The Use of the iPACK Block with the Adductor Canal Block (ACB) Decreases 48-hour Narcotic Usage and Postoperative Pain following Total Knee Arthroplasty

Adductor Canal and iPACK Blocks reduce pain levels and narcotic consumption following Total Knee Arthroplastyhttps://knowledgeconnection.mainehealth.org/lambrew-retreat-2023/1023/thumbnail.jp

KEAP1-modifying small molecule reveals muted NRF2 signaling responses in neural stem cells from Huntington's disease patients

The activity of the transcription factor nuclear factor-erythroid 2 p45-derived factor 2 (NRF2) is orchestrated and amplified through enhanced transcription of antioxidant and antiinflammatory target genes. The present study has characterized a triazole-containing inducer of NRF2 and elucidated the mechanism by which this molecule activates NRF2 signaling. In a highly selective manner, the compound covalently modifies a critical stress-sensor cysteine (C151) of the E3 ligase substrate adaptor protein Kelch-like ECH-associated protein 1 (KEAP1), the primary negative regulator of NRF2. We further used this inducer to probe the functional consequences of selective activation of NRF2 signaling in Huntington's disease (HD) mouse and human model systems. Surprisingly, we discovered a muted NRF2 activation response in human HD neural stem cells, which was restored by genetic correction of the disease-causing mutation. In contrast, selective activation of NRF2 signaling potently repressed the release of the proinflammatory cytokine IL-6 in primary mouse HD and WT microglia and astrocytes. Moreover, in primary monocytes from HD patients and healthy subjects, NRF2 induction repressed expression of the proinflammatory cytokines IL-1, IL-6, IL-8, and TNFα. Together, our results demonstrate a multifaceted protective potential of NRF2 signaling in key cell types relevant to HD pathology

Safety and Tolerability of SRX246, a Vasopressin 1a Antagonist, in Irritable Huntington\u27s Disease Patients-A Randomized Phase 2 Clinical Trial.

SRX246 is a vasopressin (AVP) 1a receptor antagonist that crosses the blood-brain barrier. It reduced impulsive aggression, fear, depression and anxiety in animal models, blocked the actions of intranasal AVP on aggression/fear circuits in an experimental medicine fMRI study and demonstrated excellent safety in Phase 1 multiple-ascending dose clinical trials. The present study was a 3-arm, multicenter, randomized, placebo-controlled, double-blind, 12-week, dose escalation study of SRX246 in early symptomatic Huntington\u27s disease (HD) patients with irritability. Our goal was to determine whether SRX246 was safe and well tolerated in these HD patients given its potential use for the treatment of problematic neuropsychiatric symptoms. Participants were randomized to receive placebo or to escalate to 120 mg twice daily or 160 mg twice daily doses of SRX246. Assessments included standard safety tests, the Unified Huntington\u27s Disease Rating Scale (UHDRS), and exploratory measures of problem behaviors. The groups had comparable demographics, features of HD and baseline irritability. Eighty-two out of 106 subjects randomized completed the trial on their assigned dose of drug. One-sided exact-method confidence interval tests were used to reject the null hypothesis of inferior tolerability or safety for each dose group vs. placebo. Apathy and suicidality were not affected by SRX246. Most adverse events in the active arms were considered unlikely to be related to SRX246. The compound was safe and well tolerated in HD patients and can be moved forward as a candidate to treat irritability and aggression

Spacework: Labor and culture in America\u27s astronaut corps, 1959–1979

Previous discussions of American astronauts as a labor force have emphasized the flamboyant cultural traits of the earliest members of this select group. Despite periods of celebrity, though, astronauts, like countless young military officers before them, have nearly always been organization men : middle class strivers expert in managing the demands of large institutions, not unlike other elite professionals of the late-20th century. Through reference to archival documents, oral history, published sources, and popular culture, this historical analysis examines the origins of this new American profession and follows it through several critical transitions, including the end of Project Apollo and the beginning of the Space Shuttle program. As celebrities in a growing government agency, astronauts of the 1960s balanced a determination to meet the expectations of their superiors with a desire to gain more control over their work and lives. Despite occasional professional and personal stumbles, their culture remained largely unchallenged for half-a-decade, as successive groups of astronauts accepted and reinforced the standards of conduct, professional outlook, and workplace dynamics of the earliest spacemen. The arrival of scientists into the astronaut corps in the late-1960s undermined the authority of NASA\u27s pilot-astronauts and signaled a fundamental shift in both national space policy and the space workplace. Having enjoyed unprecedented celebrity and authority in the 1960s but no longer in the spotlight, astronauts of the 1970s adjusted to a work culture that placed them more firmly under the control of NASA management and demanded new skills of negotiation and adjustment. Meanwhile, NASA increasingly sought to capitalize on the public fascination with space travel its astronauts had inspired

The PTB domain of ShcA couples receptor activation to the cytoskeletal regulator IQGAP1

Adaptor proteins respond to stimuli and recruit downstream complexes using interactions conferred by associated protein domains and linear motifs. The ShcA adaptor contains two phosphotyrosine recognition modules responsible for binding activated receptors, resulting in the subsequent recruitment of Grb2 and activation of Ras/MAPK. However, there is evidence that Grb2-independent signalling from ShcA has an important role in development. Using mass spectrometry, we identified the multidomain scaffold IQGAP1 as a ShcA-interacting protein. IQGAP1 and ShcA co-precipitate and are co-recruited to membrane ruffles induced by activated receptors of the ErbB family, and a reduction in ShcA protein levels inhibits the formation of lamellipodia. We used NMR to characterize a direct, non-canonical ShcA PTB domain interaction with a helical fragment from the IQGAP1 N-terminal region that is pTyr-independent. This interaction is mutually exclusive with binding to a more conventional PTB domain peptide ligand from PTP–PEST. ShcA-mediated recruitment of IQGAP1 may have an important role in cytoskeletal reorganization downstream of activated receptors at the cell surface

Single-Molecule Protein Unfolding and Translocation by an ATP-Fueled Proteolytic Machine

All cells employ ATP-powered proteases for protein-quality control and regulation. In the ClpXP protease, ClpX is a AAA+ machine that recognizes specific protein substrates, unfolds these molecules, and then translocates the denatured polypeptide through a central pore and into ClpP for degradation. Here, we use optical-trapping nanometry to probe the mechanics of enzymatic unfolding and translocation of single molecules of a multidomain substrate. Our experiments demonstrate the capacity of ClpXP and ClpX to perform mechanical work under load, reveal very fast and highly cooperative unfolding of individual substrate domains, suggest a translocation step size of 5–8 amino acids, and support a power-stroke model of denaturation in which successful enzyme-mediated unfolding of stable domains requires coincidence between mechanical pulling by the enzyme and a transient stochastic reduction in protein stability. We anticipate that single-molecule studies of the mechanical properties of other AAA+ proteolytic machines will reveal many shared features with ClpXP.National Science Foundation (U.S.) (Career Award 0643745)Howard Hughes Medical InstituteNational Institutes of Health (U.S.) (grant AI-82929)National Institutes of Health (U.S.) (grant AI-15706