high-grade (54.4% grade 3) invasive ductal carcinomas (90.0%). Receptor subtypes included hormone receptor positive (HR+)/human epidermal growth factor receptor 2 positive (HER2+, 30%), HR+/HER2- (35%), HR-/HER2+ (12.5%) and triple negative breast cancer (TNBC, 22.5%). Simulated tumor volume was significantly correlated with post-treatment radiographic MRI calculated volumes (r = 0.53, p = 1.3 × 10-7, mean absolute error of 6.57%). TS prediction of pCR compared favorably to pathological assessment (pCR: TS n = 28; Path n = 27; RD: TS n = 52; Path n = 53), for an overall accuracy of 91.2% (95% CI: 82.8% - 96.4%; Clopper-Pearson interval). Five-year risk of recurrence demonstrated similar prognostic performance between TS predictions (Hazard ratio (HR): - 1.99; 95% CI [- 3.96, - 0.02]; p = 0.043) and clinically assessed pCR (HR: - 1.76; 95% CI [- 3.75, 0.23]; p = 0.054). CONCLUSION: We demonstrated TS ability to simulate and model tumor in vivo conditions in silico and forecast volume response to NAT across breast tumor subtypes.

Germanium(II) Dithiolene Complexes.

The 1 : 2 reaction of the imidazole-based dithiolate (2) with GeCl2 • dioxane in THF/TMEDA gives 3, a TMEDA-complexed dithiolene-based germylene. Compound 3 is converted to monothiolate-complexed (5) and N-heterocyclic carbene-complexed (7) germanium(II) dithiolene complexes via Lewis base ligand exchange. A bis-dithiolene-based germylene (8), involving a 3c-4e S-Ge-S bond, has also been synthesized through controlled hydrolysis of 7. The bonding nature of 3, 5, and 8 was investigated by both experimental and theoretical methods.

Comparing clinical success and procedural difficulty between treatment-naïve and treatment-refractory patients with esophageal motility disorders during peroral endoscopic myotomy.

BACKGROUND AND AIMS: Peroral endoscopic myotomy (POEM) can successfully treat patients with achalasia. Prior therapy with Botox (Allergan, Madison, NJ, USA) injections, pneumatic dilation (PD), and/or laparoscopic Heller myotomy (LHM) is believed to increase the difficulty of POEM procedures. We aimed to determine if prior treatment methods were associated with longer procedure times or lower clinical success. METHODS: In this single-center retrospective study, consecutive patients who underwent POEM for achalasia between February 2017 and September 2021 were studied. Collected data were patient demographics, prior treatment, pre- and postprocedure Eckardt score (ES), distensibility indices (DIs), and procedure times. Primary outcomes were clinical success and procedure difficulty. RESULTS: Of 95 patients (mean age, 55.6 years; 45% women), 25 patients underwent POEM for type I achalasia, 31 for type II achalasia, and 33 for spastic esophageal pathologies. Thirty-three patients (34.7%) were treated for achalasia before POEM with onabotulinumtoxinA injections (n = 18), PD (n = 17), and LHM (n = 3). There were no significant differences in post-treatment ESs or technical success between the 2 groups (P = .98 and P = .66, respectively). Multivariate analysis showed that prior treatment was associated with decreased case time and easier tunneling during POEM. CONCLUSIONS: Prior treatment did not impact the clinical success rate of POEM and led to decreased case times and easier tunneling difficulty, likely because of persistent lower esophageal sphincter changes and differences in diagnostic indications. POEM should be considered for patients with treatment-refractory symptoms as a safe and feasible option. Further large-scale studies are needed to validate our findings.