Identification of a DNA N6-Adenine Methyltransferase Complex and Its Impact on Chromatin Organization.

DNA N6-adenine methylation (6mA) has recently been described in diverse eukaryotes, spanning unicellular organisms to metazoa. Here, we report a DNA 6mA methyltransferase complex in ciliates, termed MTA1c. It consists of two MT-A70 proteins and two homeobox-like DNA-binding proteins and specifically methylates dsDNA. Disruption of the catalytic subunit, MTA1, in the ciliate Oxytricha leads to genome-wide loss of 6mA and abolishment of the consensus ApT dimethylated motif. Mutants fail to complete the sexual cycle, which normally coincides with peak MTA1 expression. We investigate the impact of 6mA on nucleosome occupancy in vitro by reconstructing complete, full-length Oxytricha chromosomes harboring 6mA in native or ectopic positions. We show that 6mA directly disfavors nucleosomes in vitro in a local, quantitative manner, independent of DNA sequence. Furthermore, the chromatin remodeler ACF can overcome this effect. Our study identifies a diverged DNA N6-adenine methyltransferase and defines the role of 6mA in chromatin organization.

Quantum gas mixtures and dual-species atom interferometry in space.

The capability to reach ultracold atomic temperatures in compact instruments has recently been extended into space1,2. Ultracold temperatures amplify quantum effects, whereas free fall allows further cooling and longer interactions time with gravity-the final force without a quantum description. On Earth, these devices have produced macroscopic quantum phenomena such as Bose-Einstein condensates (BECs), superfluidity, and strongly interacting quantum gases3. Terrestrial quantum sensors interfering the superposition of two ultracold atomic isotopes have tested the universality of free fall (UFF), a core tenet of Einstein's classical gravitational theory, at the 10-12 level4. In space, cooling the elements needed to explore the rich physics of strong interactions or perform quantum tests of the UFF has remained elusive. Here, using upgraded hardware of the multiuser Cold Atom Lab (CAL) instrument aboard the International Space Station (ISS), we report, to our knowledge, the first simultaneous production of a dual-species BEC in space (formed from 87Rb and 41K), observation of interspecies interactions, as well as the production of 39K ultracold gases. Operating a single laser at a 'magic wavelength' at which Rabi rates of simultaneously applied Bragg pulses are equal, we have further achieved the first spaceborne demonstration of simultaneous atom interferometry with two atomic species (87Rb and 41K). These results are an important step towards quantum tests of UFF in space and will allow scientists to investigate aspects of few-body physics, quantum chemistry and fundamental physics in new regimes without the perturbing asymmetry of gravity.

Acidic chitinase primes the protective immune response to gastrointestinal nematodes.

Acidic mammalian chitinase (AMCase) is known to be induced by allergens and helminths, yet its role in immunity is unclear. Using AMCase-deficient mice, we show that AMCase deficiency reduced the number of group 2 innate lymphoid cells during allergen challenge but was not required for establishment of type 2 inflammation in the lung in response to allergens or helminths. In contrast, AMCase-deficient mice showed a profound defect in type 2 immunity following infection with the chitin-containing gastrointestinal nematodes Nippostrongylus brasiliensis and Heligmosomoides polygyrus bakeri. The impaired immunity was associated with reduced mucus production and decreased intestinal expression of the signature type 2 response genes Il13, Chil3, Retnlb, and Clca1. CD103(+) dendritic cells, which regulate T cell homing, were also reduced in mesenteric lymph nodes of infected AMCase-deficient mice. Thus, AMCase functions as a critical initiator of protective type 2 responses to intestinal nematodes but is largely dispensable for allergic responses in the lung.

Author Correction: Observation of Bose-Einstein condensates in an Earth-orbiting research lab.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Observation of Bose-Einstein condensates in an Earth-orbiting research lab.

Quantum mechanics governs the microscopic world, where low mass and momentum reveal a natural wave-particle duality. Magnifying quantum behaviour to macroscopic scales is a major strength of the technique of cooling and trapping atomic gases, in which low momentum is engineered through extremely low temperatures. Advances in this field have achieved such precise control over atomic systems that gravity, often negligible when considering individual atoms, has emerged as a substantial obstacle. In particular, although weaker trapping fields would allow access to lower temperatures1,2, gravity empties atom traps that are too weak. Additionally, inertial sensors based on cold atoms could reach better sensitivities if the free-fall time of the atoms after release from the trap could be made longer3. Planetary orbit, specifically the condition of perpetual free-fall, offers to lift cold-atom studies beyond such terrestrial limitations. Here we report production of rubidium Bose-Einstein condensates (BECs) in an Earth-orbiting research laboratory, the Cold Atom Lab. We observe subnanokelvin BECs in weak trapping potentials with free-expansion times extending beyond one second, providing an initial demonstration of the advantages offered by a microgravity environment for cold-atom experiments and verifying the successful operation of this facility. With routine BEC production, continuing operations will support long-term investigations of trap topologies unique to microgravity4,5, atom-laser sources6, few-body physics7,8 and pathfinding techniques for atom-wave interferometry9-12.

Type 2 Interleukin-4 Receptor Signaling in Neutrophils Antagonizes Their Expansion and Migration during Infection and Inflammation.

Neutrophils are the first immune cells recruited to sites of inflammation and infection. However, patients with allergic disorders such as atopic dermatitis show a paucity of skin neutrophils and are prone to bacterial skin infections, suggesting that allergic inflammation curtails neutrophil responses. Here we have shown that the type 2 cell signature cytokine interleukin-4 (IL-4) hampers neutrophil expansion and migration by antagonizing granulocyte colony-stimulating factor (G-CSF) and chemokine receptor-mediated signals. Cutaneous bacterial infection in mice was exacerbated by IL-4 signaling and improved with IL-4 inhibition, each outcome inversely correlating with neutrophil migration to skin. Likewise, systemic bacterial infection was worsened by heightened IL-4 activity, with IL-4 restricting G-CSF-induced neutrophil expansion and migration to tissues by affecting CXCR2-CXCR4 chemokine signaling in neutrophils. These effects were dependent on IL-4 acting through type 2 IL-4 receptors on neutrophils. Thus, targeting IL-4 might be beneficial in neutropenic conditions with increased susceptibility to bacterial infections.

Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3.

Chemical modifications of histones can mediate diverse DNA-templated processes, including gene transcription1-3. Here we provide evidence for a class of histone post-translational modification, serotonylation of glutamine, which occurs at position 5 (Q5ser) on histone H3 in organisms that produce serotonin (also known as 5-hydroxytryptamine (5-HT)). We demonstrate that tissue transglutaminase 2 can serotonylate histone H3 tri-methylated lysine 4 (H3K4me3)-marked nucleosomes, resulting in the presence of combinatorial H3K4me3Q5ser in vivo. H3K4me3Q5ser displays a ubiquitous pattern of tissue expression in mammals, with enrichment observed in brain and gut, two organ systems responsible for the bulk of 5-HT production. Genome-wide analyses of human serotonergic neurons, developing mouse brain and cultured serotonergic cells indicate that H3K4me3Q5ser nucleosomes are enriched in euchromatin, are sensitive to cellular differentiation and correlate with permissive gene expression, phenomena that are linked to the potentiation of TFIID4-6 interactions with H3K4me3. Cells that ectopically express a H3 mutant that cannot be serotonylated display significantly altered expression of H3K4me3Q5ser-target loci, which leads to deficits in differentiation. Taken together, these data identify a direct role for 5-HT, independent from its contributions to neurotransmission and cellular signalling, in the mediation of permissive gene expression.

Reduced sister chromatid cohesion acts as a tumor penetrance modifier.

Sister chromatid cohesion (SCC) is an important process in chromosome segregation. ESCO2 is essential for establishment of SCC and is often deleted/altered in human cancers. We demonstrate that esco2 haploinsufficiency results in reduced SCC and accelerates the timing of tumor onset in both zebrafish and mouse p53 heterozygous null models, but not in p53 homozygous mutant or wild-type animals. These data indicate that esco2 haploinsufficiency accelerates tumor onset in a loss of heterozygosity (LOH) sensitive background. Analysis of The Cancer Genome Atlas (TCGA) confirmed ESCO2 deficient tumors have elevated number of LOH events throughout the genome. Further, we demonstrated heterozygous loss of sgo1, important in maintaining SCC, also results in reduced SCC and accelerated tumor formation in a p53 heterozygous background. Surprisingly, while we did observe elevated levels of chromosome missegregation and micronuclei formation in esco2 heterozygous mutant animals, this chromosomal instability did not contribute to the accelerated tumor onset in a p53 heterozygous background. Interestingly, SCC also plays a role in homologous recombination, and we did observe elevated levels of mitotic recombination derived p53 LOH in tumors from esco2 haploinsufficient animals; as well as elevated levels of mitotic recombination throughout the genome of human ESCO2 deficient tumors. Together these data suggest that reduced SCC contributes to accelerated tumor penetrance through elevated mitotic recombination.

Histone H3Q5 serotonylation stabilizes H3K4 methylation and potentiates its readout.

Serotonylation of glutamine 5 on histone H3 (H3Q5ser) was recently identified as a permissive posttranslational modification that coexists with adjacent lysine 4 trimethylation (H3K4me3). While the resulting dual modification, H3K4me3Q5ser, is enriched at regions of active gene expression in serotonergic neurons, the molecular outcome underlying H3K4me3-H3Q5ser crosstalk remains largely unexplored. Herein, we examine the impact of H3Q5ser on the readers, writers, and erasers of H3K4me3. All tested H3K4me3 readers retain binding to the H3K4me3Q5ser dual modification. Of note, the PHD finger of TAF3 favors H3K4me3Q5ser, and this binding preference is dependent on the Q5ser modification regardless of H3K4 methylation states. While the activity of the H3K4 methyltransferase, MLL1, is unaffected by H3Q5ser, the corresponding H3K4me3/2 erasers, KDM5B/C and LSD1, are profoundly inhibited by the presence of the mark. Collectively, this work suggests that adjacent H3Q5ser potentiates H3K4me3 function by either stabilizing H3K4me3 from dynamic turnover or enhancing its physical readout by downstream effectors, thereby potentially providing a mechanism for fine-tuning critical gene expression programs.

Venographic classification and long-term surgical treatment outcomes for axillary-subclavian vein thrombosis due to venous thoracic outlet syndrome (Paget-Schroetter syndrome).

OBJECTIVE: We assessed the clinical presentation, operative findings, and surgical treatment outcomes for axillary-subclavian vein (AxSCV) thrombosis due to venous thoracic outlet syndrome (VTOS). METHODS: We performed a retrospective, single-center review of 266 patients who had undergone primary surgical treatment of VTOS between 2016 and 2022. The clinical outcomes were compared between the patients in four treatment groups determined by intraoperative venography. RESULTS: Of the 266 patients, 132 were male and 134 were female. All patients had a history of spontaneous arm swelling and idiopathic AxSCV thrombosis, including 25 (9%) with proven pulmonary embolism, at a mean age of 32.1 ± 0.8 years (range, 12-66 years). The timing of clinical presentation was acute (<15 days) for 132 patients (50%), subacute (15-90 days) for 71 (27%), and chronic (>90 days) for 63 patients (24%). Venography with catheter-directed thrombolysis or thrombectomy (CDT) and/or balloon angioplasty had been performed in 188 patients (71%). The median interval between symptom onset and surgery was 78 days. After paraclavicular thoracic outlet decompression and external venolysis, intraoperative venography showed a widely patent AxSCV in 150 patients (56%). However, 26 (10%) had a long chronic AxSCV occlusion with axillary vein inflow insufficient for bypass reconstruction. Patch angioplasty was performed for focal AxSCV stenosis in 55 patients (21%) and bypass graft reconstruction for segmental AxSCV occlusion in 35 (13%). The patients who underwent external venolysis alone (patent or occluded AxSCV; n = 176) had a shorter mean operative time, shorter postoperative length of stay and fewer reoperations and late reinterventions compared with those who underwent AxSCV reconstruction (patch or bypass; n = 90), with no differences in the incidence of overall complications or 30-day readmissions. At a median clinical follow-up of 38.7 months, 246 patients (93%) had no arm swelling, and only 17 (6%) were receiving anticoagulation treatment; 95% of those with a patent AxSCV at the end of surgery were free of arm swelling vs 69% of those with a long chronic AxSCV occlusion (P < .001). The patients who had undergone CDT at the initial diagnosis were 32% less likely to need AxSCV reconstruction at surgery (30% vs 44%; P = .034) and 60% less likely to have arm swelling at follow-up (5% vs 13%; P < .05) vs those who had not undergone CDT. CONCLUSIONS: Paraclavicular decompression, external venolysis, and selective AxSCV reconstruction determined by intraoperative venography findings can provide successful and durable treatment for >90% of all patients with VTOS. Further work is needed to achieve earlier recognition of AxSCV thrombosis, prompt usage of CDT, and even more effective surgical treatment.

Boutonniere Versus Pseudoboutonniere Deformities: Pathoanatomy, Diagnosis, and Treatment.

Finger injuries involving the proximal interphalangeal (PIP) joint are common, particularly among athletes. Injury severity is often underappreciated at initial presentation and may be dismissed broadly as a "jammed finger" injury. Delayed diagnosis and treatment of certain injuries can have an important impact on the patient's chance of regaining full function. Central slip and PIP volar plate injuries are frequently encountered injuries that, if left untreated, can lead to the permanent loss of function of the proximal interphalangeal joint. Despite the differing mechanisms of these 2 pathologies, volar plate hyperextension injuries often present with a PIP joint flexion contracture and mild distal interphalangeal joint hyperextension deformity. This is similar to a boutonniere deformity seen after an injury to the central slip, and thus, has been referred to as a "pseudo-boutonnière" deformity. Distinguishing these 2 diagnoses is important, as treatment differs, and highlights the importance of thoroughly understanding the anatomy and relevant clinical applications when evaluating PIP joint injuries.

Reliability and validity of the standardized elevated arm stress test in the diagnosis of neurogenic thoracic outlet syndrome.

OBJECTIVE: We developed a standardized elevated arm stress test (sEAST) meter to standardize patients' posture and measure additional grip and fatigue parameters. In the present prospective cohort study, we aimed to determine the reliability and validity of the sEAST in the diagnosis of neurogenic thoracic outlet syndrome (NTOS). METHODS: Patients evaluated for NTOS between October 2018 and February 2020 were included and performed the sEAST. The patients were classified into a proven NTOS group or a symptomatic control group using the reporting standards for NTOS and the outcome of thoracic outlet decompression surgery. Healthy persons were recruited as an asymptomatic control group. The test-retest reliability, area under the receiver operating characteristic curve, and positive and negative predictive values were calculated for each sEAST parameter. RESULTS: A total of 426 patients with suspected NTOS and 147 healthy controls had performed the sEAST. The validity analysis was performed with data from 111 patients with proven NTOS, 94 symptomatic controls, and 147 asymptomatic controls. The reporting standards were inconclusive for 116 patients; 77 patients had been excluded because thoracic outlet decompression surgery had not been performed or was unsuccessful, and 28 because they had arterial or venous thoracic outlet syndrome. The area under the receiver operating characteristic curve for the proven NTOS group compared with the asymptomatic control and symptomatic control groups ranged from 0.59 to 0.77 and 0.54 to 0.63, respectively. The positive predictive value ranged from 46% to 65% and the negative predictive value from 51% to 66%. The test-retest reliability analysis for 80 patients with multiple sEAST measurements showed moderate to good (0.52-0.87) intraclass correlation coefficient values for the duration and grip strength parameters. However, the grip fatigue parameters demonstrated poor (0.46-0.16) intraclass correlation coefficient values. CONCLUSIONS: The sEAST showed good test-retest reliability for the duration and grip strength parameters. However, the discriminative value of all sEAST parameters was low for NTOS diagnostics. The good test-retest reliability of the sEAST parameters indicates that they could be valuable outcome measures for comparison in a diagnostic care pathway.

Reliability and validity of the elevated arm stress test in the diagnosis of neurogenic thoracic outlet syndrome.

OBJECTIVES: The objective of this retrospective analysis of prospectively collected data was to assess the test-retest reliability and validity of the elevated arm stress test (EAST) as measured by the duration in a cohort of patients with suspected neurogenic thoracic outlet syndrome (NTOS). METHODS: Patients evaluated for NTOS between January 2017 and September 2018 were identified. Test-retest reliability by the intraclass correlation coefficient was determined for duration of the EAST. For the validity analysis, patients were classified in a proven NTOS group or a symptomatic control group without NTOS using the Society for Vascular Surgery reporting standards and the outcome of thoracic outlet decompression surgery. A receiver operating characteristic curve was made for the duration of EAST. The area under the curve, and positive and negative predictive values were calculated for the EAST. RESULTS: In total, 428 patients with suspected NTOS were retrospectively analyzed. Of these patients, 61 were excluded because no EAST data was available. Another 101 patients were excluded because of inconclusive reporting standards, arterial or venous TOS, or because thoracic outlet decompression surgery was not performed or had a negative result. The validity analysis in the remaining 266 patients showed an area under the curve for the duration of the EAST of 0.62 (95% confidence interval, 0.55-0.69). The positive predictive value of the duration ranged between 65% and 66%, and the negative predictive value between 53% and 58%. For the test-retest reliability analysis, 118 patients were excluded because they performed only one measurement in a 100-day time period. Analysis in the remaining 148 patients showed an intraclass correlation coefficient value of 0.65 (95% confidence interval, 0.55-0.74) for duration. CONCLUSIONS: The EAST measured by the duration showed a moderate test-retest reliability, but the discriminative value was low in the diagnosis of NTOS. The outcome of the EAST measured by the duration should be used with caution.

Chemoenzymatic Semisynthesis of Proteins.

Protein semisynthesis-defined herein as the assembly of a protein from a combination of synthetic and recombinant fragments-is a burgeoning field of chemical biology that has impacted many areas in the life sciences. In this review, we provide a comprehensive survey of this area. We begin by discussing the various chemical and enzymatic methods now available for the manufacture of custom proteins containing noncoded elements. This section begins with a discussion of methods that are more chemical in origin and ends with those that employ biocatalysts. We also illustrate the commonalities that exist between these seemingly disparate methods and show how this is allowing for the development of integrated chemoenzymatic methods. This methodology discussion provides the technical foundation for the second part of the review where we cover the great many biological problems that have now been addressed using these tools. Finally, we end the piece with a short discussion on the frontiers of the field and the opportunities available for the future.

Duplex Ultrasound Studies Are Neither Necessary or Sufficient for the Diagnosis of Neurogenic Thoracic Outlet Syndrome.

BACKGROUND: Duplex ultrasound (DU) is used in the diagnosis of neurogenic thoracic outlet syndrome (NTOS) to measure compression of the subclavian artery (SCA) which is thought to strengthen the NTOS diagnosis. However, the value of DU in NTOS remains unclear. METHODS: A retrospective review of a prospectively acquired database from the TOS center of the Catharina Hospital Eindhoven was performed of patients referred between January 2017 and December 2019. Only "proven NTOS" patients, defined as a successful response to thoracic outlet decompression (TOD) surgery based on patient-reported outcomes (NRS pain scale, CBSQ and DASH score) were included to exclude wrongfully diagnosed NTOS patient. The presence of vascular symptoms (defined as discoloration, edema or temperature changes of the hand or fingers), results of provocative maneuvers, and outcome of DU was used for analysis. To assess the link between vascular symptoms and compression on DU, a chi-squared test was performed. Further, we looked for a correlation between vascular symptoms, compression on DU and clinical outcome using a repeated measures analysis of variance (ANOVA). RESULTS: Vascular symptoms were seen in 49 of 133 patients (36.8%). In total, 51 of 133 patients (38.3%) had at least 50% variation in SCA peak systolic velocity (PSV) during DU at the level of SCA stenosis. SCA occlusion was seen in 11 patients (8.3%) during provocative maneuvers. The presence of clinical "arterial symptoms" was not significantly correlated with vascular laboratory findings, neither for alterations in PSV during DU (P = 0.245) nor for positional SCA occlusion (P = 0.540). No statistically significant correlations between the degree of SCA stenosis and postoperative outcomes, as measured with the DASH, CBSQ, or NRS scale for pain were found (P = 0.787). CONCLUSIONS: The role of DU in the work-up of NTOS in patients with vascular complaints is questionable. Changes in flow velocities are seen in NTOS patients and do not correlate with "vascular symptoms" or clinical outcome.

Mass Measurements of Neutron-Deficient Yb Isotopes and Nuclear Structure at the Extreme Proton-Rich Side of the N=82 Shell.

High-accuracy mass measurements of neutron-deficient Yb isotopes have been performed at TRIUMF using TITAN's multiple-reflection time-of-flight mass spectrometer (MR-TOF-MS). For the first time, an MR-TOF-MS was used on line simultaneously as an isobar separator and as a mass spectrometer, extending the measurements to two isotopes further away from stability than otherwise possible. The ground state masses of ^{150,153}Yb and the excitation energy of ^{151}Yb^{m} were measured for the first time. As a result, the persistence of the N=82 shell with almost unmodified shell gap energies is established up to the proton drip line. Furthermore, the puzzling systematics of the h_{11/2}-excited isomeric states of the N=81 isotones are unraveled using state-of-the-art mean field calculations.

Ruminiclostridium 5, Parabacteroides distasonis, and bile acid profile are modulated by prebiotic diet and associate with facilitated sleep/clock realignment after chronic disruption of rhythms.

Chronic disruption of rhythms (CDR) impacts sleep and can result in circadian misalignment of physiological systems which, in turn, is associated with increased disease risk. Exposure to repeated or severe stressors also disturbs sleep and diurnal rhythms. Prebiotic nutrients produce favorable changes in gut microbial ecology, the gut metabolome, and reduce several negative impacts of acute severe stressor exposure, including disturbed sleep, core body temperature rhythmicity, and gut microbial dysbiosis. In light of previous compelling evidence that prebiotic diet broadly reduces negative impacts of acute, severe stressors, we hypothesize that prebiotic diet will also effectively mitigate the negative impacts of chronic disruption of circadian rhythms on physiology and sleep/wake behavior. Male, Sprague Dawley rats were fed diets enriched in prebiotic substrates or calorically matched control chow. After 5 weeks on diet, rats were exposed to CDR (12 h light/dark reversal, weekly for 8 weeks) or remained on undisturbed normal light/dark cycles (NLD). Sleep EEG, core body temperature, and locomotor activity were recorded via biotelemetry in freely moving rats. Fecal samples were collected on experimental days -33, 0 (day of onset of CDR), and 42. Taxonomic identification and relative abundances of gut microbes were measured in fecal samples using 16S rRNA gene sequencing and shotgun metagenomics. Fecal primary, bacterially modified secondary, and conjugated bile acids were measured using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Prebiotic diet produced rapid and stable increases in the relative abundances of Parabacteroides distasonis and Ruminiclostridium 5. Shotgun metagenomics analyses confirmed reliable increases in relative abundances of Parabacteroides distasonis and Clostridium leptum, a member of the Ruminiclostridium genus. Prebiotic diet also modified fecal bile acid profiles; and based on correlational and step-wise regression analyses, Parabacteroides distasonis and Ruminiclostridium 5 were positively associated with each other and negatively associated with secondary and conjugated bile acids. Prebiotic diet, but not CDR, impacted beta diversity. Measures of alpha diversity evenness were decreased by CDR and prebiotic diet prevented that effect. Rats exposed to CDR while eating prebiotic, compared to control diet, more quickly realigned NREM sleep and core body temperature (ClockLab) diurnal rhythms to the altered light/dark cycle. Finally, both cholic acid and Ruminiclostridium 5 prior to CDR were associated with time to realign CBT rhythms to the new light/dark cycle after CDR; whereas both Ruminiclostridium 5 and taurocholic acid prior to CDR were associated with NREM sleep recovery after CDR. These results support our hypothesis and suggest that ingestion of prebiotic substrates is an effective strategy to increase the relative abundance of health promoting microbes, alter the fecal bile acid profile, and facilitate the recovery and realignment of sleep and diurnal rhythms after circadian disruption.

The formation of submillimetre-bright galaxies from gas infall over a billion years.

Submillimetre-bright galaxies at high redshift are the most luminous, heavily star-forming galaxies in the Universe and are characterized by prodigious emission in the far-infrared, with a flux of at least five millijanskys at a wavelength of 850 micrometres. They reside in haloes with masses about 10(13) times that of the Sun, have low gas fractions compared to main-sequence disks at a comparable redshift, trace complex environments and are not easily observable at optical wavelengths. Their physical origin remains unclear. Simulations have been able to form galaxies with the requisite luminosities, but have otherwise been unable to simultaneously match the stellar masses, star formation rates, gas fractions and environments. Here we report a cosmological hydrodynamic galaxy formation simulation that is able to form a submillimetre galaxy that simultaneously satisfies the broad range of observed physical constraints. We find that groups of galaxies residing in massive dark matter haloes have increasing rates of star formation that peak at collective rates of about 500-1,000 solar masses per year at redshifts of two to three, by which time the interstellar medium is sufficiently enriched with metals that the region may be observed as a submillimetre-selected system. The intense star formation rates are fuelled in part by the infall of a reservoir gas supply enabled by stellar feedback at earlier times, not through major mergers. With a lifetime of nearly a billion years, our simulations show that the submillimetre-bright phase of high-redshift galaxies is prolonged and associated with significant mass buildup in early-Universe proto-clusters, and that many submillimetre-bright galaxies are composed of numerous unresolved components (for which there is some observational evidence).

Erector Spinae Plane Block versus Continuous Perineural Local Anesthetic Infusion for Postoperative Pain Control After Supraclavicular Decompression for Neurogenic Thoracic Outlet Syndrome: A Matched Case-Control Comparison.

OBJECTIVE: The purpose of this study was to determine if single injection erector spinae plane blocks are associated with improved pain control, opioid use, numbness, length of stay, or patient satisfaction compared to intraoperatively placed continuous perineural infusion of local anesthetic after decompression of neurogenic thoracic outlet syndrome. METHODS: This is a retrospective cohort study at a tertiary academic center of eighty patients that underwent supraclavicular decompression for thoracic outlet syndrome between May 2019 and January 2020. Forty consecutive patients treated with single-injection preoperative erector spinae plane blocks were retrospectively compared to 40 age- and gender-matched controls treated with continuous perineural infusion. RESULTS: The primary outcome of mean pain scores was not significantly different between the erector spinae and perineural infusion groups over the three-day study period (4.2-5.3 vs 3.0-5.1 P=0.08). On post-operative day 0, mean pain scores were significantly higher in the erector spinae group (4.2 vs 3.0, P=0.02). While statistically significant, the score was still lower in the erector spinae group on day 0 than on day 1,2, or 3 in either group. Opioid use, nausea, length of stay and patient satisfaction were also similar. Upper extremity numbness was significantly less severe in the erector spinae group (36% vs 73% moderate-extreme, P=0.03) at 6-month follow-up. CONCLUSIONS: Seventy-two-hour perineural local anesthetic infusion did not provide superior analgesia compared to preoperative single-injection erector spinae blocks. Furthermore, there was significantly less long-term postoperative numbness associated with erector spinae blocks compared to perineural local anesthetic infusion.

Ixazomib for Chronic Graft-versus-Host Disease Prophylaxis following Allogeneic Hematopoietic Cell Transplantation.

Chronic graft-versus-host disease (cGVHD) is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Ixazomib is an oral, second-generation, proteasome inhibitor that has been shown in preclinical models to prevent GVHD. We conducted a phase I/II trial in 57 patients to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT. Oral ixazomib was administered on a weekly basis for a total of 4 doses, beginning days +60 through +90, to recipients of matched related donor (MRD, n = 25) or matched unrelated donor (MUD, n = 26) allogeneic HCT in phase II portion of the study, once the recommended phase II dose of 4 mg was identified in phase I (n = 6). All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate. Ixazomib administration was safe and well tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints, and fatigue the most common adverse events (>10%). In phase II (n = 51), the cumulative incidence of cGVHD at 1 year was 36% (95% confidence interval [CI], 19% to 54%) in the MRD cohort and 39% (95% CI, 21% to 56%) in the MUD cohort. One-year cumulative incidence of nonrelapse mortality (NRM) and relapse was 0% and 20% (95% CI, 8% to 36%) in the MRD cohort, respectively. In the MUD cohort, the respective NRM and relapse rates were 4% (0% to 16%) and 34% (17% to 52%). The outcomes on the study were compared post hoc with contemporaneous matched Center for International Blood and Marrow Transplant Research (CIBMTR) controls. This post hoc analysis showed no significant improvement in cGVHD rates in both the MRD (hazard ratio [HR] = 0.85, P = .64) or MUD cohorts (HR = 0.68, P = .26) on the study compared with CIBMTR controls. B cell activating factor plasma levels were significantly higher after ixazomib dosing in those who remained cGVHD free compared with those developed cGVHD. This study shows that the novel strategy of short-course oral ixazomib following allogeneic HCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation compared with matched CIBMTR controls. This study is registered at www.clinicaltrials.gov as NCT02250300.