Modeling Henry's law and phase separations of water-NaCl-organic mixtures with solvation and ion-pairing.

Empirical measurements of solution vapor pressure of ternary acetonitrile (MeCN) H2O-NaCl-MeCN mixtures were recorded, with NaCl concentrations ranging from zero to the saturation limit, and MeCN concentrations ranging from zero to an absolute mole fraction of 0.64. After accounting for speciation, the variability of the Henry's law coefficient at vapor-liquid equilibrium (VLE) of MeCN ternary mixtures decreased from 107% to 5.1%. Solute speciation was modeled using a mass action solution model that incorporates solute solvation and ion-pairing phenomena. Two empirically determined equilibrium constants corresponding to solute dissociation and ion pairing were utilized for each solute. When speciation effects were considered, the solid-liquid equilibrium of H2O-NaCl-MeCN mixtures appear to be governed by a simple saturation equilibrium constant that is consistent with the binary H2O-NaCl saturation coefficient. Further, our results indicate that the precipitation of NaCl in the MeCN ternary mixtures was not governed by changes in the dielectric constant. Our model indicates that the compositions of the salt-induced liquid-liquid equilibrium (LLE) boundary of the H2O-NaCl-MeCN mixture correspond to the binary plateau activity of MeCN, a range of concentrations over which the activity remains largely invariant in the binary water-MeCN system. Broader comparisons with other ternary miscible organic solvent (MOS) mixtures suggest that salt-induced liquid-liquid equilibrium exists if: (1) the solution displays a positive deviation from the ideal limits governed by Raoult's law; and (2) the minimum of the mixing free energy profile for the binary water-MOS system is organic-rich. This work is one of the first applications of speciation-based solution models to a ternary system, and the first that includes an organic solute.

Digital dashboards for direct oral anticoagulant surveillance, intervention and operational efficiency: uptake, obstacles, and opportunities.

Direct oral anticoagulants (DOAC) are the most widely prescribed oral anticoagulants in the United States. Despite advantages over warfarin, system-level improvements are needed to optimize outcomes. While Veterans Health Administration and others have described successful DOAC management dashboard implementation, the extent of use nationally is unknown. A survey of Anticoagulation Forum's members was conducted to assess access to digital tools available within a dashboard and to describe implementation models. An Expert Forum was subsequently convened to identify barriers to dashboard development and adoption. Responses were received from 340 targeted recipients (8.5% of invitees). Only a minority of inpatient (25/52, 48.1%) and outpatient (47/133, 35.3%) respondents outside of Veterans Health Administration were able to generate rosters of DOAC users on-demand, and fewer had the ability to digitally display key clinical data elements, identify drug-related problems, document interventions, or generate reports. The lack of regulatory requirements regarding Anticoagulation Stewardship was identified by the Expert Forum as the major barrier to widespread development of digital tools for improved anticoagulation management. While some health systems have demonstrated the feasibility of DOAC dashboards and described their impact on quality and efficiency, these tools do not appear to be widely available in the United States apart from Veterans Health Administration. The lack of regulatory requirements for Anticoagulation Stewardship may be the primary barrier to the development of digital resources to better manage anticoagulants. Efforts to secure regulatory requirements for Anticoagulation Stewardship are needed, and evidence of improvements in clinical and financial outcomes through DOAC dashboard use will likely bolster such efforts.

Digital dashboards for oral anticoagulation management: a literature scoping review.

This scoping review summarizes the extent and characteristics of the published literature describing digital population management dashboards implemented to improve the quality of anticoagulant management. A standardized search protocol was executed to identify relevant manuscripts published between January 1, 2015 and May 31, 2022. The resulting records were systematically evaluated by multiple blinded reviewers and the findings from selected papers were evaluated and summarized. Twelve manuscripts were identified, originating from 5 organizations within the US and 2 from other countries. The majority (75%) described implementation in the outpatient setting. The identified papers described a variety of positive results of dashboard use, including a 24.5% reduction of questionable direct oral anticoagulant dosing in one organization, a 33.3% relative improvement in no-show appointments in an ambulatory care clinic, and a 75% improvement in intervention efficiency. One medical center achieved a 98.4% risk-appropriate venous thromboembolism risk prophylaxis prescribing rate and 40.6% reduction in anticoagulation-related adverse event rates. The manuscripts primarily described retrospective findings from single-center dashboard implementation experiences. Digital dashboards have been successfully implemented to support the anticoagulation of acute and ambulatory patients and available manuscripts suggest a positive impact on care-related processes and relevant patient outcomes. Prospective studies are needed to better characterize the implementation and impact of dashboards for anticoagulation management. Published reports suggest that digital dashboards may improve the quality, safety, and efficiency of anticoagulation management. Additional research is needed to validate these findings and to understand how best to implement these tools.

Versatile microbial communities rapidly assimilate ammonium hydroxide-treated plastic waste.

Waste plastic presently accumulates in landfills or the environment. While natural microbial metabolisms can degrade plastic polymers, biodegradation of plastic is very slow. This study demonstrates that chemical deconstruction of polyethylene terephthalate (PET) with ammonium hydroxide can replace the rate limiting step (depolymerization) and by producing plastic-derived terephthalic acid and terephthalic acid monoamide. The deconstructed PET (DCPET) is neutralized with phosphoric acid prior to bioprocessing, resulting in a product containing biologically accessible nitrogen and phosphorus from the process reactants. Three microbial consortia obtained from compost and sediment degraded DCPET in ultrapure water and scavenged river water without addition of nutrients. No statistically significant difference was observed in growth rate compared to communities grown on DCPET in minimal culture medium. The consortia were dominated by Rhodococcus spp., Hydrogenophaga spp., and many lower abundance genera. All taxa were related to species known to degrade aromatic compounds. Microbial consortia are known to confer flexibility in processing diverse substrates. To highlight this, we also demonstrate that two microbial consortia can grow on similarly deconstructed polyesters, polyamides, and polyurethanes in water instead of medium. Our findings suggest that microbial communities may enable flexible bioprocessing of mixed plastic wastes when coupled with chemical deconstruction.

Pharmacist-led, checklist intervention did not improve adherence in ambulatory patients starting/resuming DOACs.

BACKGROUND: High adherence to direct-acting oral anticoagulant (DOAC) is critical to treat and prevent thromboembolic disease. The Anticoagulation Forum recently endorsed a checklist (DOAC checklist) that recommends care processes that may improve adherence. OBJECTIVES: This study aimed to determine whether checklist-driven care from a clinical pharmacist improves adherence in ambulatory patients starting a DOAC or resuming it after a setback. METHODS: This study included ambulatory patients starting a DOAC or resuming it after setback (thromboembolic event or bleeding) in an ambulatory setting. Settings included office, emergency department, and short-stay hospital visit. Following the DOAC checklist, a clinical pharmacist verified DOAC appropriateness, instructed dose de-escalation, educated through 3 tele-visits, fielded hotline calls, and handed off to a continuity provider after 3 months. Intervention and control patients received coupons and help with completing manufacturer-based medication assistance applications. Using pharmacy dispense records, our group measured medication possession ratio (MPR) at 90 days (primary outcome) and proportion of days covered (PDC) at 90 days and MPR and PDC at 180 and 365 days (secondary outcomes). Given skewing, our team analyzed adherence as < 80%, 80%-89%, and 90% or more and conducted ordered logistic regression. RESULTS: Of 561 patients randomized, 427 had sufficient records to analyze. Adherence was high with only 41 patients (9.6%) having MPR less than 80% at 90 days. There was no difference in adherence between intervention and control patients for primary outcome (odds ratio 0.94 [95% CI 0.60-1.49]) or secondary outcomes. CONCLUSION: Our checklist-driven intervention did not appreciably improve adherence beyond that seen in control patients treated with usual care (plus coupons and medication assistance we provided to all patients) in ambulatory patients starting or resuming DOACs, although it should be noted that high levels of adherence in both study groups were noted. Given high adherence, reassessing the DOAC checklist outside of a traditional trial may be more fruitful.

Non-Parametric Statistical Analysis of Current Waveforms through Power System Sensors.

The protection, control, and monitoring of the power grid is not possible without accurate measurement devices. As the percentage of renewable energy sources penetrating the existing grid infrastructure increases, so do uncertainties surrounding their effects on the everyday operation of the power system. Many of these devices are sources of high-frequency transients. These transients may be useful for identifying certain events or behaviors otherwise not seen in traditional analysis techniques. Therefore, the ability of sensors to accurately capture these phenomena is paramount. In this work, two commercial-grade power system distribution sensors are investigated in terms of their ability to replicate high-frequency phenomena by studying their responses to three events: a current inrush, a microgrid "close-in", and a fault on the terminals of a wind turbine. Kernel density estimation is used to derive the non-parametric probability density functions of these error distributions and their adequateness is quantified utilizing the commonly used root mean square error (RMSE) metric. It is demonstrated that both sensors exhibit characteristics in the high harmonic range that go against the assumption that measurement error is normally distributed.

Ultrasound guided paralaryngeal pressure versus cricoid pressure on the occlusion of esophagus: a crossover study.

The primary objective of this study is to compare the effectiveness of cricoid pressure (CP) and paralaryngeal pressure (PLP) on occlusion of eccentric esophagus in patients under general anesthesia (GA). Secondary objectives include the prevalence of patients with central or eccentric esophagus both before and after GA, and the success rate of CP in occluding centrally located esophagus in patients post GA. Fifty-one ASA physical status I and II patients, undergoing GA for elective surgery were enrolled in this study. Ultrasonography imaging were performed to determine the position of the esophagus relative to the trachea: (i) before induction of GA, (ii) after GA before external CP maneuver, (iii) after GA with CP, and (iv) after GA with PLP. CP was applied to all patients whilst PLP via fingertip technique was only applied to patients with an eccentric esophagus. Among a total of 51 patients, 28 of them (55%) had eccentric esophagus pre GA, while this number increase to 33 (65%) after induction of GA. CP success rate was 100% in 18 patients with central esophagus post GA versus 27% in 33 patients with eccentric esophagus post GA (P<0.00001). Overall success rate for CP was 53%. In 33 patients with eccentric esophagus anatomy post GA, PLP success rate was 30% compared with 27% with CP (P=1.000). Ultrasound guided PLP fingertips technique was not effective in patients with an eccentrically located esophagus post GA. Ultrasound guided CP achieved 100% success rate in patients with a centrally located esophagus post GA.

Bacterially expressed HIV-1 gp120 outer-domain fragment immunogens with improved stability and affinity for CD4-binding site neutralizing antibodies.

Protein minimization is an attractive approach for designing vaccines against rapidly evolving pathogens such as human immunodeficiency virus, type 1 (HIV-1), because it can help in focusing the immune response toward conserved conformational epitopes present on complex targets. The outer domain (OD) of HIV-1 gp120 contains epitopes for a large number of neutralizing antibodies and therefore is a primary target for structure-based vaccine design. We have previously designed a bacterially expressed outer-domain immunogen (ODEC) that bound CD4-binding site (CD4bs) ligands with 3-12 µm affinity and elicited a modest neutralizing antibody response in rabbits. In this study, we have optimized ODEC using consensus sequence design, cyclic permutation, and structure-guided mutations to generate a number of variants with improved yields, biophysical properties, stabilities, and affinities (KD of 10-50 nm) for various CD4bs targeting broadly neutralizing antibodies, including the germline-reverted version of the broadly neutralizing antibody VRC01. In contrast to ODEC, the optimized immunogens elicited high anti-gp120 titers in rabbits as early as 6 weeks post-immunization, before any gp120 boost was given. Following two gp120 boosts, sera collected at week 22 showed cross-clade neutralization of tier 1 HIV-1 viruses. Using a number of different prime/boost combinations, we have identified a cyclically permuted OD fragment as the best priming immunogen, and a trimeric, cyclically permuted gp120 as the most suitable boosting molecule among the tested immunogens. This study also provides insights into some of the biophysical correlates of improved immunogenicity.

Low-Voltage Flow-Through Electroporation in Gold-Microtube Membranes.

Electroporation is used to create pores within the membrane of living cells in order to deliver a substance, for example, a gene, into the cytoplasm. To achieve the high electric field gradients required to porate the membrane, current electroporation devices deliver voltage pulses in the kV range to the cell medium. We describe a new device based on gold-microtube membranes that can accomplish electroporation with voltage pulses that are orders of magnitude smaller, ≤5 V. This is possible because the voltage pulses are applied to the gold microtubes resulting in large electric field gradients down the length of the tubes. We used COMSOL simulations to calculate the electric field gradients, and these theoretical results were compared with known experimental values required to electroporate Escherichia coli. We developed two fluorescence-based methods to demonstrate successful electroporation of E. coli. The percentages of electroporated bacteria were found to be more than an order of magnitude higher than obtained with a commercial electroporator, although the voltage employed was 500 times lower. Furthermore, this microtube membrane device is flow through and is therefore capable of continuous, as opposed to batch-wise, electroporation and cell analysis. Cell throughput of >30 million cells per min, higher than any previously reported device, were obtained.

Service user led organisations in mental health today.

BACKGROUND: Since 1990, health policy in England has stressed the importance of user involvement in shaping and delivering services. AIMS: To explore mental health service user-led organisations (ULOs) in England, as they interact with decision-makers to bring about change desired by them with a focus on institutional norms behaviour and specialised knowledge impacting service users' relationships with services. METHOD: An ethnography of five ULOs in two provider organisations (NHS Trusts) including observing their meetings and interactions with decision-makers, conducting in-depth interviews and collecting reflective diaries kept by two members of each group. RESULTS: During the study, one group ceased to operate. This was a group which refused to adopt the institutional rules and norms of managerial discourse. The other four groups survived by navigating the changing environment which existed at the time of the study, although often at some cost. Themes of autonomy and leadership were also identified. CONCLUSION: The current environment is one of the organisational complexity and change and the place of ULOs is an ambiguous one as they strive to maintain autonomy whilst at the same time being an acceptable voice to managers.

Service user governors in mental health foundation trusts: accountability or business as usual?

CONTEXT: National Health Foundation Trusts present opportunities for individual mental health service users to be active in the governance of trusts. This is one of a range of mechanisms for patient and public involvement and one which promotes an individual rather than collective approach to involvement. OBJECTIVE: Within the context of a broader study of the impact of service user involvement in mental health services, the objective of this article was to explore the experience of service user governors in foundation trusts and their capacity to hold boards to account. DESIGN, SETTING AND PARTICIPANTS: The Council of Governors in three foundation trusts were observed for a year. Focus groups with service user governors were undertaken in each trust. RESULTS: Service users had different expectations and understandings of the role and approached it in different ways. Key themes that emerged concerned: the role of a governor, conduct and content of meetings, agenda setting, relationships and representation. DISCUSSION AND CONCLUSIONS: The experiences of mental health service user governors need to be understood within the complex environment of patient and public involvement in general and of mental health service user involvement in particular. The dislocation of the service user governor role from other forms of service user activity and involvement result in confusion about how notions of holding a trust to account and representation of other service users can be addressed within a boundaried institutional environment.

Identification of an HIV-1 clade A envelope that exhibits broad antigenicity and neutralization sensitivity and elicits antibodies targeting three distinct epitopes.

Broadly neutralizing antibodies (bNAbs) PG9 and PG16 were isolated from an International AIDS Vaccine Initiative (IAVI) Protocol G subject infected with human immunodeficiency virus type 1 (HIV-1) clade A. Both antibodies are highly potent and neutralize greater than 70% of viruses tested. We sought to begin immunogen design based on viral sequences from this patient; however, pseudoviruses prepared with 19 envelope sequences from this subject were resistant to neutralization by PG9 and PG16. Therefore, we used a bioinformatics approach to identify closely related viruses that were potentially sensitive to PG9 and PG16. A most-recent common ancestor (MRCA) sequence for the viral envelope (Env) was determined and aligned with 99 subtype A gp160 sequences from the Los Alamos HIV database. Virus BG505.W6M.ENV.C2 (BG505) was found to have the highest degree of homology (73%) to the MRCA sequence. Pseudoviruses prepared with this Env were sensitive to neutralization with a broad panel of bNAbs, including PG9 and PG16. When expressed by 293T cells as soluble gp120, the BG505 monomer bound well to both PG9 and PG16. We further showed that a point mutation (L111A) enabled more efficient production of a stable gp120 monomer that preserves the major neutralization epitopes. Finally, we showed that an adjuvanted formulation of this gp120 protein elicited neutralizing antibodies in rabbits (following a gp120 DNA vaccine prime) and that the antisera competed with bNAbs from 3 classes of nonoverlapping epitopes. Thus, the BG505 Env protein warrants further investigation as an HIV vaccine candidate, as a stand-alone protein, or as a component of a vaccine vector.

A highly efficient transgene knock-in technology in clinically relevant cell types.

Inefficient knock-in of transgene cargos limits the potential of cell-based medicines. In this study, we used a CRISPR nuclease that targets a site within an exon of an essential gene and designed a cargo template so that correct knock-in would retain essential gene function while also integrating the transgene(s) of interest. Cells with non-productive insertions and deletions would undergo negative selection. This technology, called SLEEK (SeLection by Essential-gene Exon Knock-in), achieved knock-in efficiencies of more than 90% in clinically relevant cell types without impacting long-term viability or expansion. SLEEK knock-in rates in T cells are more efficient than state-of-the-art TRAC knock-in with AAV6 and surpass more than 90% efficiency even with non-viral DNA cargos. As a clinical application, natural killer cells generated from induced pluripotent stem cells containing SLEEK knock-in of CD16 and mbIL-15 show substantially improved tumor killing and persistence in vivo.

Justice and lung cancer.

Lung cancer is the leading cause of cancer deaths, yet research funding is by far the lowest for lung cancer than for any other cancer compared with respective death rates. Although this discrepancy should appear alarming, one could argue that lung cancer deserves less attention because it is more attributable to poor life choices than other common cancers. Accordingly, the general question that I ask in this article is whether victims of more avoidable diseases, such as lung cancer, deserve to have their needs taken into less consideration than those of less avoidable diseases, on the grounds of either retributive or distributive justice. Such unequal treatment may be the "penalty" one incurs for negligent or reckless behavior. However, I hope to show that such unequal treatment cannot be supported by any coherent accounts of retributive or distributive justice.

From self-regulated learning to computer-delivered integrated speaking testing: Does monitoring always monitor?

Despite the salience of monitoring in self-regulated learning (SRL) and foreign and/or second language (L2) speech production in non-testing conditions, little is known about the metacognitive construct in testing contexts and its effects on learner performance. Given the reciprocal effects between L2 testing and L2 learning, a research effort in monitoring working in speaking tests, in particular computer-delivered integrated speaking tests, a testing format that has been advocated as an internal part of L2 classroom instruction and represents the future direction of L2 testing, is warranted. This study, therefore, serves as such an effort through investigating the use of monitoring by 95 Chinese English as foreign language (EFL) learners on a self-reported questionnaire after they performed three computer-delivered integrated speaking test tasks. Descriptive analysis followed by Hierarchical Linear Modelling (HLM) testing reveals that monitoring was used in a high-frequency manner, but it exerted no substantial effects on learner performance. Primarily, the results are expected to provide pedagogical implications for SRL: while fostering self-regulating learners, especially self-monitoring L2 speakers, it is necessary for L2 teachers to purposefully reduplicate testing conditions in their classroom instructions for helping the self-regulating learners be equally self-regulating test-takers. Moreover, the results are hoped to offer some insights into L2 testing through the perspective of self-monitoring, one proposed component of strategic competence, a construct that has been extensively acknowledged to reflect the essence of L2 testing.

Current and Future Climate Extremes Over Latin America and Caribbean: Assessing Earth System Models from High Resolution Model Intercomparison Project (HighResMIP).

Extreme temperature and precipitation events are the primary triggers of hazards, such as heat waves, droughts, floods, and landslides, with localized impacts. In this sense, the finer grids of Earth System models (ESMs) could play an essential role in better estimating extreme climate events. The performance of High Resolution Model Intercomparison Project (HighResMIP) models is evaluated using the Expert Team on Climate Change Detection and Indices (ETCCDI) over the 1981-2014 period and future changes (2021-2050) under Shared Socioeconomic Pathway SSP5-8.5, over ten regions in Latin America and the Caribbean. The impact of increasing the horizontal resolution in estimating extreme climate variability on a regional scale is first compared against reference gridded datasets, including reanalysis, satellite, and merging products. We used three different groups based on the resolution of the model's grid (sg): (i) low (0.8° ≤ sg ≤ 1.87°), (ii) intermediate (0.5° ≤ sg ≤ 0.7°), and (iii) high (0.23° ≥ sg ≤ 0.35°). Our analysis indicates that there was no clear evidence to support the posit that increasing horizontal resolution improves model performance. The ECMWF-IFS family of models appears to be a plausible choice to represent climate extremes, followed by the ensemble mean of HighResMIP in their intermediate resolution. For future climate, the projections indicate a consensus of temperature and precipitation climate extremes increase across most of the ten regions. Despite the uncertainties presented in this study, climate models have been and will continue to be an important tool for assessing risk in the face of extreme events. Supplementary Information: The online version contains supplementary material available at 10.1007/s41748-022-00337-7.

α-Crystallin B prevents apoptosis after H2O2 exposure in mouse neonatal cardiomyocytes.

α-Crystallin B (cryAB) is the most abundant small heat shock protein in cardiomyocytes (CMs) and has been shown to have potent antiapoptotic properties. Because the mechanism by which cryAB prevents apoptosis has not been fully characterized, we examined its protective effects at the cellular level by silencing cryAB in mouse neonatal CMs using lentivector-mediated transduction of short hairpin RNAs. Subcellular fractionation of whole hearts showed that cryAB is cytosolic under control conditions, and after H(2)O(2) exposure, it translocates to the mitochondria. Phosphorylated cryAB (PcryAB) is mainly associated with the mitochondria, and any residual cytosolic PcryAB translocates to the mitochondria after H(2)O(2) exposure. H(2)O(2) exposure caused increases in cryAB and PcryAB levels, and cryAB silencing resulted in increased levels of apoptosis after exposure to H(2)O(2). Coimmunoprecipitation assays revealed an apparent interaction of both cryAB and PcryAB with mitochondrial voltage-dependent anion channels (VDAC), translocase of outer mitochondrial membranes 20 kDa (TOM 20), caspase 3, and caspase 12 in mouse cardiac tissue. Our results are consistent with the conclusion that the cardioprotective effects of cryAB are mediated by its translocation from the cytosol to the mitochondria under conditions of oxidative stress and that cryAB interactions with VDAC, TOM 20, caspase 3, and caspase 12 may be part of its protective mechanism.

Enhanced control of pathogenic Simian immunodeficiency virus SIVmac239 replication in macaques immunized with an interleukin-12 plasmid and a DNA prime-viral vector boost vaccine regimen.

DNA priming has previously been shown to elicit augmented immune responses when administered by electroporation (EP) or codelivered with a plasmid encoding interleukin-12 (pIL-12). We hypothesized that the efficacy of a DNA prime and recombinant adenovirus 5 boost vaccination regimen (DNA/rAd5) would be improved when incorporating these vaccination strategies into the DNA priming phase, as determined by pathogenic simian immunodeficiency virus SIVmac239 challenge outcome. The whole SIVmac239 proteome was delivered in 5 separate DNA plasmids (pDNA-SIV) by EP with or without pIL-12, followed by boosting 4 months later with corresponding rAd5-SIV vaccine vectors. Remarkably, after repeated low-dose SIVmac239 mucosal challenge, we demonstrate 2.6 and 4.4 log reductions of the median SIV peak and set point viral loads in rhesus macaques (RMs) that received pDNA-SIV by EP with pIL-12 compared to the median peak and set point viral loads in mock-immunized controls (P < 0.01). In 5 out of 6 infected RMs, strong suppression of viremia was observed, with intermittent "blips" in virus replication. In 2 RMs, we could not detect the presence of SIV RNA in tissue and lymph nodes, even after 13 viral challenges. RMs immunized without pIL-12 demonstrated a typical maximum of 1.5 log reduction in virus load. There was no significant difference in the overall magnitude of SIV-specific antibodies or CD8 T-cell responses between groups; however, pDNA delivery by EP with pIL-12 induced a greater magnitude of SIV-specific CD4 T cells that produced multiple cytokines. This vaccine strategy is relevant for existing vaccine candidates entering clinical evaluation, and this model may provide insights into control of retrovirus replication.

Crystal structure of type I ryanodine receptor amino-terminal beta-trefoil domain reveals a disease-associated mutation "hot spot" loop.

Muscle contraction and relaxation is regulated by transient elevations of myoplasmic Ca(2+). Ca(2+) is released from stores in the lumen of the sarco(endo)plasmic reticulum (SER) to initiate formation of the Ca(2+) transient by activation of a class of Ca(2+) release channels referred to as ryanodine receptors (RyRs) and is pumped back into the SER lumen by Ca(2+)-ATPases (SERCAs) to terminate the Ca(2+) transient. Mutations in the type 1 ryanodine receptor gene, RYR1, are associated with 2 skeletal muscle disorders, malignant hyperthermia (MH), and central core disease (CCD). The evaluation of proposed mechanisms by which RyR1 mutations cause MH and CCD is hindered by the lack of high-resolution structural information. Here, we report the crystal structure of the N-terminal 210 residues of RyR1 (RyR(NTD)) at 2.5 A. The RyR(NTD) structure is similar to that of the suppressor domain of type 1 inositol 1,4,5-trisphosphate receptor (IP(3)Rsup), but lacks most of the long helix-turn-helix segment of the "arm" domain in IP(3)Rsup. The N-terminal beta-trefoil fold, found in both RyR and IP(3)R, is likely to play a critical role in regulatory mechanisms in this channel family. A disease-associated mutation "hot spot" loop was identified between strands 8 and 9 in a highly basic region of RyR1. Biophysical studies showed that 3 MH-associated mutations (C36R, R164C, and R178C) do not adversely affect the global stability or fold of RyR(NTD), supporting previously described mechanisms whereby mutations perturb protein-protein interactions.