Cryo-electron microscopy structures of the N501Y SARS-CoV-2 spike protein in complex with ACE2 and 2 potent neutralizing antibodies.

The recently reported "UK variant" (B.1.1.7) of SARS-CoV-2 is thought to be more infectious than previously circulating strains as a result of several changes, including the N501Y mutation. We present a 2.9-Å resolution cryo-electron microscopy (cryo-EM) structure of the complex between the ACE2 receptor and N501Y spike protein ectodomains that shows Y501 inserted into a cavity at the binding interface near Y41 of ACE2. This additional interaction provides a structural explanation for the increased ACE2 affinity of the N501Y mutant, and likely contributes to its increased infectivity. However, this mutation does not result in large structural changes, enabling important neutralization epitopes to be retained in the spike receptor binding domain. We confirmed this through biophysical assays and by determining cryo-EM structures of spike protein ectodomains bound to 2 representative potent neutralizing antibody fragments.

Analgesic Effectiveness of Motor-sparing Nerve Blocks for Total Knee Arthroplasty: A Network Meta-analysis.

BACKGROUND: The analgesic effectiveness of contemporary motor-sparing nerve blocks used in combination for analgesia in total knee arthroplasty is unclear. This network meta-analysis was conducted to evaluate the analgesic effectiveness of adding single-injection or continuous adductor canal block (ACB) with or without infiltration of the interspace between the popliteal artery and the capsule of the posterior knee (iPACK) to intraoperative local infiltration analgesia (LIA), compared to LIA alone, after total knee arthroplasty. METHODS: Randomized trials examining the addition of single-injection or continuous ACB with or without single-injection block at the iPACK to LIA for total knee arthroplasty were considered. The two primary outcomes were area-under-the-curve pain scores over 24 to 48 h and postoperative function at greater than 24 h. Secondary outcomes included rest pain scores at 0, 6, 12, and 24 h; opioid consumption (from 0 to 24 h and from 25 to 48 h); and incidence of nausea/vomiting. Network meta-analysis was conducted using a frequentist approach. RESULTS: A total of 27 studies (2,317 patients) investigating the addition of (1) single-injection ACB, (2) continuous ACB, (3) single-injection ACB and single-injection block at the iPACK, and (4) continuous ACB and single-injection block at the iPACK to LIA, as compared to LIA alone, were included. For area-under-the-curve 24- to 48-h pain, the addition of continuous ACB with single-injection block at the iPACK displayed the highest P-score probability (89%) of being most effective for pain control. The addition of continuous ACB without single-injection block at the iPACK displayed the highest P-score probability (87%) of being most effective for postoperative function. CONCLUSIONS: The results suggest that continuous ACB, but not single-injection ACB and/or single-injection block at the iPACK, provides statistically superior analgesia when added to LIA for total knee arthroplasty compared to LIA alone. However, the magnitude of these additional analgesic benefits is clinically questionable.

Incidence and Predictors of Inadvertent Dural Puncture After Percutaneous Spinal Cord Stimulation: A Retrospective Database Analysis.

OBJECTIVES: Inadvertent dural puncture (IDP) is a known complication associated with traditional neuraxial procedures; however, its characterization after percutaneous spinal cord stimulation (SCS) lead placement has yet to be clearly established in large population studies. This retrospective analysis aims to understand the incidence and associated characteristics of patients with IDP after percutaneous SCS lead placement. MATERIALS AND METHODS: The PearlDiver Mariner database of national all-payer claims was used to identify patients who received percutaneous SCS leads and had a claim for IDP (intraoperative IDP or postdural puncture headache [PDPH] claim) within 45 days. The primary outcome was to determine the overall incidence of IDP. Secondary outcomes included an evaluation of associated risk factors for IDP and treatments used in symptomatic management. RESULTS: A total of 90,952 patients who underwent percutaneous lead SCS placement were included. The incidence of IDP was 0.48% (436/90,952 patients). Older age (odds ratio [OR]: 0.96; 95% CI: 0.95-0.97; p < 0.0001) and male sex (OR: 0.66; 95% CI: 0.53-0.81; p < 0.001) had a lower odds of having a claim for IDP, whereas a history of IDP was associated with a higher OR (95% CI) by 13.72 times (10.72-17.58) (p < 0.0001). Of the IDP patients, 64% (277/436 patients) had a claim for a therapeutic blood patch. Discrepancy in type of claim for IDP was observed, with most being for PDPH. CONCLUSIONS: Our findings suggest that IDP after percutaneous SCS lead placement is an uncommon event; however, certain factors are associated with its development. Overall, early recognition of IDP after percutaneous SCS lead placement is imperative to facilitate the delivery of targeted treatments and prevent further harmful consequences to the patient.

The Leadership Stories Our Youth Are Told: Characterizations of Leadership Behaviors and Orientations in Popular Youth TV Shows.

Given the consistently high viewership of television (TV) by youth, the social, behavioral, developmental, and psychological impact of such viewing has been studied for decades. Yet, little research has focused on the connections between youth, the TV shows to which they are exposed, and the characterizations of leadership presented to them. This study examines the type of leadership behaviors and orientations presented through youth TV shows in the United States across a continuum of viewership age targets. Shows were selected through purposeful sampling from the most popular youth TV shows in the United States, and episodes were chosen based on synopsis, selecting for the greatest possibility of leadership scenarios. Researchers identified three shows for each viewer target age group and five episodes for each TV show, for a total of 75 episodes. The findings include the discovery that show-prescribed viewer target age group positively predicted leadership behavior such as direction-setting-i.e., gathering information, organizing information, sense-making, and forecasting. Additionally, as viewer target age range increased, shows presented with a decrease in communal leadership-characterized as caring, warm, trustworthy, empathetic, helpful, and/or friendly. Such findings suggest that the representations of leadership depicted in popular youth TV shows are transmitting potentially counterproductive messages to future leaders, deprioritizing crucial leadership elements.

Epidural anesthesia for post-operative pain is associated with a higher incidence of complications following open ventral hernia repair.

INTRODUCTION: Ventral/incisional hernia repair is a common procedure. Epidural anesthesia for post-operative pain control has been used to attempt to limit opioids. The complications associated with epidural anesthesia are starting to be recognized in open ventral hernia repair patients. METHODS: Data were abstracted from the National Surgical Quality Improvement Program (NSQIP) participant use data file for 2015. Adult patients with an open ventral hernia repair were identified. In an effort to identify complex hernias, patients who required the implantation of mesh and remained inpatient for 2 or more days were included. Patients with epidural anesthesia and general anesthesia (epidural group) were compared to those with general anesthesia alone (non-epidural). Descriptive statistics and complications were recorded and compared. RESULTS: A total of 1943 patients met inclusion criteria: 1009 patients (51.9%) in the non-epidural group and 934 (48.1%) in the epidural group. There were fewer clean cases in the epidural group (63.2%) than the non-epidural group (68.8%, p = 0.007). Otherwise, there was no difference in gender, age, body mass index, American Society of Anesthesiologists physical status, and current smoking status. There were more pulmonary emboli in the epidural group (1.39%) compared to the non-epidural group (0.50%, p = 0.04). Urinary tract infection was also significantly higher in the epidural group (3.10%) compared to the non-epidural group (1.59%, p = 0.03). Transfusions were also administered to more of the epidural patients (5.14%) compared to non-epidural patients (2.78%, p = 0.007). The rates of other post-operative complications were not statistically significant between the two groups. Total length of stay in the hospital was also greater in the epidural group (6.7 vs. 5.0 days, p < 0.0001). CONCLUSIONS: This is an association with the use of epidural anesthesia in open ventral hernia repairs and an increased incidence of pulmonary emboli, transfusions, and urinary tract infections, as well as an increased length of stay.

Sex Differences in Airway Remodeling in a Mouse Model of Chronic Obstructive Pulmonary Disease.

RATIONALE: After adjustment for the amount of smoking, women have a 50% increased risk of chronic obstructive pulmonary disease (COPD) compared with men. The anatomic basis and/or mechanism(s) of these sex-related differences in COPD are unknown. OBJECTIVES: To characterize the impact of female sex hormones on chronic cigarette smoke-induced airway remodeling and emphysema in a mouse model of COPD. METHODS: Airway remodeling and emphysema were determined morphometrically in male, female, and ovariectomized mice exposed to 6 months of cigarette smoke. Antioxidant- and transforming growth factor (TGF)-ß-related genes were profiled in airway tissues. The selective estrogen receptor modulator tamoxifen was also administered during smoke exposure in a short-term model. Airway wall thickness of male and female human smokers at risk of or with mild COPD was measured using optical coherence tomography. MEASUREMENTS AND MAIN RESULTS: Small airway wall remodeling was increased in female but not male or ovariectomized mice and was associated with increased distal airway resistance, down-regulation of antioxidant genes, increased oxidative stress, and activation of TGF-ß1. These effects were prevented by ovariectomy. Use of tamoxifen as a therapeutic intervention mitigated smoke-induced increase in oxidative stress in female mice. Compared with male human smokers, female human smokers had significantly thicker airway walls. CONCLUSIONS: The excess risk of small airway disease in female mice after chronic smoke exposure was associated with increased oxidative stress and TGF-ß1 signaling and also was related to the effects of female sex hormones. Estrogen receptor antagonism might be of value in reducing oxidative stress in female smokers.

Fibroblast signal transducer and activator of transcription 4 drives cigarette smoke-induced airway fibrosis.

Cigarette smoke-induced emphysema and small airway remodeling are the anatomic bases of chronic obstructive pulmonary disease (COPD), but the pathogenesis of these changes is unclear, and current treatments for COPD are minimally effective. To evaluate the role of signal transducer and activator of transcription (STAT)-4 in cigarette smoke-induced small airway remodeling, we used C57BL/6J (wild type [WT]) and STAT4-/- mice exposed to air or cigarette smoke for 6 months and isolated airway and parenchymal fibroblasts. We also compared the results with those obtained with human fibroblasts. We found that STAT4-/- mice were protected against smoke-induced small airway remodeling but not emphysema. STAT4 is abundantly expressed in airway compared with parenchymal-derived fibroblasts isolated from normal human and murine lung. WT airway fibroblasts proliferate faster than STAT4-/- airway fibroblasts, whereas there is no difference between strains for parenchymal fibroblasts. IL-12 is up-regulated in the lung after smoke exposure, and IL-12 receptor B2 is expressed on airway and parenchymal fibroblasts in mouse and human lung. Treatment with IL-12 causes phosphorylation of STAT4 in WT airway fibroblasts. Exposure of WT airway, but not parenchymal, fibroblasts to IL-12 causes increased expression of collagen 1α1 and transforming growth factor ß1, factors involved in small airway remodeling, whereas STAT4-/- fibroblasts are unresponsive to IL-12. These results indicate that IL-12 can drive small airway remodeling via STAT4 signaling and suggest that treatment with clinically available anti-IL-12p40 drugs might provide a new approach to preventing small airway remodeling in cigarette smokers.

Investigating the accuracy of machine vision and augmented reality in percutaneous computed tomography-guided interventions: A phantom study.

OBJECTIVES: This study aimed to evaluate the accuracy of percutaneous computed tomography (CT)-guided puncture based on machine vision and augmented reality in a phantom. MATERIALS AND METHODS: The surgical space coordinate system was established, and accurate registration was ensured using the hierarchical optimization framework. Machine vision tracking and augmented reality display technologies were used for puncture navigation. CT was performed on a phantom, and puncture paths with three different lengths were planned from the surface of the phantom to the metal ball. Puncture accuracy was evaluated by measuring the target positioning error (TPE), lateral error (LE), angular error (AE), and first success rate (FSR) based on the obtained CT images. RESULTS: A highly qualified attending interventional physician performed a total of 30 punctures using puncture navigation. For the short distance (4.5-5.5 cm), the TPE, LE, AE, and FSR were 1.90 ± 0.62 mm, 1.23 ± 0.70 mm, 1.39 ± 0.86°, and 60%, respectively. For the medium distance (9.5-10.5 cm), the TPE, LE, AE, and FSR were 2.35 ± 0.95 mm, 2.00 ± 1.07 mm, 1.20 ± 0.62°, and 40%, respectively. For the long distance (14.5-15.5 cm), the TPE, LE, AE, and FSR were 2.81 ± 1.17 mm, 2.33 ± 1.34 mm, 0.99 ± 0.55°, and 30%, respectively. CONCLUSION: The augmented reality and machine vision-based CT-guided puncture navigation system allows for precise punctures in a phantom. Further studies are needed to explore its clinical applicability.

Late intervention with a myeloperoxidase inhibitor stops progression of experimental chronic obstructive pulmonary disease.

RATIONALE: Inflammation and oxidative stress are linked to the deleterious effects of cigarette smoke in producing chronic obstructive pulmonary disease (COPD). Myeloperoxidase (MPO), a neutrophil and macrophage product, is important in bacterial killing, but also drives inflammatory reactions and tissue oxidation. OBJECTIVES: To determine the role of MPO in COPD. METHODS: We treated guinea pigs with a 2-thioxanthine MPO inhibitor, AZ1, in a 6-month cigarette smoke exposure model, with one group receiving compound from Smoking Day 1 and another group treated after 3 months of smoke exposure. RESULTS: At 6 months both treatments abolished smoke-induced increases in lavage inflammatory cells, largely ameliorated physiological changes, and prevented or stopped progression of morphologic emphysema and small airway remodeling. Cigarette smoke caused a marked increase in immunohistochemical staining for the myeloperoxidase-generated protein oxidation marker dityrosine, and this effect was considerably decreased with both treatment arms. Serum 8-isoprostane, another marker of oxidative stress, showed similar trends. Both treatments also prevented muscularization of the small intrapulmonary arteries, but only partially ameliorated smoke-induced pulmonary hypertension. Acutely, AZ1 prevented smoke-induced increases in expression of cytokine mediators and nuclear factor-κB binding. CONCLUSIONS: We conclude that an MPO inhibitor is able to stop progression of emphysema and small airway remodeling and to partially protect against pulmonary hypertension, even when treatment starts relatively late in the course of long-term smoke exposure, suggesting that inhibition of MPO may be a novel and useful therapeutic treatment for COPD. Protection appears to relate to inhibition of oxidative damage and down-regulation of the smoke-induced inflammatory response.

A Case Report of Iliopsoas Abscess Secondary to Small Bowel Fistula.

Iliopsoas abscesses (IPAs) are rare infections in the musculature that can be difficult to diagnose due to nonspecific presentations. These abscesses are most commonly caused by either the hematogenous spread of a separate infectious source in the body or secondary to Crohn's disease and are typically treated with antibiotic therapy and percutaneous drainage. For cases complicated by bowel disease, multiloculated psoas abscess, or gas-forming organisms, surgical drainage may be indicated. We present the case of an 81-year-old female with a history of colon cancer status post-cecum resection who presented with back pain, thigh pain, and constipation. Computerized tomography imaging showed concurrent small bowel obstruction and a right IPA extending down to the right thigh. Laparoscopic exploration revealed a small bowel fistulization to the right iliopsoas as the source of infection. Resection of the small bowel and surgical incision and drainage of the abscess were necessary for her treatment. The patient was discharged with vacuum-assisted closure of her wound after a hospital course complicated with chronic diarrhea. Bowel fistulization should be considered a potential cause of IPAs in patients with a complicated gastrointestinal history.

Analgesic benefits of single-shot versus continuous adductor canal block for total knee arthroplasty: a systemic review and meta-analysis of randomized trials.

BACKGROUND: Adductor canal block (ACB) can provide important analgesic benefits following total knee arthroplasty (TKA), however, the extent to which these benefits can be enhanced or prolonged by a continuous catheter-based infusion compared with a single-shot injection of local anesthetic is unclear. OBJECTIVES: This systematic review and meta-analysis (PROSPERO: CRD42021292738) review sought to compare the analgesic effectiveness of single shot to continuous ACB following TKA. EVIDENCE REVIEW: We sought randomized trials from the US National Library of Medicine database (MEDLINE), Excerpta Medica database (EMBASE), and Cochrane Database of Systematic Reviews from inception to November 1, 2021, that compared single-shot to continuous ACB in adult patients undergoing TKA. The primary outcomes were (1) area under the curve (AUC) pain severity at rest and (2) cumulative opioid (oral morphine equivalent) consumption during the first 48 hours postoperatively. Secondary outcomes included postoperative pain severity scores up to 48 hours, cumulative opioid consumption at 24 hours, functional recovery, opioid-related side effects, and block-related complications. Risk of bias of included studies was assessed using the Cochrane risk of bias tool. Statistical pooling was conducted using the Hartung-Knapp-Sidik-Jonkman method for random effects. No funding was obtained for this review. FINDINGS: Eleven trials (1185 patients) were included. No differences were observed in rest pain severity (AUC) or cumulative opioid consumption up to 48 hours postoperatively. In addition, no differences were observed in individual postoperative rest pain scores in the recovery room and at 12 and 24 hours, or in cumulative opioid consumption at 24 hours, functional recovery, and opioid-related side effects. Finally, fewer block-related complications were observed with single-shot ACB, with an OR (95% CI) of 0.24 (0.14 to 0.41) (p=0.002). CONCLUSIONS: Our results suggest that continuous catheter-based ACB does not enhance or prolong the analgesic benefits when compared with single-shot ACB for TKA over the first 48 hours postoperatively. Overall, the results of our meta-analysis do not support the routine use of continuous ACB for postoperative analgesia after TKA.

Statin reverses smoke-induced pulmonary hypertension and prevents emphysema but not airway remodeling.

RATIONALE: the potential role of statins in treating chronic obstructive pulmonary disease (COPD) is controversial, and it is unclear what anatomic COPD lesions statins affect. OBJECTIVES: to determine whether an intervention of simvastatin could alter cigarette smoke-induced pulmonary hypertension. METHODS: we exposed guinea pigs to cigarette smoke for 6 months. In half the animals, simvastatin therapy was initiated after 3 months of smoke exposure. Pulmonary arterial systolic pressures were monitored weekly with a radiotelemetric catheter; additional physiologic and morphologic measurements were made at sacrifice after 6 months. Precision-cut lung explants were assessed for evidence of endothelial dysfunction, and in situ vascular nitric oxide generation was measured with 4,5-diaminofluorescein diacetate. MEASUREMENTS AND MAIN RESULTS: cigarette smoke increased the pulmonary arterial systolic pressure after approximately 4 weeks. Simvastatin returned the pressure to control levels within 4 weeks of starting treatment, and ameliorated smoke-induced small arterial remodeling as well as emphysema measured both physiologically and morphometrically at 6 months, but did not prevent smoke-induced small airway remodeling either physiologically or morphologically. In precision-cut lung slices simvastatin reversed small arterial endothelial dysfunction, and partially reversed smoke-induced loss of vascular nitric oxide generation. CONCLUSIONS: simvastatin, as an intervention therapy, reverses the pulmonary vascular effects of cigarette smoke, including pulmonary hypertension, and prevents smoke-induced emphysema, but does not prevent small airway remodeling. This is the first demonstration that an intervention can reverse a COPD-associated cigarette smoke-induced anatomic abnormality. The study also shows the importance of examining all three anatomic lung compartments when assessing the effects of a potential drug intervention in patients with COPD.

Examining Multiteam Systems Across Context and Type: A Historiometric Analysis of Failed MTS Performance.

Multiteam systems (MTSs) are complex organizational forms comprising interdependent teams that work towards their own proximal goals within and across teams to also accomplish a shared superordinate goal. MTSs operate within high-stakes, dangerous contexts with high consequences for suboptimal performance. We answer calls for nuanced exploration and cross-context comparison of MTSs "in the wild" by leveraging the MTS action sub-phase behavioral taxonomy to determine where and how MTS failures occur. To our knowledge, this is the first study to also examine how key MTS attributes (boundary status, goal type) influence MTS processes and performance. We conducted historiometric analysis on 40 cases of failed MTS performance across various contexts (e.g., emergency response, commercial transportation, military, and business) to uncover patterns of within- and between-team behaviors of failing MTSs, resulting in four themes. First, component teams of failing MTSs over-engaged in within-team alignment behaviors (vs. between-team behaviors) by enacting acting, monitoring, and recalibrating behaviors more often within than between teams. Second, failing MTSs over-focused on acting behaviors (vs. monitoring or recalibrating) and tended to not fully enact the action sub-phase cycle. Third and fourth, boundary status and goal type exacerbated these behavioral patterns, as external and physical MTSs were less likely to enact sufficient between-team behaviors or fully enact the action sub-phase cycle compared to internal and intellectual MTSs. We propose entrainment as a mechanism for facilitating MTS performance wherein specific, cyclical behavioral patterns enacted by teams align to facilitate goal achievement via three multilevel behavioral cycles (i.e., acting-focused, alignment-focused, and adjustment-focused). We argue that the degree to which these cycles are aligned both between teams and with the overarching MTS goal determines whether and how an MTS fails. Our findings add nuance beyond single-context MTS studies by showing that the identified behavioral patterns hold both across contexts and almost all types of MTS action-phase behaviors. We show that these patterns vary by MTS boundary status and goal type. Our findings inform MTS training best practices, which should be structured to integrate all component teams and tailored to both MTS attributes (i.e., boundary status, goal type) and situation type (e.g., contingency planning).

Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants.

The Delta and Kappa variants of SARS-CoV-2 co-emerged in India in late 2020, with the Delta variant underlying the resurgence of COVID-19, even in countries with high vaccination rates. In this study, we assess structural and biochemical aspects of viral fitness for these two variants using cryo-electron microscopy (cryo-EM), ACE2-binding and antibody neutralization analyses. Both variants demonstrate escape of antibodies targeting the N-terminal domain, an important immune hotspot for neutralizing epitopes. Compared to wild-type and Kappa lineages, Delta variant spike proteins show modest increase in ACE2 affinity, likely due to enhanced electrostatic complementarity at the RBD-ACE2 interface, which we characterize by cryo-EM. Unexpectedly, Kappa variant spike trimers form a structural head-to-head dimer-of-trimers assembly, which we demonstrate is a result of the E484Q mutation and with unknown biological implications. The combination of increased antibody escape and enhanced ACE2 binding provides an explanation, in part, for the rapid global dominance of the Delta variant.

SARS-CoV-2 variants of concern: spike protein mutational analysis and epitope for broad neutralization.

Mutations in the spike glycoproteins of SARS-CoV-2 variants of concern have independently been shown to enhance aspects of spike protein fitness. Here, we describe an antibody fragment (VH ab6) that neutralizes all major variants including the recently emerged BA.1 and BA.2 Omicron subvariants, with a unique mode of binding revealed by cryo-EM studies. Further, we provide a comparative analysis of the mutational effects within previously emerged variant spikes and identify the structural role of mutations within the NTD and RBD in evading antibody neutralization. Our analysis shows that the highly mutated Gamma N-terminal domain exhibits considerable structural rearrangements, partially explaining its decreased neutralization by convalescent sera. Our results provide mechanistic insights into the structural, functional, and antigenic consequences of SARS-CoV-2 spike mutations and highlight a spike protein vulnerability that may be exploited to achieve broad protection against circulating variants.

Detail Preserving Coarse-to-Fine Matching for Stereo Matching and Optical Flow.

The Coarse-To-Fine (CTF) matching scheme has been widely applied to reduce computational complexity and matching ambiguity in stereo matching and optical flow tasks by converting image pairs into multi-scale representations and performing matching from coarse to fine levels. Despite its efficiency, it suffers from several weaknesses, such as tending to blur the edges and miss small structures like thin bars and holes. We find that the pixels of small structures and edges are often assigned with wrong disparity/flow in the upsampling process of the CTF framework, introducing errors to the fine levels and leading to such weaknesses. We observe that these wrong disparity/flow values can be avoided if we select the best-matched value among their neighborhood, which inspires us to propose a novel differentiable Neighbor-Search Upsampling (NSU) module. The NSU module first estimates the matching scores and then selects the best-matched disparity/flow for each pixel from its neighbors. It effectively preserves finer structure details by exploiting the information from the finer level while upsampling the disparity/flow. The proposed module can be a drop-in replacement of the naive upsampling in the CTF matching framework and allows the neural networks to be trained end-to-end. By integrating the proposed NSU module into a baseline CTF matching network, we design our Detail Preserving Coarse-To-Fine (DPCTF) matching network. Comprehensive experiments demonstrate that our DPCTF can boost performances for both stereo matching and optical flow tasks. Notably, our DPCTF achieves new state-of-the-art performances for both tasks - it outperforms the competitive baseline (Bi3D) by 28.8% (from 0.73 to 0.52) on EPE of the FlyingThings3D stereo dataset, and ranks first in KITTI flow 2012 benchmark. The code is available at https://github.com/Deng-Y/DPCTF.

Peripheral Nerve Stimulation for Treatment of Headaches: An Evidence-Based Review.

Headaches are one of the most common medical complaints worldwide, and treatment is often made difficult because of misclassification. Peripheral nerve stimulation has emerged as a novel treatment for the treatment of intractable headaches in recent years. While high-quality evidence does exist regarding its use, efficacy is generally limited to specific nerves and headache types. While much research remains to bring this technology to the mainstream, clinicians are increasingly able to provide safe yet efficacious pain control.

Lipid-mimicking phosphorus-based glycosidase inactivators as pharmacological chaperones for the treatment of Gaucher's disease.

Gaucher's disease, the most prevalent lysosomal storage disorder, is caused by missense mutation of the GBA gene, ultimately resulting in deficient GCase activity, hence the excessive build-up of cellular glucosylceramide. Among different therapeutic strategies, pharmacological chaperoning of mutant GCase represents an attractive approach that relies on small organic molecules acting as protein stabilizers. Herein, we expand upon a new class of transient GCase inactivators based on a reactive 2-deoxy-2-fluoro-ß-d-glucoside tethered to an array of lipid-mimicking phosphorus-based aglycones, which not only improve the selectivity and inactivation efficiency, but also the stability of these compounds in aqueous media. This hypothesis was further validated with kinetic and cellular studies confirming restoration of catalytic activity in Gaucher cells after treatment with these pharmacological chaperones.

Structural analysis of receptor binding domain mutations in SARS-CoV-2 variants of concern that modulate ACE2 and antibody binding.

The recently emerged severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Beta (B.1.351) and Gamma (P.1) variants of concern (VoCs) include a key mutation (N501Y) found in the Alpha (B.1.1.7) variant that enhances affinity of the spike protein for its receptor, angiotensin-converting enzyme 2 (ACE2). Additional mutations are found in these variants at residues 417 and 484 that appear to promote antibody evasion. In contrast, the Epsilon variants (B.1.427/429) lack the N501Y mutation yet exhibit antibody evasion. We have engineered spike proteins to express these receptor binding domain (RBD) VoC mutations either in isolation or in different combinations and analyze the effects using biochemical assays and cryoelectron microscopy (cryo-EM) structural analyses. Overall, our findings suggest that the emergence of new SARS-CoV-2 variant spikes can be rationalized as the result of mutations that confer increased ACE2 affinity, increased antibody evasion, or both, providing a framework to dissect the molecular factors that drive VoC evolution.

Expression of profibrotic mediators in small airways versus parenchyma after cigarette smoke exposure.

Cigarette smoke-induced lung disease presents a morphologic contradiction in that the small airways become fibrotic but the parenchyma becomes emphysematous over time. To examine the mechanisms behind these phenomena, we exposed mice to cigarette smoke for up to 6 months and isolated small airways from histologic sections by laser capture microdissection. We then removed residual airway tissue and vessels, and collected the remaining parenchymal tissue. Gene expression of 13 fibrogenic growth/signaling factors (particularly TGF-beta-related genes), matrix proteins, or enzymes involved in matrix production was examined by real-time RT-PCR. Combining present and previously published data from our laboratory, in the airways over the long term there was a sustained and marked increase in expression of almost all of these genes. By contrast, in the parenchyma, expression of most genes was elevated at 2 and 24 hours after initial exposure, and all were elevated at 1 month; but by 6 months, when emphysema was present, most genes (9/13) were either at control values or down-regulated below control. At 3 months, several genes that were considerably elevated at 1 month were back to control levels, suggesting that loss of the parenchymal response precedes the development of emphysema. We conclude that with smoke exposure the airways demonstrate an ongoing profibrotic/proelastogenic response and the parenchyma a generally anti-fibrotic/anti-elastogenic response, but one that develops only with long-term exposure to smoke. These observations support the idea that the parenchyma largely fails to repair smoke-induced matrix damage, but this phenomenon is a relatively late event.