The ARGUS Vertex Trigger

A fast second level trigger has been developed for the ARGUS experiment which recognizes tracks originating from the interaction region. The processor compares the hits in the ARGUS Micro Vertex Drift Chamber to 245760 masks stored in random access memories. The masks which are fully defined in three dimensions are able to reject tracks originating in the wall of the narrow beampipe of 10.5\,mm radius.Comment: gzipped Postscript, 27 page

Human 343delT HSPB5 Chaperone associated with Early-onset Skeletal Myopathy causes Defects in Protein Solubility

Mutations of HSPB5 (also known as CRYAB or αB-crystallin), a bona fide heat shock protein and molecular chaperone encoded by the HSPB5 (crystallin, alpha B) gene, are linked to various multisystem disorders featuring variable combinations of cataracts, cardiomyopathy, and skeletal myopathy. This study aims at investigating the pathological mechanisms involved in an early onset myofibrillar myopathy manifesting in a child harboring a homozygous recessive mutation in HSPB5, 343delT. To study HSPB5 343delT protein dynamics, we utilize model cell culture systems including induced pluripotent stem cells (iPSCs) derived from the 343delT patient (343delT/343delT) along with isogenic, heterozygous, gene-corrected control cells (WT KI/343delT), and BHK21 cells, a cell line lacking endogenous HSPB5 expression. 343delT/343delT and WT KI/343delT iPSC-derived skeletal myotubes (iSKMs) and cardiomyocytes (iCMs) did not express detectable levels of 343delT protein, contributable to extreme insolubility of the mutant protein. Overexpression of HSPB5 343delT resulted in insoluble mutant protein aggregates and induction of a cellular stress response. Co-expression of 343delT with WT prevented visible aggregation of 343delT and improved its solubility. Additionally, in vitro refolding of 343delT in the presence of WT rescued its solubility. We demonstrate an interaction between WT and 343delT both in vitro and within cells. These data support a loss of function model for the myopathy observed in the patient, as the insoluble mutant would be unavailable to perform normal functions of HSPB5, though additional gain-of-function effects of the mutant protein cannot be excluded. Additionally, our data highlights the solubilization of 343delT by WT, concordant with the recessive inheritance of the disease and absence of symptoms in carrier individuals.</p

Symptomatic and Asymptomatic Host Range of <i>Fusarium virguliforme</i>, the Causal Agent of Soybean Sudden Death Syndrome

Sudden death syndrome, caused by Fusarium virguliforme, is an important disease of soybean in the United States. Fifteen species of crops, weeds, or prairie plants were evaluated for their potential as hosts of F. virguliforme. Root and foliar symptoms and plant biomass were assessed following greenhouse inoculation studies. Root colonization of F. virguliforme was determined with isolations and with polymerase chain reaction assays. Soybean, alfalfa, pinto and navy bean, white and red clover, pea, and Canadian milk vetch developed root necrosis. Soybean, alfalfa, and red clover also developed foliar symptoms following inoculation. Sugar beet and canola did not develop symptoms but had significant reductions in biomass, suggesting that they are also hosts of F. virguliforme. Corn, wheat, ryegrass, pigweed, and lambsquarters did not develop symptoms. However, these species appeared to be asymptomatic hosts because quantities of pathogen DNA detected in inoculated roots were similar to quantities detected in inoculated soybean roots. These results suggest that the number and diversity of hosts for F. virguliforme are greater than previously reported. The likely broad host range limits the efficacy of crop rotation and indicates that crops other than soybean can be damaged by F. virguliforme and maintain or increase inoculum in soil. </jats:p

Sugar, Sugar: Evaluation of Insulin Requirements with Initiation of Glucagon-Like Peptide-1 Agonists and Sodium-Glucose Co-Transporter-2 Inhibitors

Introduction: Glucagon-like peptide-1 agonists (GLP1a) and sodium-glucose co-transporter-2 inhibitors (SGLT2i) are newer classes of agents used in the treatment of Type 2 Diabetes Mellitus (T2DM) and may provide additional cardiorenal benefits. While there is currently some evidence that insulin dose should be reduced upon initiation of these agents, there is little real-world guidance supporting specific dose adjustments. Research Question or Hypothesis: The purpose of the study is to describe the insulin adjustments made upon initiation of GLP1a and SGLT2i for T2DM patients in the ambulatory care setting. Study Design: Multi-center, retrospective, cohort study. Methods: Adults with T2DM initiated on a GLP1a or SGLT2i while on concomitant insulin therapy and managed by an ambulatory care pharmacist at time of initiation were included in the study. The primary endpoint measured the percent change in total insulin at different time points after initiation of agent. The secondary endpoints were discontinuation of sulfonylurea therapy at 6 months, frequency of HbA1c targets achieved (A1c \u3c8%), change from baseline HbA1c, and adverse effect profile of the agents. Results: Of the 150 patients included, 123 were initiated on a GLP1a and 27 on a SGLT2i. After 6 months of therapy, GLP1a initiation resulted in an 18.4% decrease (p\u3c0.001) in insulin dosages while SGLT2i had a 6.5% increase (p=0.95). Of patients initially on a sulfonylurea, it was discontinued in 8/17 patients (47.1%) who were initiated on GLP1a and 4/5 patients initiated (80%) on SGLT2i. HbA1c targets were achieved in 72.4% of patients with GLP1a and 59.3% with SGLT2i. Absolute change in HbA1c was-1.7% for GLP1a and-1.5% for SGLT2i. Hypoglycemia occurred in 21.1% and 11.1% of patients started on GLP1a and SGLT2i, respectively. Conclusion: GLP1a initiation provided a significant decrease in total insulin dose of 18% after 6 months, whereas total insulin requirements increased after SGLT2i initiation

The human Obg protein GTPBP10 is involved in mitoribosomal biogenesis.

The human mitochondrial translation apparatus, which synthesizes the core subunits of the oxidative phosphorylation system, is of central interest as mutations in several genes encoding for mitoribosomal proteins or translation factors cause severe human diseases. Little is known, how this complex machinery assembles from nuclear-encoded protein components and mitochondrial-encoded RNAs, and which ancillary factors are required to form a functional mitoribosome. We have characterized the human Obg protein GTPBP10, which associates specifically with the mitoribosomal large subunit at a late maturation state. Defining its interactome, we have shown that GTPBP10 is in a complex with other mtLSU biogenesis factors including mitochondrial RNA granule components, the 16S rRNA module and late mtLSU assembly factors such as MALSU1, SMCR7L, MTERF4 and NSUN4. GTPBP10 deficiency leads to a drastic reduction in 55S monosome formation resulting in defective mtDNA-expression and in a decrease in cell growth. Our results suggest that GTPBP10 is a ribosome biogenesis factor of the mtLSU required for late stages of maturation

Real-world evaluation of insulin requirements after GLP1 agonist or SGLT2 inhibitor initiation and titration

DISCLAIMER: In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. PURPOSE: To describe insulin adjustments made following initiation of glucagon-like peptide 1 agonist (GLP1a) or sodium-glucose cotransporter-2 inhibitor (SGLT2i) therapy in patients within a primary care setting. METHODS: This was a multicenter, retrospective cohort study conducted at an academic health system. Adults with type 2 diabetes mellitus initiated on a GLP1a or SGLT2i while on insulin and managed by an ambulatory care pharmacist were included. The primary endpoint was the percent change in total daily insulin dose at specified time points (2 weeks, 4 weeks, 6 weeks, 3 months, and 6 months) after agent initiation. The secondary endpoints included a glycosylated hemoglobin (HbA1c) value of less than 8%, change from baseline HbA1c, and safety profiles of GLP1a therapy and SGLT2i therapy. RESULTS: Of the 150 patients included, 123 were initiated on a GLP1a and 27 on an SGLT2i. After 6 months, GLP1a initiation had resulted in a mean 23.5% decrease (P \u3c 0.001) in insulin dosage and SGLT2i resulted in a mean 0.2% increase (P = 0.20). Insulin dosage reduction with GLP1a use was significantly different between baseline and each time point (P \u3c 0.001). About 72% of patients initiated on a GLP1a and 59% of those initiated on an SGLT2i achieved an HbA1c value of less than 8%. The mean absolute change from baseline in HbA1c concentration was -1.7% with GLP1a use and -1.5% with SGLT2i use (P \u3c 0.001 for both comparisons with baseline values). Hypoglycemia occurred in 21% of patients on a GLP1a and 11% of those on an SGLT2i. CONCLUSION: After GLP1a initiation, the mean total daily insulin dose decreased by 23.5%; after SGLT2i initiation, insulin requirements increased by a mean of 0.2%. These results will help guide insulin adjustments after initiation of these medications