Single particle cryo-EM structure of the outer hair cell motor protein prestin

The mammalian outer hair cell (OHC) protein prestin (Slc26a5) differs from other Slc26 family members due to its unique piezoelectric-like property that drives OHC electromotility, the putative mechanism for cochlear amplification. Here, we use cryo-electron microscopy to determine prestin’s structure at 3.6 Å resolution. Prestin is structurally similar to the anion transporter Slc26a9. It is captured in an inward-open state which may reflect prestin’s contracted state. Two well-separated transmembrane (TM) domains and two cytoplasmic sulfate transporter and anti-sigma factor antagonist (STAS) domains form a swapped dimer. The transmembrane domains consist of 14 transmembrane segments organized in two 7+7 inverted repeats, an architecture first observed in the bacterial symporter UraA. Mutation of prestin’s chloride binding site removes salicylate competition with anions while retaining the prestin characteristic displacement currents (Nonlinear Capacitance), undermining the extrinsic voltage sensor hypothesis for prestin function.

Relationship Between Patient Sex and Serum Tumor Necrosis Factor Antagonist Drug and Anti-Drug Antibody Concentrations in Inflammatory Bowel Disease; A Nationwide Study

Introduction: Anti-drug antibodies to infliximab (ATI) and adalimumab (ATA) are associated with loss of response to tumor necrosis factor antagonist (anti-TNF) therapy in inflammatory bowel disease (IBD). We evaluated the relationship between patient sex and serum TNF antagonist drug and antibody concentrations in inflammatory bowel disease. Methods: A nationwide multicenter retrospective cohort study was conducted by evaluating patient charts from July 2018 until February 2021. The effect of patient sex on anti-drug antibodies and serum drug concentration in patients with IBD across 7 hospitals was investigated. A subgroup analysis also investigated the effect of anti-TNF combination therapy. Results: In the total study sample (n = 1093), males receiving infliximab had higher anti-drug antibody concentrations (38.3 vs. 22.3 AU/ml; aRoGM = 1.72, 95% CI: 1.30-2.27, p-value <0.001) compared to females. Additionally, infliximab serum drug concentrations among males were lower compared to females (2.6 vs. 4.1 ug/ml; aRoGM = 0.62, 95% CI: 0.44-0.88, p-value = 0.007). In the subgroup analysis (n = 359), male compared to female patients on combination therapy with infliximab and immunomodulators had similar anti-drug antibody concentrations (30.2 vs. 21.9 AU/ml; aRoGM = 1.38, 95% CI: 0.79-2.40, p-value = 0.254). . There was no difference in the anti-drug antibody and serum drug concentrations among males and females on adalimumab. Conclusion: In patients receiving infliximab, anti-drug antibodies were higher in males than females. Consistent with this, serum drug concentrations were lower in males than females on infliximab. However, there was no difference in anti-drug antibody and serum drug concentrations among males and females on adalimumab. In addition, no difference in anti-drug antibodies between males and females receiving anti-TNF combination therapy was observed.

154 Evaluating the effects of prophylactic antibiotics on intestinal health in pigs given a corticotropin-releasing factor antagonist during weaning and transport

Prophylactic antibiotics improve intestinal health in pigs; however, it is unknown whether their efficacy interacts with a pig’s stress response following weaning and transport. The study objective was to determine whether a corticotropin-releasing factor (CRF) antagonist would impact the efficacy of prophylactic antibiotics on improving intestinal health in transported weaned pigs. Mixed-sex pigs (n = 56; 5.70 ± 1.05 kg BW) were weaned (20.49 ± 0.64 d), a blood sample was taken, pigs were given an i.p. injection of saline (SAL) or a CRF antagonist (CRFA; 30 µg/kg BW; Astressin B), and then were transported for 12 h. Pigs were given a second and third i.p. injection at 6 and 12 h of transport, respectively. Following transport, 4 SAL and 4 CRFA pigs were blood sampled and euthanized. The remaining 48 pigs were individually housed and assigned to an antibiotic [A; chlortetracycline (441 ppm) + tiamulin (38.6 ppm)] or no antibiotic (NA) diet treatment balanced by injection treatment (n = 12 pigs/treatment combination). Blood was collected at 12 h and on d 3, 7, and 14 and pigs were euthanized on d 7 (n = 24) and d 14 (n = 24) post-weaning and transport. Plasma adrenocorticotropic hormone was reduced overall (P = 0.05; 9.1%) in CRFA versus SAL pigs. On d 7, jejunal villus height was greater (P = 0.04; 33%) in A versus NA pigs. Jejunal zonula occludens-1 (58.8%) and ileal claudin-1 (100.5%) mRNA abundance tended to be increased (P = 0.09) in CRFA+NA versus SAL+NA pigs on d 7. On d 14, jejunal tumor necrosis factor-alpha mRNA abundance was reduced (P = 0.02; 29.9%) in A versus NA pigs and jejunal glucagon-like peptide-2 mRNA abundance was increased (P = 0.03) in CRFA+NA versus SAL+NA (48.4%) and SAL+A versus SAL+NA (55.8%) pigs. No intestinal health parameter differences were detected (P &gt; 0.05) between CRFA+NA and SAL+A pigs. In conclusion, CRFA and A impacted weaned pig intestinal health measures at similar levels.