The data-driven future of high-energy-density physics.

High-energy-density physics is the field of physics concerned with studying matter at extremely high temperatures and densities. Such conditions produce highly nonlinear plasmas, in which several phenomena that can normally be treated independently of one another become strongly coupled. The study of these plasmas is important for our understanding of astrophysics, nuclear fusion and fundamental physics-however, the nonlinearities and strong couplings present in these extreme physical systems makes them very difficult to understand theoretically or to optimize experimentally. Here we argue that machine learning models and data-driven methods are in the process of reshaping our exploration of these extreme systems that have hitherto proved far too nonlinear for human researchers. From a fundamental perspective, our understanding can be improved by the way in which machine learning models can rapidly discover complex interactions in large datasets. From a practical point of view, the newest generation of extreme physics facilities can perform experiments multiple times a second (as opposed to approximately daily), thus moving away from human-based control towards automatic control based on real-time interpretation of diagnostic data and updates of the physics model. To make the most of these emerging opportunities, we suggest proposals for the community in terms of research design, training, best practice and support for synthetic diagnostics and data analysis.

Isatuximab Monotherapy for Desensitization in Highly Sensitized Patients Awaiting Kidney Transplant.

SIGNIFICANCE STATEMENT: There is no standardized desensitization regimen for kidney transplant candidates. CD38, expressed by plasma cells, could be targeted for desensitization to deplete plasma cells producing alloantibodies and donor-specific antibodies. Few studies and case reports are available regarding the use of CD38 antibodies for desensitization in patients awaiting kidney transplant. This study shows that isatuximab, a CD38-targeting therapy, was well tolerated in kidney transplant candidates, with a durable decrease in anti-HLA antibodies and partial desensitization activity. The short treatment period and long follow-up of this study allowed for the understanding of the mechanism and timing for any antibody rebound. Isatuximab could be further investigated as an option for adjunct therapy to existing desensitization for patients on the kidney transplant waitlist. BACKGROUND: Patients with calculated panel reactive antibody (cPRA) ≥80.00%, particularly those with cPRA ≥99.90%, are considered highly sensitized and underserved by the Kidney Allocation System. Desensitization removes circulating reactive antibodies and/or suppresses antibody production to increase the chances of a negative crossmatch. CD38 is expressed highly on plasma cells, thus is a potential target for desensitization. METHODS: This was an open-label single-arm phase 1/2 study investigating the safety, pharmacokinetics, and preliminary efficacy of isatuximab in patients awaiting kidney transplantation. There were two cohorts, cohorts A and B, which enrolled cPRA ≥99.90% and 80.00% to <99.90%, respectively. RESULTS: Twenty-three patients (12 cohort A, 11 cohort B) received isatuximab 10 mg/kg weekly for 4 weeks then every 2 weeks for 8 weeks. Isatuximab was well tolerated with pharmacokinetic and pharmacodynamic profiles that indicated similar exposure to multiple myeloma trials. It resulted in decreases in CD38 + plasmablasts, plasma cells, and NK cells and significant reductions in HLA-specific IgG-producing memory B cells. Overall response rate, on the basis of a predefined composite desensitization end point, was 83.3% and 81.8% in cohorts A and B. Most responders had decreases in anti-HLA antibodies that were maintained for 26 weeks after the last dose. Overall, cPRA values were minimally affected, however, with only 9/23 patients (39%) having cPRA decreases to target levels. By study cutoff (median follow-up of 68 weeks), six patients received transplant offers, of which four were accepted. CONCLUSIONS: In this open-label trial, isatuximab was well tolerated and resulted in a durable decrease in anti-HLA antibodies with partial desensitization activity. CLINICAL TRIAL REGISTRATION NUMBER: NCT04294459 .

Understanding Treatment Decision-Making in Older Women With Breast Cancer: A Survey-Based Study.

INTRODUCTION: For women ≥70 y old with early-stage hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, the national guidelines recommend the omission of sentinel lymph node biopsy (SLNB) and post-lumpectomy radiotherapy. However, national-level data suggest these treatments remain common. We utilized a survey-based approach to explore patient-level factors driving overutilization. METHODS: We recruited women ≥70 y old with early-stage hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer within 6 mo of surgery. An exploratory cross-sectional survey captured information on offered and pursued treatments, the importance of patient-centered outcomes, and the influence of each outcome on treatment decision-making. Descriptive statistics were used for analysis. RESULTS: 31/51 patients completed the survey with a response rate of 61%. Most patients (86%) received a lumpectomy. Twenty-eight percent of patients received SLNB, and 56% of lumpectomy patients underwent adjuvant radiotherapy. When considering treatment options, the patient-centered outcomes, most important for decision-making, were overall survival, breast-specific survival, and preventing local recurrence, while breast appearance, financial costs, and avoiding the need for pills (endocrine therapy) were the least important. CONCLUSIONS: Patients' treatment decisions align with their values. The correlation between patient-stated values and treatment decisions suggests a perceived mortality benefit of low-value SLNB and radiotherapy. These findings can inform targeted efforts to deimplement low-value care in breast cancer through patient-focused tools and education.

Assessing social disparities in inpatient vs. outpatient arthroplasty: a in-state database analysis.

INTRODUCTION: Given the growing emphasis on patient outcomes, including postoperative complications, in total joint arthroplasty (TJA), investigating the rise of outpatient arthroplasty is warranted. Concerns exist over the safety of discharging patients home on the same day due to increased readmission and complication rates. However, psychological benefits and lower costs provide an incentive for outpatient arthroplasty. The influence of social determinants of health disparities on outpatient arthroplasty remains unexplored. One metric that assesses social disparities, including the following individual components: socioeconomic status, household composition, minority status, and housing and transportation, is the Social Vulnerability Index (SVI). As such, we aimed to compare: (1) mean overall SVI and mean SVI for each component and (2) risk factors for total complications between patients undergoing inpatient and outpatient arthroplasty. METHODS: Patients who underwent TJA between January 1, 2022 and December 31, 2022 were identified. Data were drawn from the Maryland State Inpatient Database (SID). A total of 7817 patients had TJA within this time period. Patients were divided into inpatient arthroplasty (n = 1429) and outpatient arthroplasty (n = 6338). The mean SVI was compared between inpatient and outpatient procedures for each themed score. The SVI identifies communities that may need support cause by external stresses on human health based on four themed scores: socioeconomic status; household composition and disability; minority status and language; and housing and transportation. The SVI uses the United States Census data to rank census tracts for each individual theme, as well as an overall social vulnerability score. The higher the SVI, the more social vulnerability, or resources needed to thrive in that area. Multivariate logistic regression analyses were performed to identify independent risk factors for total complications following TJA after controlling for risk factors and patient comorbidities. Total complications included: infection, aseptic loosening, dislocation, arthrofibrosis, mechanical complication, pain, and periprosthetic fracture. RESULTS: Patients who had inpatient arthroplasty had higher overall SVI scores (0.45 vs. 0.42, P < 0.001). The SVI scores were higher for patients who had inpatient arthroplasty for socioeconomic status (0.36 vs. 0.32, P < 0.001), minority status and language (0.76 vs. 0.74, P < 0.001), and housing and transportation (0.53 vs. 0.50, P < 0.001) compared to outpatient arthroplasty, respectively. There was no difference between inpatient and outpatient arthroplasty for household composition and disability (0.41 vs. 0.41, P = 0.99). When controlling for comorbidities, inpatient arthroplasty [Odds Ratio (OR) 1.91, 95% Confidence Interval (CI) 1.23-2.95, P = 0.004], hypertension (OR 2.11, 95% CI 1.23-3.62, P = 0.007), and housing and transportation (OR 2.00, 95% CI 1.17-3.42, P = 0.012) were independent risk factors for total complications. CONCLUSION: Inpatient arthroplasty was associated with increased social disparities across several components of deprivation as well as an independent risk factor total complications following TJA. To the best of our knowledge, this study is the first to examine the negative repercussions of inpatient arthroplasty through the lens of social disparities and can target specific areas for intervention.

Patient Preferences and Satisfaction With Decisions in Stage-III Melanoma: A Mixed Methods Study.

INTRODUCTION: Rapid accumulation of data in surgical and medical oncology has changed the treatment landscape for patients with stage-III melanoma, introducing options for active surveillance and adjuvant systemic therapy; however, these options have increased the complexity of decision making. METHODS: We conducted an explanatory sequential mixed-methods study consisting of surveys and semistructured interviews among patients diagnosed with stage-III melanoma at a single institution from August 2019 to December 2021. The survey included the validated 30-point satisfaction with decision scale (SWD). The interview guide was developed using a shared decision-making framework. RESULTS: Twenty-six participants completed the survey (response rate 40%) and 17 were interviewed. In the survey, 69% of participants reported receiving a recommendation for active surveillance and 23% received a recommendation for adjuvant systemic therapy. Overall SWD for treatment of the lymph node basin and adjuvant systemic therapy was high at 27.94 and 26.21 out of 30, respectively. In the interviews, participants stressed the importance of the physician's recommendation as well as the desire to minimize intervention and avoid potential side effects in their decisions. However, they demonstrated persistent knowledge gaps in their understanding of the treatment options. CONCLUSIONS: Like other cancer types where the option for active surveillance exists, the physician's recommendation is influential in shaping decisions for patients with stage-III melanoma. Physicians can improve shared decision making in this complex treatment landscape through improved multidisciplinary collaboration and mechanisms for ensuring patients' understanding of the treatment options.

Adaptive regulation of testis gene expression and control of male fertility by the Drosophila hairpin RNA pathway. [Corrected].

Although endogenous siRNAs (endo-siRNAs) have been described in many species, still little is known about their endogenous utility. Here, we show that Drosophila hairpin RNAs (hpRNAs) generate an endo-siRNA class with predominant expression in testes. Although hpRNAs are universally recently evolved, we identify highly complementary protein-coding targets for all hpRNAs. Importantly, we find broad evidence for evolutionary divergences that preferentially maintain compensatory pairing between hpRNAs and targets, serving as first evidence for adaptive selection for siRNA-mediated target regulation in metazoans. We demonstrate organismal impact of hpRNA activity, since knockout of hpRNA1 derepresses its target ATP synthase-ß in testes and compromises spermatogenesis and male fertility. Moreover, we reveal surprising male-specific impact of RNAi factors on germ cell development and fertility, consistent with testis-directed function of the hpRNA pathway. Finally, the collected hpRNA loci chronicle an evolutionary timeline that reflects their origins from prospective target genes, mirroring a strategy described for plant miRNAs.

Navigating through perplex morphologic changes after exogenous hormone usage.

Clinical application of exogenous hormone as a method of contraception and/or treatment of various gynecologic disorders is exceedingly common. Unfortunately, the concurrent use of these agents also complicates the interpretation of pathology specimens. Various studies have shown that morphologic changes induced by hormonal therapies are present in both non-neoplastic and neoplastic tissues within the women's reproductive tract. It is important to understand the exogenous hormone induced morphologic changes, as it helps the pathologists make the accurate diagnosis, and in turn, guide clinicians to make optimal clinical decisions. In this review, we summarize the morphologic changes in both neoplastic and non-neoplastic endometrial, cervical, and myometrial surgical specimens after hormonal therapies, particularly after progestin treatment. In the endometrium, particularly in the scenario of progestin-treated atypical endometrial hyperplasia/endometrioid intraepithelial neoplasia (AEH/EIN), there is notoriously poor interobserver agreement and difficulty in assessing for the residual disease. We summarize current literature and propose our recommended approach in assessing these challenging endometrial biopsies, including a diagnostic algorism, the use of PAX-2, PTEN, beta-catenin immunohistochemistry panel, as well as consistency in diagnostic wording of the report. In the cervix, progestin makes dysplastic lesions appear metaplastic, thus high-grade squamous dysplastic lesions may be easily missed. Within the myometrium, lesions such as adenomyosis may show various degree of decidualization, while smooth muscle neoplasms may show apoplectic changes, and stromal lesions including endometrial stromal sarcoma may show more eosinophilic cytoplasm. All such changes may pose more or less diagnostic challenges in our daily practice. However, most are readily recognizable when we understand particular hormone related scenarios.

Heterochromatin protein 1α interacts with parallel RNA and DNA G-quadruplexes.

The eukaryotic genome is functionally organized into domains of transcriptionally active euchromatin and domains of highly compact transcriptionally silent heterochromatin. Heterochromatin is constitutively assembled at repetitive elements that include the telomeres and centromeres. The histone code model proposes that HP1α forms and maintains these domains of heterochromatin through the interaction of its chromodomain with trimethylated lysine 9 of histone 3, although this interaction is not the sole determinant. We show here that the unstructured hinge domain, necessary for the targeting of HP1α to constitutive heterochromatin, recognizes parallel G-quadruplex (G4) assemblies formed by the TElomeric Repeat-containing RNA (TERRA) transcribed from the telomere. This provides a mechanism by which TERRA can lead to the enrichment of HP1α at telomeres to maintain heterochromatin. Furthermore, we show that HP1α binds with a faster association rate to DNA G4s of parallel topology compared to antiparallel G4s that bind slowly or not at all. Such G4-DNAs are found in the regulatory regions of several oncogenes. This implicates specific non-canonical nucleic acid structures as determinants of HP1α function and thus RNA and DNA G4s need to be considered as contributors to chromatin domain organization and the epigenome.

The relationship between distress tolerance and symptoms of depression: Validation of the Distress Tolerance Scale (DTS) and short-form (DTS-SF).

OBJECTIVE: Distress tolerance (DT) has been found to be implicated in the development and maintenance of depressive symptomatology and various other significant psychological conditions. As such, it is critical to have measures of DT that are effective and easy to administer. This study aimed to examine the factor structure, psychometric properties, and clinical utility of the Distress Tolerance Scale (DTS) and the short-form version, the Distress Tolerance Scale Short-form (DTS-SF), in a large population of individuals with varying levels of self-reported depressive symptoms. METHOD: A total of 959 participants completed an online battery of questionnaires which included an assessment of depressive symptoms as well as the DTS and related measures. Results: Confirmatory factor analyses validated the four-factor structure of the DTS and the one-factor structure of the DTS-SF. Good construct validity and good internal consistency were observed across both the DTS and DTS-SF. CONCLUSION: Overall, this paper provides new evidence for the validity, reliability and discriminative ability of the DTS and the brief version of the questionnaire, the DTS-SF.

Interferon-stimulated GTPases in autoimmune and inflammatory diseases: promising role for the guanylate-binding protein (GBP) family.

Human IFNs are secreted cytokines shown to stimulate the expression of over one thousand genes. These IFN-inducible genes primarily encode four major protein families, known as IFN-stimulated GTPases (ISGs), namely myxovirus-resistance proteins, guanylate-binding proteins (GBPs), p47 immunity-related GTPases and very large inducible guanosine triphosphate hydrolases (GTPases). These families respond specifically to type I or II IFNs and are well reported in coordinating immunity against some well known as well as newly discovered viral, bacterial and parasitic infections. A growing body of evidence highlights the potential contributory and regulatory roles of ISGs in dysregulated inflammation and autoimmune diseases. Our focus was to draw attention to studies that demonstrate increased expression of ISGs in the serum and affected tissues of patients with RA, SS, lupus, IBD and psoriasis. In this review, we analysed emerging literature describing the potential roles of ISGs, particularly the GBP family, in the context of autoimmunity. We also highlighted the promise and implications for therapeutically targeting IFNs and GBPs in the treatment of rheumatic diseases.

Takinib Inhibits Inflammation in Human Rheumatoid Arthritis Synovial Fibroblasts by Targeting the Janus Kinase-Signal Transducer and Activator of Transcription 3 (JAK/STAT3) Pathway.

TGF ß-activated kinase 1 (TAK1) is an important participant in inflammatory pathogenesis for diseases such as rheumatoid arthritis (RA) and gouty arthritis. The central position it occupies between the mitogen activated protein kinase (MAPK) and nuclear factor kappa B (NF-κB) pathways makes it an attractive therapeutic target. As this field has developed in recent years, several novel inhibitors have been presented as having specific activity that reduces the TAK1 function either covalently as in the case of 5Z-7-oxozeanol (5Z7O) or reversibly (NG-25). However, the mechanism through which takinib elicits its anti-inflammatory activity remains elusive. While this inhibitor shows great promise, a thorough analysis of its inhibitor function and its potential off-target effects is necessary before addressing its clinical potential or its use in inflammatory conditions. An analysis through Western blot showed an unexpected increase in IL-1ß-induced TAK1 phosphorylation-a prerequisite for and indicator of its functional potential-by takinib while simultaneously demonstrating the inhibition of the JAK/STAT pathway in human rheumatoid arthritis synovial fibroblasts (RASFs) in vitro. In THP-1 monocyte-derived macrophages, takinib again led to the lipopolysaccharide-induced phosphorylation of TAK1 without a marked inhibition of the TAK1 downstream effectors, namely, of c-Jun N-terminal kinase (JNK), phospho-c-Jun, NF-κB phospho-p65 or phospho-IκBα. Taken together, these findings indicate that takinib inhibits inflammation in these cells by targeting multiple signaling pathways, most notably the JAK/STAT pathway in human RASFs.

Energy Flow in Thin Shell Implosions and Explosions.

Energy flow and balance in convergent systems beyond petapascal energy densities controls the fate of late-stage stars and the potential for controlling thermonuclear inertial fusion ignition. Time-resolved x-ray self-emission imaging combined with a Bayesian inference analysis is used to describe the energy flow and the potential information stored in the rebounding spherical shock at 0.22 PPa (2.2 Gbar or billions of atmospheres pressure). This analysis, together with a simple mechanical model, describes the trajectory of the shell and the time history of the pressure at the fuel-shell interface, ablation pressure, and energy partitioning including kinetic energy of the shell and internal energy of the fuel. The techniques used here provide a fully self-consistent uncertainty analysis of integrated implosion data, a thermodynamic-path independent measurement of pressure in the petapascal range, and can be used to deduce the energy flow in a wide variety of implosion systems to petapascal energy densities.

The Effect of Neuraxial Anesthesia on Postoperative Outcomes in Total Joint Arthroplasty With Rapid Recovery Protocols.

BACKGROUND: Compared to general anesthesia (GA), neuraxial anesthesia (NA) has been associated with improved outcomes after total joint arthroplasty (TJA). We examined the impact of NA on patient outcomes in an institution with an established rapid recovery protocol. METHODS: This is a single-institution retrospective analysis of 5914 consecutive primary TJA performed from July 2015 to June 2018. Univariate tests and multivariate regression compared length of stay (LOS), transfusion rates, hematocrit levels, discharge disposition, and emergency room returns between patients receiving GA and NA. RESULTS: Patients receiving NA had a significantly shorter LOS (total hip arthroplasty [THA]: GA 1.74 vs NA 1.36 days, P < .001; total knee arthroplasty [TKA]: GA 1.77 vs NA 1.64 days, P < .001). Both THA and TKA patients receiving NA were less likely to require transfusion (THA: GA 5.8% vs NA 1.6%, P < .001; TKA: GA 2.5% vs NA 0.5%, P < .001) and had a higher postoperative hematocrit (THA: GA 32.50% vs NA 33.22%, P < .001; TKA GA 33.57 vs NA 34.50%, P < .001). Patients receiving NA were more likely to discharge home (THA: GA 83.4% vs NA 92.3%, P < .001; TKA: GA 83.3% vs NA 86.3%, P = .010) (THA: NA adjusted OR [aOR] 2.04, P < .001; TKA: NA aOR 1.23, P = .048) and had significantly lower rates of 90-day emergency room visits (THA: NA aOR 0.61, P = .005; TKA: NA aOR 0.74, P = .034). CONCLUSION: NA appears to contribute to decreased LOS, short-term complications, and transfusions while facilitating home discharge following TKA and THA. These trends are consistent when controlling for patient-specific risk factors, suggesting NA may enhance outcomes for patients with increased age, body mass index, and comorbidities. LEVEL OF EVIDENCE: Level III Retrospective Cohort Study.

Correction: Correction: A Novel Rhabdovirus Associated with Acute Hemorrhagic Fever in Central Africa.

[This corrects the article DOI: 10.1371/journal.ppat.1002924.].

Mammalian microRNAs: experimental evaluation of novel and previously annotated genes.

MicroRNAs (miRNAs) are small regulatory RNAs that derive from distinctive hairpin transcripts. To learn more about the miRNAs of mammals, we sequenced 60 million small RNAs from mouse brain, ovary, testes, embryonic stem cells, three embryonic stages, and whole newborns. Analysis of these sequences confirmed 398 annotated miRNA genes and identified 108 novel miRNA genes. More than 150 previously annotated miRNAs and hundreds of candidates failed to yield sequenced RNAs with miRNA-like features. Ectopically expressing these previously proposed miRNA hairpins also did not yield small RNAs, whereas ectopically expressing the confirmed and newly identified hairpins usually did yield small RNAs with the classical miRNA features, including dependence on the Drosha endonuclease for processing. These experiments, which suggest that previous estimates of conserved mammalian miRNAs were inflated, provide a substantially revised list of confidently identified murine miRNAs from which to infer the general features of mammalian miRNAs. Our analyses also revealed new aspects of miRNA biogenesis and modification, including tissue-specific strand preferences, sequential Dicer cleavage of a metazoan precursor miRNA (pre-miRNA), consequential 5' heterogeneity, newly identified instances of miRNA editing, and evidence for widespread pre-miRNA uridylation reminiscent of miRNA regulation by Lin28.

The kinase regulator mob1 acts as a patterning protein for stentor morphogenesis.

Morphogenesis and pattern formation are vital processes in any organism, whether unicellular or multicellular. But in contrast to the developmental biology of plants and animals, the principles of morphogenesis and pattern formation in single cells remain largely unknown. Although all cells develop patterns, they are most obvious in ciliates; hence, we have turned to a classical unicellular model system, the giant ciliate Stentor coeruleus. Here we show that the RNA interference (RNAi) machinery is conserved in Stentor. Using RNAi, we identify the kinase coactivator Mob1--with conserved functions in cell division and morphogenesis from plants to humans-as an asymmetrically localized patterning protein required for global patterning during development and regeneration in Stentor. Our studies reopen the door for Stentor as a model regeneration system.

Formation, regulation and evolution of Caenorhabditis elegans 3'UTRs.

Post-transcriptional gene regulation frequently occurs through elements in mRNA 3' untranslated regions (UTRs). Although crucial roles for 3'UTR-mediated gene regulation have been found in Caenorhabditis elegans, most C. elegans genes have lacked annotated 3'UTRs. Here we describe a high-throughput method for reliable identification of polyadenylated RNA termini, and we apply this method, called poly(A)-position profiling by sequencing (3P-Seq), to determine C. elegans 3'UTRs. Compared to standard methods also recently applied to C. elegans UTRs, 3P-Seq identified 8,580 additional UTRs while excluding thousands of shorter UTR isoforms that do not seem to be authentic. Analysis of this expanded and corrected data set suggested that the high A/U content of C. elegans 3'UTRs facilitated genome compaction, because the elements specifying cleavage and polyadenylation, which are A/U rich, can more readily emerge in A/U-rich regions. Indeed, 30% of the protein-coding genes have mRNAs with alternative, partially overlapping end regions that generate another 10,480 cleavage and polyadenylation sites that had gone largely unnoticed and represent potential evolutionary intermediates of progressive UTR shortening. Moreover, a third of the convergently transcribed genes use palindromic arrangements of bidirectional elements to specify UTRs with convergent overlap, which also contributes to genome compaction by eliminating regions between genes. Although nematode 3'UTRs have median length only one-sixth that of mammalian 3'UTRs, they have twice the density of conserved microRNA sites, in part because additional types of seed-complementary sites are preferentially conserved. These findings reveal the influence of cleavage and polyadenylation on the evolution of genome architecture and provide resources for studying post-transcriptional gene regulation.

PRG-1 and 21U-RNAs interact to form the piRNA complex required for fertility in C. elegans.

In metazoans, Piwi-related Argonaute proteins have been linked to germline maintenance, and to a class of germline-enriched small RNAs termed piRNAs. Here we show that an abundant class of 21 nucleotide small RNAs (21U-RNAs) are expressed in the C. elegans germline, interact with the C. elegans Piwi family member PRG-1, and depend on PRG-1 activity for their accumulation. The PRG-1 protein is expressed throughout development and localizes to nuage-like structures called P granules. Although 21U-RNA loci share a conserved upstream sequence motif, the mature 21U-RNAs are not conserved and, with few exceptions, fail to exhibit complementarity or evidence for direct regulation of other expressed sequences. Our findings demonstrate that 21U-RNAs are the piRNAs of C. elegans and link this class of small RNAs and their associated Piwi Argonaute to the maintenance of temperature-dependent fertility.

The posttranslational modification cascade to the thiopeptide berninamycin generates linear forms and altered macrocyclic scaffolds.

Berninamycin is a member of the pyridine-containing thiopeptide class of antibiotics that undergoes massive posttranslational modifications from ribosomally generated preproteins. Berninamycin has a 2-oxazolyl-3-thiazolyl-pyridine core embedded in a 35-atom macrocycle rather than typical trithiazolylpyridine cores embedded in 26-atom and 29-atom peptide macrocycles. We describe the cloning of an 11-gene berninamycin cluster from Streptomyces bernensis UC 5144, its heterologous expression in Streptomyces lividans TK24 and Streptomyces venezuelae ATCC 10712, and detection of variant and incompletely processed scaffolds. Posttranslational maturation in S. lividans of both the wild-type berninamycin prepeptide (BerA) and also a T3A mutant generates macrocyclic compounds as well as linear variants, which have failed to form the pyridine and the macrocycle. Expression of the gene cluster in S. venezuelae generates a variant of the 35-atom skeleton of berninamycin, containing a methyloxazoline in the place of a methyloxazole within the macrocyclic framework.

Three-Tesla imaging of the pituitary and parasellar region: T1-weighted 3-dimensional fast spin echo cube outperforms conventional 2-dimensional magnetic resonance imaging.

OBJECTIVE: We explored how a novel T1-weighted 3-dimensional (3D) fast spin echo (FSE) sequence (Cube; GE, Waukesha, Wis) might outperform conventional 2-dimensional (2D) FSE techniques for contrast-enhanced imaging of the pituitary and parasellar region. METHODS: Ninety-one patients were imaged with 3D Cube and conventional 2D FSE on a 3.0-T magnetic resonance scanner. Two neuroradiologists independently assessed images for anatomical delineation (infundibulum, optic apparatus, and cavernous sinus), degree of artifact, and confidence in lesion definition or exclusion using a 5-point scale. In addition, the readers were asked to rank overall preference. RESULTS: Readers A and B found 3D Cube to be better or equal to 2D FSE in 84% and 86% of the cases. Three-dimensional Cube provided significantly better images than 2D FSE with respect to delineation of the infundibulum (P < 0.0001), cavernous sinus (P < 0.0001), optic apparatus (P = 0.002 for reader A and P = 0.265 for reader B), and fewer artifacts at the sellar floor (P < 0.0001). Three-dimensional Cube provided greater lesion conspicuity or confidence in lesion exclusion (P < 0.0001). CONCLUSIONS: Three-dimensional Cube provides superior quality with thinner slices as well as diminished artifact and can replace conventional 2D FSE sequences for routine evaluations of the pituitary and parasellar region.