The importance of incorporating ventricular-ventricular interaction (VVI) in the study of pulmonary hypertension.

Ventricular ventricular interaction (VVI) affects blood volume and pressure in the right and left ventricles of the heart due to the location and balance of forces on the septal wall separating the ventricles. In healthy patients, the pressure of the left ventricle is considerably higher than the right, resulting in a septal wall that bows into the right ventricle. However, in patients with pulmonary hypertension, the pressure in the right ventricle increases significantly to a point where the pressure is similar to or surpasses that of the left ventricle during portions of the cardiac cycle. For these patients, the septal wall deviates towards the left ventricle, impacting its function. It is possible to study this effect using mathematical modeling, but existing models are nonlinear, leading to a system of algebraic differential equations that can be challenging to solve in patient-specific optimizations of clinical data. This study demonstrates that a simplified linearized model is sufficient to account for the effect of VVI and that, as expected, the impact is significantly more pronounced in patients with pulmonary hypertension.

Integrated modeling and simulation of recruitment of myocardial perfusion and oxygen delivery in exercise.

While exercise-mediated vasoregulation in the myocardium is understood to be governed by autonomic, myogenic, and metabolic-mediated mechanisms, we do not yet understand the spatial heterogeneity of vasodilation or its effects on microvascular flow patterns and oxygen delivery. This study uses a simulation and modeling approach to explore the mechanisms underlying the recruitment of myocardial perfusion and oxygen delivery in exercise. The simulation approach integrates model components representing: whole-body cardiovascular hemodynamics, cardiac mechanics and myocardial work; myocardial perfusion; and myocardial oxygen transport. Integrating these systems together, model simulations reveal: (1.) To match expected flow and transmural flow ratios at increasing levels of exercise, a greater degree of vasodilation must occur in the subendocardium compared to the subepicardium. (2.) Oxygen extraction and venous oxygenation are predicted to substantially decrease with increasing exercise level preferentially in the subendocardium, suggesting that an oxygen-dependent error signal driving metabolic mediated recruitment of flow would be operative only in the subendocardium. (3.) Under baseline physiological conditions approximately 4% of the oxygen delivered to the subendocardium may be supplied via retrograde flow from coronary veins.

Better flexion and early recovery with medial-stabilized vs single-radius total knee arthroplasty with kinematic alignment: Two-year clinical results.

BACKGROUND: There are few studies comparing outcomes in patients with posterior cruciate ligament-sacrificing single-radius (SR) versus medial-stabilized (MS) knee devices. Both types of implants are designed to maximize deep-flexion and to maintain stability throughout the knee flexion arc. The aim of this study was to determine whether two-year outcomes differ between these two implant groups. METHODS: Two-hundred and ten patients took part in this retrospective cohort single center study. The SR patients (n = 109) were enrolled in one randomized trial, and the MS knees (n = 101) in another. Patient consent and Investigative Review Board approval was obtained. Radiographs and clinical outcomes were gathered preoperatively and at six weeks, six months, one year and two years. RESULTS: There were no statistically significant differences between treatment groups in terms of preoperative demographic characteristics. The MS group had significantly better knee flexion starting at six months postoperative through two years postoperatively (p < 0.05 - p< 0.001). The Knee Society Pain/Motion score was better in the MS group at one year (95.41 vs 90.86, p < 0.002). The Knee Society Pain score was also better in the MS group starting at six weeks through one year (six weeks: 35.3 vs 30, p = 0.007; one year: 46.4 vs 42.4, p = 0.005, respectively). CONCLUSION: The MS group had better clinical outcomes than the SR group, with significantly greater knee flexion from six months through two years, better Knee Society Pain scores at six weeks through one year, and higher Knee Society Pain/Motion scores at six weeks and one year postoperatively. LEVEL OF EVIDENCE: I.

Increased Risk of Lateral Femoral Cutaneous Nerve Injury in Patients With Previous Hip Arthroscopy Who Underwent a Direct Anterior Approach Total Hip Arthroplasty.

Purpose: To evaluate the rates of lateral femoral cutaneous nerve (LFCN) injury in patients who underwent a direct anterior approach (DAA) total hip arthroplasty (THA) with and without previous hip arthroscopy. Methods: We retrospectively investigated consecutive DAA THAs performed by a single surgeon. These cases were grouped into patients with and without a history of previous ipsilateral hip arthroscopy. LFCN sensation was assessed during the initial follow-up (6 weeks) and 1-year (or most recent) follow-up visits. The incidence and character of LFCN injury was compared between the 2 groups. Results: In total, 166 patients underwent a DAA THA with no previous hip arthroscopy, and 13 had a history of previous arthroscopy. Of the 179 total patients who underwent THA, 77 experienced some form of LFCN injury at initial follow-up (43%). The rate of injury for the cohort with no previous arthroscopy was 39% (n = 65/166) on initial follow-up, whereas the rate of injury for the cohort with a history of previous ipsilateral arthroscopy was 92% (n =12/13) on initial follow-up (P < .001). In addition, although the difference was not significant, 28% (n = 46/166) of the group without history of previous arthroscopy and 69% (n = 9/13) of the group with a history of previous arthroscopy had continued symptoms of LFCN injury at most recent follow-up. Conclusions: In this study, patients who underwent hip arthroscopy before an ipsilateral DAA THA were at increased risk of LFCN injury compared with patients who underwent a DAA THA without a previous hip arthroscopy. At final follow-up of patients with initial LFCN injury, symptoms resolved in 29% (n = 19/65) of patients with no previous hip arthroscopy and 25% (n = 3/12) of patients with previous hip arthroscopy. Level of Evidence: Level III, case-control study.

Positive end-expiratory pressure and postoperative complications in patients with obesity: a review and meta-analysis.

OBJECTIVE: In patients with obesity, use of positive end-expiratory pressure (PEEP) > 5 cm H2 O (centimeters of water) has been shown to prevent intraoperative atelectasis. This study compares the rate of postoperative pulmonary complications (PPCs) associated with PEEP > 5 cm H2 O and PEEP ≤ 5 cm H2 O in patients with obesity who underwent surgery under general anesthesia with mechanical ventilation. METHODS: This study searched Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) using the terms "PEEP," "anesthesia," and "ventilation." Cochrane ReviewManager (RevMan) version 5 was used for data analysis. The primary outcome was a composite of PPCs, including atelectasis, pneumonia, pneumothorax, and acute respiratory failure. RESULTS: The initial search identified 903 titles and abstracts, and 4 randomized controlled trials were included for analysis. We included a total of 2116 participants from four randomized controlled trials that compared PEEP ≤ 5 cm H2 O with PEEP > 5 cm H2 O in adult patients with obesity. There was no statistically significant difference in PPCs between the PEEP ≤ 5 cm H2 O and PEEP > 5 cm H2 O groups (risk ratio = 2.21, 95% CI: 0.41-11.83; p = 0.35). However, a significant heterogeneity was found within included studies (I2  = 53%). CONCLUSIONS: It is unclear whether PEEP > 5 cm H2 O improves the postoperative clinical outcome in patients with obesity, which is in contrast to previously established evidence that it reduces atelectasis in patients with obesity.

A prospective comparison of total knee arthroplasty using ultra-congruent, condylar-stabilizing, and posterior-stabilized devices implanted with kinematic alignment: better 2-year outcomes with ultra-congruent.

PURPOSE: This study compared the 5-year results of posterior cruciate ligament (PCL)-sacrificing total knee arthroplasty (TKA) with either a post and cam posterior-stabilized (PS) device, a dished, congruent condylar-stabilizing (CS) device, or a deep-dished ultra-congruent (UC) device. The hypothesis was that the clinical and radiographic outcomes would be equivalent. CS and PS participants were part of a prospective, randomized trial, and UC participants were part of a separate prospective, non-randomized protocol that was otherwise identical. A kinematic alignment surgical technique was utilized. METHODS: Participants were assessed preoperatively, and postoperatively at 6 weeks, 6 months, and annually for 5 years by Knee Society Score (KSS), SF-36 v2, Lower Extremity Activity Scale (LEAS), and physical and radiographic evaluation. There were 116 CS/PS participants and 69 UC participants who participated in the study. RESULTS: Tourniquet (P = .02) and operative (P = .01) times for the CS and UC groups were significantly shorter than the PS group. KSS Function scores were better for the UC group than the CS and PS groups at 6 months (P = .04) and 1 year (P = .03), and better in the UC group vs. CS at 2 years (P = .04). The KSS Pain-only score was also better in the UC compared to PS at 6 months (P = .04). There were no significant differences for the KSS Pain/Motion scores, flexion, SF-36, and LEAS scores at any time. CONCLUSION: These data confirm the hypothesis that there are no clinically meaningful significant differences in outcomes between the three groups at a 5-year minimum follow-up, though there is a trend toward less pain and better function at earlier visits in the UC group. LEVEL OF EVIDENCE: II.

Immediate Effects of Adding Dry Needling to Thoracic Manipulation and Exercise in Cervical Range of Motion for Adults With Neck Pain: A Randomized Clinical Trial.

OBJECTIVE: The purpose of this study was to determine the immediate effects of adding dry needling (DN) to thoracic spine manipulation and neck-specific exercise in individuals with neck pain. METHODS: Forty-two participants with neck pain were randomized to either the true (n = 21) or sham (n = 21) DN groups, receiving treatment on the initial visit and 2 to 3 days later. Outcomes were assessed on day 1, both at baseline and immediately after the initial treatment, at the second treatment 2 to 3 days later, and at the final visit 5 to 7 days after visit 2. Primary outcomes were Neck Disability Index (NDI) (0-50) and current pain via numeric pain rating scale (0-10). Secondary outcomes were cervical range of motion, pain pressure threshold, and global rating of change. RESULTS: Repeated measures analysis of covariance with baseline value as covariate revealed no significant difference in NDI scores at either follow-up time point with adjusted mean differences (95% confidence interval) of -0.11 (-2.70 to 2.48) and 0.31 (-1.96 to 2.57). There were no between-group differences in pain at any time point via Independent-Samples Median Test (P value range of .54-1.0). Secondary outcome measures were similarly not statistically different between groups except for immediate improvements in rotation to the side opposite of pain, which favored DN, with an adjusted mean difference (95% confidence interval) of 7.85 (3.54-12.15) degrees. CONCLUSION: The addition of DN to thoracic spinal manipulation and neck-specific exercise did not affect improvements in NDI score or numeric pain rating scale but showed an increase in cervical range of motion.

A Case Report of a Subdural Hematoma following Spinal Epidural prior to a Total Knee Arthroplasty.

Introduction: This case report adds to current literature on management of a subdural hematoma following total knee arthroplasty and is particularly important as joint replacement moves into outpatient surgery centers where the orthopedic surgery team becomes the sole patient contact point. Case Presentation. A 66-year-old male presented to the emergency department five days after elective robotic-assisted left total knee arthroplasty performed with spinal epidural with the symptoms of a persistent nonpostural headache. CT of the head revealed a small bifrontal acute subdural hematoma. He was admitted for overnight monitoring as a precaution. No vascular abnormalities or underlying pathology was found on further advanced imaging. He was discharged the following morning after follow-up CT showed no focal changes. Magnetic resonance imaging (MRI) one month later confirmed resolution of the subdural hematoma. Conclusion: Orthopedic surgeons should be aware of the signs and symptoms, as well as the risk factors for subdural hematomas following lumbar puncture, as it is a rare, but potentially life-threatening complication of spinal epidural.

Clinical outcomes and survivorship of cementless triathlon total knee arthroplasties: a systematic review.

BACKGROUND: Over the last decade, cementless total knee arthroplasty has demonstrated improved outcomes and survivorship due to advances in technologies of implant design, manufacturing capabilities, and biomaterials. Due to increasing interest in cementless implant design for TKA, our aim was to perform a systematic review of the literature to evaluate the clinical outcomes and revision rates of the Triathlon Total Knee system over the past decade. METHODS: A systematic review of the literature was conducted following PRISMA guidelines for patients who underwent total knee arthroplasty with cementless Triathalon Total Knee System implants. Patients had a minimum of two-year follow-up and data included clinical outcome scores and survivorship data. RESULTS: Twenty studies were included in the final analysis. The survivability of the Stryker Triathlon TKA due to all causes was 98.7%, with an aseptic survivability of 99.2%. The overall revision incidence per 1,000 person-years was 3.4. Re-revision incidence per 1,000 person-years was 2.2 for infection, and 1.3 for aseptic loosening. The average KSS for pain was 92.2 and the average KSS for function was 82.7. CONCLUSIONS: This systematic review demonstrated excellent clinical outcomes and survivorship at a mean time of 3.8 years. Additional research is necessary to examine the long-term success of the Stryker Triathlon TKA and the use of cementless TKAs in obese and younger populations. LEVEL OF EVIDENCE: III.

Systems analysis of the mechanisms governing the cardiovascular response to changes in posture and in peripheral demand during exercise.

Blood flows and pressures throughout the human cardiovascular system are regulated in response to various dynamic perturbations, such as changes to peripheral demands in exercise, rapid changes in posture, or loss of blood from hemorrhage, via the coordinated action of the heart, the vasculature, and autonomic reflexes. To assess how the systemic and pulmonary arterial and venous circulation, the heart, and the baroreflex work together to effect the whole-body responses to these perturbations, we integrated an anatomically-based large-vessel arterial tree model with the TriSeg heart model, models capturing nonlinear characteristics of the large and small veins, and baroreflex-mediated regulation of vascular tone and cardiac chronotropy and inotropy. The model was identified by matching data from the Valsalva maneuver (VM), exercise, and head-up tilt (HUT). Thirty-one parameters were optimized using a custom parameter-fitting tool chain, resulting in an unique, high-fidelity whole-body human cardiovascular systems model. Because the model captures the effects of exercise and posture changes, it can be used to simulate numerous clinical assessments, such as HUT, the VM, and cardiopulmonary exercise stress testing. The model can also be applied as a framework for representing and simulating individual patients and pathologies. Moreover, it can serve as a framework for integrating multi-scale organ-level models, such as for the heart or the kidneys, into a whole-body model. Here, the model is used to analyze the relative importance of chronotropic, inotropic, and peripheral vascular contributions to the whole-body cardiovascular response to exercise. It is predicted that in normal physiological conditions chronotropy and inotropy make roughly equal contributions to increasing cardiac output and cardiac power output during exercise. Under upright exercise conditions, the nonlinear pressure-volume relationship of the large veins and sympathetic-mediated venous vasoconstriction are both required to maintain preload to achieve physiological exercise levels. The developed modeling framework is built using the open Modelica modeling language and is freely distributed.

Phenotyping heart failure using model-based analysis and physiology-informed machine learning.

To phenotype mechanistic differences between heart failure with reduced (HFrEF) and preserved (HFpEF) ejection fraction, a closed-loop model of the cardiovascular system coupled with patient-specific transthoracic echocardiography (TTE) and right heart catheterization (RHC) data was used to identify key parameters representing haemodynamics. Thirty-one patient records (10 HFrEF, 21 HFpEF) were obtained from the Cardiovascular Health Improvement Project database at the University of Michigan. Model simulations were tuned to match RHC and TTE pressure, volume, and cardiac output measurements in each patient. The underlying physiological model parameters were plotted against model-based norms and compared between HFrEF and HFpEF. Our results confirm the main mechanistic parameter driving HFrEF is reduced left ventricular (LV) contractility, whereas HFpEF exhibits a heterogeneous phenotype. Conducting principal component analysis, k -means clustering, and hierarchical clustering on the optimized parameters reveal (i) a group of HFrEF-like HFpEF patients (HFpEF1), (ii) a classic HFpEF group (HFpEF2), and (iii) a group of HFpEF patients that do not consistently cluster (NCC). These subgroups cannot be distinguished from the clinical data alone. Increased LV active contractility ( p<0.001 ) and LV passive stiffness ( p<0.001 ) at rest are observed when comparing HFpEF2 to HFpEF1. Analysing the clinical data of each subgroup reveals that elevated systolic and diastolic LV volumes seen in both HFrEF and HFpEF1 may be used as a biomarker to identify HFrEF-like HFpEF patients. These results suggest that modelling of the cardiovascular system and optimizing to standard clinical data can designate subgroups of HFpEF as separate phenotypes, possibly elucidating patient-specific treatment strategies. KEY POINTS: Analysis of data from right heart catheterization (RHC) and transthoracic echocardiography (TTE) of heart failure (HF) patients using a closed-loop model of the cardiovascular system identifies key parameters representing haemodynamic cardiovascular function in patients with heart failure with reduced and preserved ejection fraction (HFrEF and HFpEF). Analysing optimized parameters representing cardiovascular function using machine learning shows mechanistic differences between HFpEF groups that are not seen analysing clinical data alone. HFpEF groups presented here can be subdivided into three subgroups: HFpEF1 described as 'HFrEF-like HFpEF', HFpEF2 as 'classic HFpEF', and a third group of HFpEF patients that do not consistently cluster. Focusing purely on cardiac function consistently captures the underlying dysfunction in HFrEF, whereas HFpEF is better characterized by dysfunction in the entire cardiovascular system. Our methodology reveals that elevated left ventricular systolic and diastolic volumes are potential biomarkers for identifying HFrEF-like HFpEF patients.

A chromosome-level genome of Astyanax mexicanus surface fish for comparing population-specific genetic differences contributing to trait evolution.

Identifying the genetic factors that underlie complex traits is central to understanding the mechanistic underpinnings of evolution. Cave-dwelling Astyanax mexicanus populations are well adapted to subterranean life and many populations appear to have evolved troglomorphic traits independently, while the surface-dwelling populations can be used as a proxy for the ancestral form. Here we present a high-resolution, chromosome-level surface fish genome, enabling the first genome-wide comparison between surface fish and cavefish populations. Using this resource, we performed quantitative trait locus (QTL) mapping analyses and found new candidate genes for eye loss such as dusp26. We used CRISPR gene editing in A. mexicanus to confirm the essential role of a gene within an eye size QTL, rx3, in eye formation. We also generated the first genome-wide evaluation of deletion variability across cavefish populations to gain insight into this potential source of cave adaptation. The surface fish genome reference now provides a more complete resource for comparative, functional and genetic studies of drastic trait differences within a species.

Potential role of intermittent functioning of baroreflexes in the etiology of hypertension in spontaneously hypertensive rats.

The spontaneously hypertensive rat (SHR) is a genetic model of primary hypertension with an etiology that includes sympathetic overdrive. To elucidate the neurogenic mechanisms underlying the pathophysiology of this model, we analyzed the dynamic baroreflex response to spontaneous fluctuations in arterial pressure in conscious SHRs, as well as in the Wistar-Kyoto (WKY), the Dahl salt-sensitive, the Dahl salt-resistant, and the Sprague-Dawley rat. Observations revealed the existence of long intermittent periods (lasting up to several minutes) of engagement and disengagement of baroreflex control of heart rate. Analysis of these intermittent periods revealed a predictive relationship between increased mean arterial pressure and progressive baroreflex disengagement that was present in the SHR and WKY strains but absent in others. This relationship yielded the hypothesis that a lower proportion of engagement versus disengagement of the baroreflex in SHR compared with WKY contributes to the hypertension (or increased blood pressure) in SHR compared with WKY. Results of experiments using sinoaortic baroreceptor denervation were consistent with the hypothesis that dysfunction of the baroreflex contributes to the etiology of hypertension in the SHR. Thus, this study provides experimental evidence for the roles of the baroreflex in long-term arterial pressure regulation and in the etiology of primary hypertension in this animal model.

Deep phenotyping of cardiac function in heart transplant patients using cardiovascular system models.

KEY POINTS: Right heart catheterization data from clinical records of heart transplant patients are used to identify patient-specific models of the cardiovascular system. These patient-specific cardiovascular models represent a snapshot of cardiovascular function at a given post-transplant recovery time point. This approach is used to describe cardiac function in 10 heart transplant patients, five of which had multiple right heart catheterizations allowing an assessment of cardiac function over time. These patient-specific models are used to predict cardiovascular function in the form of right and left ventricular pressure-volume loops and ventricular power, an important metric in the clinical assessment of cardiac function. Outcomes for the longitudinally tracked patients show that our approach was able to identify the one patient from the group of five that exhibited post-transplant cardiovascular complications. ABSTRACT: Heart transplant patients are followed with periodic right heart catheterizations (RHCs) to identify post-transplant complications and guide treatment. Post-transplant positive outcomes are associated with a steady reduction of right ventricular and pulmonary arterial pressures, toward normal levels of right-side pressure (about 20 mmHg) measured by RHC. This study shows that more information about patient progression is obtained by combining standard RHC measures with mechanistic computational cardiovascular system models. The purpose of this study is twofold: to understand how cardiovascular system models can be used to represent a patient's cardiovascular state, and to use these models to track post-transplant recovery and outcome. To obtain reliable parameter estimates comparable within and across datasets, we use sensitivity analysis, parameter subset selection, and optimization to determine patient-specific mechanistic parameters that can be reliably extracted from the RHC data. Patient-specific models are identified for 10 patients from their first post-transplant RHC, and longitudinal analysis is carried out for five patients. Results of the sensitivity analysis and subset selection show that we can reliably estimate seven non-measurable quantities; namely, ventricular diastolic relaxation, systemic resistance, pulmonary venous elastance, pulmonary resistance, pulmonary arterial elastance, pulmonary valve resistance and systemic arterial elastance. Changes in parameters and predicted cardiovascular function post-transplant are used to evaluate the cardiovascular state during recovery of five patients. Of these five patients, only one showed inconsistent trends during recovery in ventricular pressure-volume relationships and power output. At the four-year post-transplant time point this patient exhibited biventricular failure along with graft dysfunction while the remaining four exhibited no cardiovascular complications.

Of Mice and Monkeys: Neuroprotective Efficacy of the p38 Inhibitor BIRB 796 Depends on Model Duration in Experimental Glaucoma.

Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). Early progression involves retinal ganglion cell (RGC) axon dysfunction that precedes frank degeneration. Previously we demonstrated that p38 MAPK inhibition abates axonal dysfunction and slows degeneration in the inducible microbead occlusion model of glaucoma in rat. Here, we assessed the neuroprotective effect of topical eye delivery of the p38 MAPK inhibitor BIRB 796 in three models of glaucoma (microbead occlusion in rat and squirrel monkey and the genetic DBA/2 J mouse model) with distinct durations of IOP elevation. While BIRB 796 did not influence IOP, treatment over four weeks in rats prevented degradation of anterograde axonal transport to the superior colliculus and degeneration in the optic nerve. Treatment over months in the chronic DBA/2 J model and in the squirrel monkey model reduced expression and activation of p38 downstream targets in the retina and brain but did not rescue RGC axon transport or degeneration, suggesting the efficacy of BIRB 796 in preventing associated degeneration of the RGC projection depends on the duration of the experimental model. These results emphasize the importance of evaluating potential therapeutic compounds for neuroprotection in multiple models using elongated treatment paradigms for an accurate assessment of efficacy.

Dispatches from the neighborhood watch: Using citizen science and field survey data to document color morph frequency in space and time.

Heritable color polymorphisms have a long history of study in evolutionary biology, though they are less frequently examined today than in the past. These systems, where multiple discrete, visually identifiable color phenotypes co-occur in the same population, are valuable for tracking evolutionary change and ascertaining the relative importance of different evolutionary mechanisms. Here, we use a combination of citizen science data and field surveys in the Great Lakes region of North America to identify patterns of color morph frequencies in the eastern gray squirrel (Sciurus carolinensis). Using over 68,000 individual squirrel records from both large and small spatial scales, we identify the following patterns: (a) the melanistic (black) phenotype is often localized but nonetheless widespread throughout the Great Lakes region, occurring in all states and provinces sampled. (b) In Ohio, where intensive surveys were performed, there is a weak but significantly positive association between color morph frequency and geographic proximity of populations. Nonetheless, even nearby populations often had radically different frequencies of the melanistic morph, which ranged from 0% to 96%. These patterns were mosaic rather than clinal. (c) In the Wooster, Ohio population, which had over eight years of continuous data on color morph frequency representing nearly 40,000 records, we found that the frequency of the melanistic morph increased gradually over time on some survey routes but decreased or did not change over time on others. These differences were statistically significant and occurred at very small spatial scales (on the order of hundreds of meters). Together, these patterns are suggestive of genetic drift as an important mechanism of evolutionary change in this system. We argue that studies of color polymorphism are still quite valuable in advancing our understanding of fundamental evolutionary processes, especially when coupled with the growing availability of data from citizen science efforts.

Substrate Promiscuity of a Paralytic Shellfish Toxin Amidinotransferase.

Secondary metabolites are assembled by enzymes that often perform reactions with high selectivity and specificity. Many of these enzymes also tolerate variations in substrate structure, exhibiting promiscuity that enables various applications of a given biocatalyst. However, initial enzyme characterization studies frequently do not explore beyond the native substrates. This limited assessment of substrate scope contributes to the difficulty of identifying appropriate enzymes for specific synthetic applications. Here, we report the natural function of cyanobacterial SxtG, an amidinotransferase involved in the biosynthesis of paralytic shellfish toxins, and demonstrate its ability to modify a breadth of non-native substrates. In addition, we report the first X-ray crystal structure of SxtG, which provides rationale for this enzyme's substrate scope. Taken together, these data confirm the function of SxtG and exemplify its potential utility in biocatalytic synthesis.

Model annotation and discovery with the Physiome Model Repository.

BACKGROUND: Mathematics and Phy sics-based simulation models have the potential to help interpret and encapsulate biological phenomena in a computable and reproducible form. Similarly, comprehensive descriptions of such models help to ensure that such models are accessible, discoverable, and reusable. To this end, researchers have developed tools and standards to encode mathematical models of biological systems enabling reproducibility and reuse, tools and guidelines to facilitate semantic description of mathematical models, and repositories in which to archive, share, and discover models. Scientists can leverage these resources to investigate specific questions and hypotheses in a more efficient manner. RESULTS: We have comprehensively annotated a cohort of models with biological semantics. These annotated models are freely available in the Physiome Model Repository (PMR). To demonstrate the benefits of this approach, we have developed a web-based tool which enables users to discover models relevant to their work, with a particular focus on epithelial transport. Based on a semantic query, this tool will help users discover relevant models, suggesting similar or alternative models that the user may wish to explore or use. CONCLUSION: The semantic annotation and the web tool we have developed is a new contribution enabling scientists to discover relevant models in the PMR as candidates for reuse in their own scientific endeavours. This approach demonstrates how semantic web technologies and methodologies can contribute to biomedical and clinical research. The source code and links to the web tool are available at https://github.com/dewancse/model-discovery-tool.

Towards A Microbead Occlusion Model of Glaucoma for a Non-Human Primate.

Glaucoma is a group of optic neuropathies associated with aging and sensitivity to intraocular pressure (IOP). The disease causes vision loss through the degeneration of retinal ganglion cell neurons and their axons in the optic nerve. Using an inducible model of glaucoma, we elevated IOP in the squirrel monkey (Saimiri boliviensis) using intracameral injection of 35 µm polystyrene microbeads and measured common pathogenic outcomes in the optic projection. A 42% elevation in IOP over 28 weeks reduced anterograde transport of fluorescently-labeled cholera toxin beta from retina to the lateral geniculate nucleus (60% decrease), and to the superior colliculus (49% decrease). Pressure also reduced survival of ganglion cellaxons in the optic nerve by 22%. The same elevation caused upregulation of proteins associated with glaucomatous neurodegeneration in the retina and optic nerve, including complement 1q, interleukin 6, and brain-derived neurotrophic factor. That axon degeneration in the nerve lagged deficits in anterograde transport is consistent with progression in rodent models, while the observed protein changes also occur in tissue from human glaucoma patients. Thus, microbead occlusion in a non-human primate with a visual system similar to our own represents an attractive model to investigate neurodegenerative mechanisms and therapeutic interventions for glaucoma.

A simulation study of left ventricular decompression using a double lumen arterial cannula prototype during a veno-arterial extracorporeal membrane oxygenation.

BACKGROUND: Veno-arterial extracorporeal membrane oxygenation can be vital to support patients in severe or rapidly progressing cardiogenic shock. In cases of left ventricular distension, left ventricular decompression during veno-arterial extracorporeal membrane oxygenation may be a crucial factor influencing the patient outcome. Application of a double lumen arterial cannula for a left ventricular unloading is an alternative, straightforward method for left ventricular decompression during extracorporeal membrane oxygenation in a veno-arterial configuration. OBJECTIVES: The purpose of this article is to use a mathematical model of the human adult cardiovascular system to analyze the left ventricular function of a patient in cardiogenic shock supported by veno-arterial extracorporeal membrane oxygenation with and without the application of left ventricular unloading using a novel double lumen arterial cannula. METHODS: A lumped model of cardiovascular system hydraulics has been coupled with models of non-pulsatile veno-arterial extracorporeal membrane oxygenation, a standard venous cannula, and a drainage lumen of a double lumen arterial cannula. Cardiogenic shock has been induced by decreasing left ventricular contractility to 10% of baseline normal value. RESULTS: The simulation results indicate that applying double lumen arterial cannula during veno-arterial extracorporeal membrane oxygenation is associated with reduction of left ventricular end-systolic volume, end-diastolic volume, end-systolic pressure, and end-diastolic pressure. CONCLUSIONS: A double lumen arterial cannula is a viable alternative less invasive method for left ventricular decompression during veno-arterial extracorporeal membrane oxygenation. However, to allow for satisfactory extracorporeal membrane oxygenation flow, the cannula design has to be revisited.