cssi/SciSciGPT-SciSciNet huggingface dataset:
The catalytic mechanism of electron-bifurcating electron transfer flavoproteins (ETFs) involves an intermediary complex with NAD+

Electron bifurcation plays a key role in anaerobic energy metabolism, but it is a relatively new discovery, and only limited mechanistic information is available on the diverse enzymes that employ it. Herein, we focused on the bifurcating electron transfer flavoprotein (ETF) from the hyperthermophilic archaeon Pyrobaculum aerophilum. The EtfABCX enzyme complex couples NADH oxidation to the endergonic reduction of ferredoxin and exergonic reduction of menaquinone. We developed a model for the enzyme structure by using nondenaturing MS, cross-linking, and homology modeling in which EtfA, -B, and -C each contained FAD, whereas EtfX contained two [4Fe-4S] clusters. On the basis of analyses using transient absorption, EPR, and optical titrations with NADH or inorganic reductants with and without NAD+, we propose a catalytic cycle involving formation of an intermediary NAD+-bound complex. A charge transfer signal revealed an intriguing interplay of flavin semiquinones and a protein conformational change that gated electron transfer between the low- and high-potential pathways. We found that despite a common bifurcating flavin site, the proposed EtfABCX catalytic cycle is distinct from that of the genetically unrelated bifurcating NADH-dependent ferredoxin NADP+ oxidoreductase (NfnI). The two enzymes particularly differed in the role of NAD+, the resting and bifurcating-ready states of the enzymes, how electron flow is gated, and the two two-electron cycles constituting the overall four-electron reaction. We conclude that P. aerophilum EtfABCX provides a model catalytic mechanism that builds on and extends previous studies of related bifurcating ETFs and can be applied to the large bifurcating ETF family.
Genome-wide interrogation of extracellular vesicle biology using barcoded miRNAs

Extracellular vesicles mediate transfer of biologically active molecules between neighboring or distant cells, and these vesicles may play important roles in normal physiology and the pathogenesis of multiple disease states including cancer. However, the underlying molecular mechanisms of their biogenesis and release remain unknown. We designed artificially barcoded, exosomal microRNAs (bEXOmiRs) to monitor extracellular vesicle release quantitatively using deep sequencing. We then expressed distinct pairs of CRISPR guide RNAs and bEXOmiRs, enabling identification of genes influencing bEXOmiR secretion from Cas9-edited cells. This approach uncovered genes with unrecognized roles in multivesicular endosome exocytosis, including critical roles for Wnt signaling in extracellular vesicle release regulation. Coupling bEXOmiR reporter analysis with CRISPR-Cas9 screening provides a powerful and unbiased means to study extracellular vesicle biology and for the first time, to associate a nucleic acid tag with individual membrane vesicles.
The Biological InteractionsOpen image in new window

Life on land and in the sea is experiencing climate change at a rate unprecedented since the catastrophic impact of an asteroid 65 million years ago.
CD19 Directed Chimeric Antigen Receptor T Cell Therapy in Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis

Introduction Chimeric antigen receptor (CAR) T-cells targeting CD19 have led to complete response (CR) rates of 70-90% in children and adults with refractory/relapsed B-cell acute lymphoblastic leukemia (ALL), which led to their FDA approval in 2017. However, different constructs have been used and the response rates vary among different studies. Toxicities in the form of cytokine release syndrome (CRS) and neurotoxicity remain a challenge. We conducted a systematic review and meta-analysis of all published and presented trials of anti-CD19 CAR T-cells in relapsed/refractory ALL. Objectives 1) To determine the efficacy of anti-CD19 CAR T-cells in ALL. 2) To describe the toxicities of anti-CD19 CAR T-cells in ALL. 3) To examine differences in efficacy and toxicity by age groups and construct type. Methods We searched MEDLINE and EMBASE and included studies that reported raw data on the outcomes of adults and children that were treated with anti-CD19 CAR T-cells for ALL. The random effects model was used to derive estimates of complete response (CR) and progression-free survival (PFS) at 1 year and toxicities. Secondary outcome was minimal residual disease (MRD) at 1 year. We planned subgroup analysis based on age (adults vs. children) and construct type. Results Of 1,139 potentially relevant references, 18 noncomparative trials were included with a total of 573 patients (309 adults and 264 children). Pooled CR was comparable between adults [84% (95 CI 80-86%)] and children [83% (95 CI 79-88%)], but varied by construct [86% (95 CI 82-90%) for 41BB co-stimulated CART cells vs 74% (95 CI 68-81%) for CD28 co-stimulated CART cells vs 86% (95 CI 80-91%) for fourth generation CART cells]. Pooled 1-year PFS was comparable for adults and children [53% (95 CI 31-74%) vs 56% (95 CI 50-65%)]. CRS rates were comparable among adults and children [76% (95 CI 71-81%) vs 72% (95% CI 68-77%)]. CRS was lower in CD28 compared to other constructs [47% (95 CI 41-53%) in CD28 vs 86% (95 CI 82-91%) in 41BB vs 76% (95 CI 69-83%) in fourth generation]. Neurotoxicity occurred more commonly in adults [44% (95 CI 35-54%) vs 17% (95 CI 12-22%)] and in those treated with 41BB compared to those treated with CD28 [34% (95 CI 27-40%) vs 14% (95% CI 9-20%)]. Pooled MRD negativity at 1 year was 77% (95 CI 71-82%) in adults and 82% (95 CI 77-87%) in children. CD28 construct led to lower MRD negativity [62% (95 CI 54-70%) vs 85% (95 CI 81-89%) in 41BB vs 81% (95 CI 69-93%) in fourth generation]. These data are summarized in Figure 1. Conclusions Pooled 1-year CR was 84%, pooled 1-year PFS was 57% and the efficacy of CAR T-cell therapy was comparable between adults and children. Analysis by construct type revealed differences in the efficacy and toxicity between different constructs with CD28 leading to lower efficacy and toxicity. This is the first study to systemically analyze the outcomes of anti-CD19 CAR T-cell therapy in ALL.
Seer: Leveraging Big Data to Navigate the Complexity of Performance Debugging in Cloud Microservices

Performance unpredictability is a major roadblock towards cloud adoption, and has performance, cost, and revenue ramifications. Predictable performance is even more critical as cloud services transition from monolithic designs to microservices. Detecting QoS violations after they occur in systems with microservices results in long recovery times, as hotspots propagate and amplify across dependent services. We present Seer, an online cloud performance debugging system that leverages deep learning and the massive amount of tracing data cloud systems collect to learn spatial and temporal patterns that translate to QoS violations. Seer combines lightweight distributed RPC-level tracing, with detailed low-level hardware monitoring to signal an upcoming QoS violation, and diagnose the source of unpredictable performance. Once an imminent QoS violation is detected, Seer notifies the cluster manager to take action to avoid performance degradation altogether. We evaluate Seer both in local clusters, and in large-scale deployments of end-to-end applications built with microservices with hundreds of users. We show that Seer correctly anticipates QoS violations 91% of the time, and avoids the QoS violation to begin with in 84% of cases. Finally, we show that Seer can identify application-level design bugs, and provide insights on how to better architect microservices to achieve predictable performance.
Antimicrobial Peptides: Potential Application in Liver Cancer

The physicochemical properties of antimicrobial peptides (AMPs) including size, net charge, amphipathic structure, hydrophobicity, and mode-of-action together determine their broad-spectrum activities against bacteria, fungi, protozoa, and viruses. Recent studies show that some AMPs have both antimicrobial and anticancer activities, suggesting a new strategy for cancer therapy. Hepatocellular carcinoma (HCC), the primary liver cancer, is a leading cause of cancer mortality worldwide, and lacks effective treatment. Anticancer peptides (ACPs) derived from AMPs or natural resources could be applied to combat HCC directly or as a synergistic treatment. However, the number of known ACPs is low compared to the number of antibacterial and antifungal peptides, and very few of them can be applied clinically for HCC treatment. In this review, we first summarize recent studies related to ACPs for HCC, followed by a description of potential modes-of-action including direct killing, anti-inflammation, immune modulation, and enhanced wound healing. We then describe the structures of AMPs and methods to design and modify these peptides to improve their anticancer efficacy. Finally, we explore the potential application of ACPs as vaccines or nanoparticles for HCC treatment. Overall, ACPs display several attractive properties as therapeutic agents, including broad-spectrum anticancer activity, ease-of-design and modification, and low production costs. As this is an emerging and novel area of cancer therapy, additional studies are needed to identify existing candidate AMPs with ACP activity, and assess their anticancer activity and specificity, and immunomodulatory effects, using in vitro, in silico, and in vivo approaches.
Comparative and Predictor Analysis of 30-day Readmission, Reoperation, and Morbidity in Patients Undergoing Multilevel ACDF Versus Single and Multilevel ACCF Using the ACS-NSQIP Dataset.

STUDY DESIGN Retrospective cohort study. OBJECTIVE The aim of this study was to determine the differences in 30-day readmission, reoperation, and morbidity for patients undergoing multilevel anterior cervical discectomy and fusion (ACDF) or single and multilevel anterior cervical corpectomy and fusion (ACCF). SUMMARY OF BACKGROUND DATA Despite increasing rates of surgical treatment of cervical spine disease, few studies have compared outcomes by surgical technique. To the best of our knowledge, this is the only large-scale administrative database study that directly evaluates early outcomes between multilevel ACDF and single and multilevel ACCF. METHODS Patients who underwent ACDF and ACCF were identified using the NSQIP database. Multivariate regression was utilized to compare rates of readmission, reoperation, morbidity, and specific complications between surgical techniques, and to evaluate for predictors of primary outcomes. RESULTS We identified 15,600 patients. ACCF independently predicted (P < 0.001) greater reoperation (odds ratio [OR] = 1.876) and morbidity (OR = 1.700), but not readmission, on multivariate analysis. ACCF was also associated with greater rates of transfusion (OR = 3.273, P < 0.001) and DVT/thrombophlebitis (OR = 2.852, P = 0.001). ACCF had significantly (P < 0.001) greater operative time and length of stay. In the cohort, increasing age (P < 0.001), diabetes (P = 0.025), chronic obstructive pulmonary disease (P = 0.027), disseminated cancer (P = 0.009), and American Society of Anesthesiologists (ASA) class ≥3 (P < 0.001) predicted readmission. Age (P = 0.011), female sex (P = 0.001), heart failure (P = 0.002), ASA class ≥3 (P < 0.001), and increased creatinine (P = 0.044), white cell count (P = 0.033), and length of stay (P < 0.001) predicted reoperation. Age (P < 0.001), female sex (P = 0.002), disseminated cancer (P = 0.010), ASA class ≥3 (P < 0.001), increased white cell count (P = 0.036) and length of stay (P < 0.001), and decreased hematocrit (P < 0.001) predicted morbidity. Within ACDF, three or more levels treated compared to two levels did not predict poorer 30-day outcomes. CONCLUSION Compared to multilevel ACDF, ACCF was associated with an 88% increased odds of reoperation and 70% increased odds of morbidity; readmission was similar between techniques. Older age, higher ASA class, and specific comorbidities predicted poorer 30-day outcomes. These findings can guide surgical solution given specific factors. LEVEL OF EVIDENCE 3.
Efficacy and safety of vorapaxar for secondary prevention in low body weight in patients with atherosclerosis: analyses from the TRA 2°P-TIMI 50 Trial.

Background:Vorapaxar inhibits the thrombin-mediated activation of platelets, reduces thrombotic events in patients with myocardial infarction or peripheral arterial disease while increasing bleedin...
Effects of anticoagulants and Ficoll on human serum antibody reactivities and functions against Mycobacterium tuberculosis.

Abstract The ability to utilize leftover samples containing anticoagulants or Ficoll would provide substantial opportunities for future antibody and biomarker studies. Some anticoagulants might influence antibody reactivity against pathogens, but comprehensive studies investigating effects in the context of TB are lacking. We enrolled 24 individuals with and without history of M. tuberculosis and/or HIV-infection and investigated TB antibody reactivities, function, and other host protein biomarkers in simultaneously obtained serum and plasma from serum separation, EDTA, heparin, acid citrate dextrose (ACD), or mononuclear cell preparation (CPT™) tubes which contain heparin and Ficoll. Antibody isotype reactivities to two mycobacterial antigens, as well as phagocytosis of M. tuberculosis, correlated strongly and significantly between serum and plasma, irrespective of type of anticoagulant or Ficoll present (r ≥ 0.85, p
Clinical Response to T-DM1 in HER2-Amplified, KRAS-Mutated Metastatic Colorectal Cancer

HER2 amplification has been identified in 2% to 3% of all colorectal cancers (CRCs). Although the prognostic role of HER2 amplification in metastatic CRC (mCRC) is unclear, studies have highlighted it as a therapeutic target. In addition, several studies have shown that HER2 amplification is implicated in the resistance to EGFR-targeted therapies. Other studies have provided scientific evidence to support the use of HER2-directed therapies in HER2-amplified CRC; however, thus far this benefit has been limited to the RAS wild-type population. There is an ongoing clinical need to identify novel means of targeting HER2 amplifications in the rare settings of HER2-amplified, RAS-mutated CRC. This case report presents a 58-year-old man with HER2-amplified mCRC and a KRAS G12D mutation whose disease progressed on all standard cytotoxic therapies as well as dual HER2 targeting using trastuzumab and pertuzumab. He subsequently derived a clinical benefit with metastatic lung disease regression on trastuzumab emtansine (T-DM1). He eventually experienced disease progression in the liver after 6 every-3-week cycles. The patient's response and disease progression were associated with ongoing decline in the HER2 copy number on the circulating tumor DNA assay, suggesting that the mechanism of resistance was related to the loss of HER2 amplification or the emergence of non-HER2-amplified CRC clones. This represents the first report of clinical benefit with T-DM1 in KRAS-mutated HER2-amplified CRC.
Comparing Skill Acquisition Under Different Stimulus Set Sizes With Adolescents With Autism Spectrum Disorder: A Replication.

A number of variables may influence the effectiveness and efficiency of skill acquisition. One variable that may be important is set size. The current study replicated and extended Kodak et al. (2020, “A Comparison of Stimulus Set Size on Tact Training for Children With Autism Spectrum Disorder,” Journal of Applied Behavior Analysis, 53(1), 265–283) by evaluating the stimulus set size that led to the most efficient skill acquisition for 2 adolescents with autism spectrum disorder. More specifically, we evaluated tact acquisition in stimulus set sizes of 3, 6, and 12. The set sizes of 3 and 6 stimuli were associated with the most efficient acquisition, whereas the set size of 12 stimuli was not.
Penetrating keratoplasty using collagen crosslinked donor tissue: A case report.

Abstract Purpose In patients with corneal melt, pretreatment crosslinking (CXL) of donor tissue prior to placement of Boston keratoprosthesis (K-Pro I) decreases graft failure. We report a case of corneal sparing in a phthisical eye following penetrating keratoplasty (PKP) with pretreatment CXL of the donor cornea. Observations A 69-year-old female with a history of familial aniridia and bilateral K-Pro I placement. Her clinical course was complicated by recurrent corneal melt and hypotony in the left eye, resulting in extraction of the K-Pro I and successive PKP with pretreatment CXL of the donor cornea. She subsequently developed phthisis of the globe with notable retention of corneal structure. At 8 years, she maintains corneal contour without recurrence of keratolysis or extension of phthisis. Conclusions and importance This is the first reported case of corneal sparing in a phthisical eye with a history of PKP, suggesting a protective role of pretreatment CXL of donor tissue against keratolysis and phthisis.
The pharmacist as a public health resource: Expanding telepharmacy services to address social determinants of health during the COVID-19 pandemic

Abstract Background The advent of COVID-19 exacerbated the impact of social determinants of health (SDOH) on patients' ability to manage their health, especially those with chronic conditions. Clinical pharmacists are well positioned to expand the patient care services they already provide to address patients' basic social needs, which may otherwise impede medication access and adherence. Objectives The purpose of this exploratory study was to evaluate the feasibility of expanding a comprehensive medication management (CMM) telepharmacy service to include SDOH support. This service was offered as part of four primary care clinics in rural and underserved North Carolina communities. More specifically, the study aimed to describe the expanded service, evaluate stakeholders' experience with the service, and assess short-term impact on patients with diabetes. Methods Data collected over the first 4 months of implementation included administrative data used to describe the expanded service; a clinic survey and interviews to assess clinic team members' experience with the service; and patient surveys to evaluate patient satisfaction, as well as impact on SDOH self-efficacy and diabetes quality of life. Results Through SDOH screening, the pharmacist identified 26 unresolved COVID-prompted SDOH concerns across 66 patients. These concerns were addressed by the pharmacist through three types of brief interventions, including information provision/education (71%), access to resources (21%), and additional care coordination (7%). Clinic team members perceived the expanded service as highly satisfactory and beneficial. Patients also reported high levels of satisfaction and significantly increased their SDOH self-efficacy and diabetes quality of life as a result of the service. Conclusion These data provide preliminary insights into the expanded role that pharmacists can play to address current population health gaps that can directly impact patients' engagement with their medication regimen and overall health status.
That’s Not Molluscum! A literature review of 109 cases of subepidermal calcified nodules

Subepidermal calcified nodule (SCN) is a rare presentation of idiopathic calcinosis cutis. A literature review was conducted, with 109 cases reported in 268 articles. We report the demographic data, SCN clinical and histological characteristics, common differential diagnoses, and treatments performed from this analysis.
Single breath counting is an effective screening tool for forced vital capacity in ALS.

Objective: To measure the correlation between single breath counting (SBC) and forced vital capacity (liters, FVCL) in amyotrophic lateral sclerosis (ALS) patients and to define the utility of SBC ...
Pairs and Pairix: a file format and a tool for efficient storage and retrieval for Hi-C read pairs

Abstract Summary As the amount of three-dimensional chromosomal interaction data continues to increase, storing and accessing such data efficiently becomes paramount. We introduce Pairs, a block-compressed text file format for storing paired genomic coordinates from Hi-C data, and Pairix, an open-source C application to index and query Pairs files. Pairix (also available in Python and R) extends the functionalities of Tabix to paired coordinates data. We have also developed PairsQC, a collapsible HTML quality control report generator for Pairs files. Availability The format specification and source code are available at https://github.com/4dn-dcic/pairix, https://github.com/4dn-dcic/Rpairix and https://github.com/4dn-dcic/pairsqc. Contact peter_park@hms.harvard.edu or burak_alver@hms.harvard.edu
Church, State, and the Abuse Crisis: The Role of Assumed Ideas of 'Reasonableness’ in Religious Liberty.

In this essay the author looks at the abuse crisis in the American Catholic Church through the lens of the often complex and uneasy relationship between Catholicism and American culture and politics. He also takes us on a brief excursion into Supreme Court jurisprudence and explains why appeals to religious liberty by themselves are ultimately ineffectual in providing a safe harbor for the Church. What he hopes to show is that the long-time — and in some cases, continued — reluctance on the part of segments of the American Church to aggressively root out and prosecute wayward clergy has the potential to provide justification to some of the most deep-rooted and pernicious prejudices about the Church and its place in a liberal democracy.
Inequality, Entanglement, and Entrepreneurship – the Role of Voluntary and Forced Investors

In her recent book “Inequality: An Entangled Political Economy Perspective,” Mikayla Novak provides a new way to understand, and analyze, income and wealth inequality. By adopting Richard Wagner’s framework of Entangled Political Economy, Novak creates a connection between inequality – an aggregate outcome - and social interactions that generate it. Novak’s approach highlights the crucial difference between socially hurtful and socially beneficial, or neutral, forms of inequality. Subsequently, Novak’s work makes it possible to recognize the vulnerability of free societies to the emergence of socially hurtful forms of inequality, in particular, as a consequence of constitutional erosion. In analyzing the importance of regulatory constitution in preventing the emergence of socially hurtful forms of inequality, Novak recognizes the embedded public choice problems. One obstacle to counterbalancing constitutional erosion is the challenge of recognizing and anticipating which activities contribute to it. I argue that the adoption of Richard Wagner’s distinction between voluntary and forced support for new entrepreneurial ventures will help scholars recognize projects that threaten the regulatory constitution and contribute to the emergence of socially hurtful forms of inequality.
Susceptibility of Chloramphenicol-Resistant Strains of Salmonella Typhi to Trimethoprim/Sulfamethoxazole

The resistance of certain strains of Salmonella typhi to chloramphenicol is due to an R-factor which also confers resistance to sulfonamides. Typhoid fever, caused by these strains, responds to treatment with TMP/SMX, but, because of their resistance to SMX, the question arises as to whether the sulfonamide contributes to the efficacy of the treatment.
STRUCTURE AND COMPOSITION OF A RIPARIAN FOREST EDGE

Actively meandering rivers advance into mature floodplain vegetation, resulting in the continual creation and destruction of cutbank edges across a floodplain with successive channel advancements. To examine specific changes in vegetation initiated by the lateral migration of a river channel, we quantify the structure and composition of woody trees and shrubs along a cutbank forest edge in an Iowa floodplain. When compared to floodplain interior sites, edge sites are more diverse and exhibit higher stem and sapling densities. These patterns are similar to contrasts between edge and interior sites observed in previous studies of upland habitats. Total basal area, however, is statistically equivalent in floodplain edge and interior sites, in contrast to results from studies of stable upland edges. Variability among all measures is greater along the riparian edge. We attribute the relatively small basal area and high variability to disequilibrium conditions caused by cutbank erosional processes along the rip...
Modeling potential hydrochemical responses to climate change and increasing CO2at the Hubbard Brook Experimental Forest using a dynamic biogeochemical model (PnET-BGC)

[1] Dynamic hydrochemical models are useful tools for understanding and predicting the interactive effects of climate change, atmospheric CO2, and atmospheric deposition on the hydrology and water quality of forested watersheds. We used the biogeochemical model, PnET-BGC, to evaluate the effects of potential future changes in temperature, precipitation, solar radiation, and atmospheric CO2on pools, concentrations, and fluxes of major elements at the Hubbard Brook Experimental Forest in New Hampshire, United States. Future climate projections used to run PnET-BGC were generated specifically for the Hubbard Brook Experimental Forest with a statistical technique that downscales climate output (e.g., air temperature, precipitation, solar radiation) from atmosphere-ocean general circulation models (AOGCMs) to a finer temporal and spatial resolution. These climate projections indicate that over the twenty-first century, average air temperature will increase at the site by 1.7°C to 6.5°C with simultaneous increases in annual average precipitation ranging from 4 to 32 cm above the long-term mean (1970–2000). PnET-BGC simulations under future climate change show a shift in hydrology characterized by later snowpack development, earlier spring discharge (snowmelt), greater evapotranspiration, and a slight increase in annual water yield (associated with CO2 effects on vegetation). Model results indicate that under elevated temperature, net soil nitrogen mineralization and nitrification markedly increase, resulting in acidification of soil and stream water, thereby altering the quality of water draining from forested watersheds. Invoking a CO2 fertilization effect on vegetation under climate change substantially mitigates watershed nitrogen loss, highlighting the need for a more thorough understanding of CO2 effects on forest vegetation.
Noise behavior in gridding reconstruction

The paper addresses the properties of the noise in gridding reconstruction, an algorithm for reconstruction from nonuniform samples. Sequences with time-varying gradients, such as spiral or projection reconstruction (PR) techniques, are being increasingly used in magnetic resonance imaging (MRI). Since these techniques sample k-space nonuniformly, some kind of algorithm is needed to map the data onto a Cartesian frame to allow an inverse Fourier transform through an FFT. The authors present an analytical characterization of the image noise after gridding and inverse Fourier transform for the most popular sampling techniques used in MRI.
CVD of SiC and A1N Thin Films Using Designed Organometallic Precursors

The chemical and physical properties of aluminum nitride have made it an attractive prospect for a wide range of applications in electronics, including substrates for integrated circuits, thin film dielectrics, protective coatings, and surface acoustic wave devices.(1,2) It is a good electrical insulator with a direct band gap of 6 eV. In addition, it has a high decomposition temperature (ca. 2400°C), good chemical stability, a thermal expansion coefficient closely matched to that of silicon, high thermal conductivity, and a dielectric constant close to that of Al2O3.
Scattering and Absorption by Short, Thin Metallic Filaments

There has arisen recently some interest in absorptive obstacles possessing low scattering cross sections. One such obstacle is the very thin, short metallic filament which can absorb, typically, 20 to 30 dB more energy than it scatters. To calculate simply and quickly the broadside backscattering and absorption cross sections versus conductivity of such filaments and to explain their nature, a Thevenin equivalent circuit is postulated which yields reasonably accurate results under suitable restrictions on filament size. The cross sections so derived are checked by an independent computer calculation based on the point matching technique.
Characterization of the target of ivermectin, the glutamate-gated chloride channel, from Anopheles gambiae

ABSTRACT The use of insecticide-treated nets and indoor residual insecticides targeting adult mosquito vectors is a key element in malaria control programs. However, mosquito resistance to the insecticides used in these applications threatens malaria control efforts. Recently, the mass drug administration of ivermectin (IVM) has been shown to kill Anopheles gambiae mosquitoes and disrupt Plasmodium falciparum transmission in the field. We cloned the molecular target of IVM from A. gambiae , the glutamate-gated chloride channel (AgGluCl), and characterized its transcriptional patterns, protein expression and functional responses to glutamate and IVM. AgGluCl cloning revealed an unpredicted fourth splice isoform as well as a novel exon and splice site. The predicted gene products contained heterogeneity in the N-terminal extracellular domain and the intracellular loop region. Responses to glutamate and IVM were measured using two-electrode voltage clamp on Xenopus laevis oocytes expressing AgGluCl. IVM induced non-persistent currents in AgGluCl-a1 and did not potentiate glutamate responses. In contrast, AgGluCl-b was insensitive to IVM, suggesting that the AgGluCl gene could produce IVM-sensitive and -insensitive homomultimers from alternative splicing. AgGluCl isoform-specific transcripts were measured across tissues, ages, blood feeding status and sex, and were found to be differentially transcribed across these physiological variables. Lastly, we stained adult, female A. gambiae for GluCl expression. The channel was expressed in the antenna, Johnston9s organ, supraesophageal ganglion and thoracic ganglia. In summary, we have characterized the first GluCl from a mosquito, A. gambiae , and described its unique activity and expression with respect to it as the target of the insecticide IVM.
Impact of bone marrow transplantation on type I diabetes.

Le diabete du type I est une maladie systemique auto-immune. On a de plus en plus de preuves que les maladies auto-immunes, telle le diabete, sont liees a la cellule souche hematopoietique (CSH) de la moelle osseuse, plutot qu'a une de ses cellules filles. Le chimisme obtenu par la transplantation de la moelle osseuse (TMO) pourrait avoir une influence sur le diabete du type I de deux manieres: soit induire une tolerance a la transplantation pancreatique et des lots soit renverser le procede auto-immun avant le developpement de complications terminales. La TMO des donneurs «normaux» aux patients ayant a la fois une maladie hematologique maligne et un diabete du type I renverse le procede auto-immune du diabete. Ainsi, les CSH «donneuses» peuvent etre utilisees pour creer une tolerance specifique du donneur aux transplants des lots. La transplantation des lots en entier du pancreas est par excellence une approche physiologique au traitement du diabete du type I. A present, ceci est limite par la necessite d'utiliser une immunodepression chronique non-specifique a haute dose pour prevenir le rejet. En depit de ces agents, le rejet chronique reste la premiere cause d'echec tardif. La tolerance specifique du donneur elimine la necessite d'immunodepression et previent le rejet chronique. La greffe de moelle osseuse n'a pas de limitations, en particulier, la morbidite associee au conditionnement letal, la maladie greffe/hote et l'echec de la prise du greffon. A present, la morbidite et la mortalite associees au conditionnement letal ne peuvent etre justifiees au nom de l'induction de la tolerance ou l'interruption de l'etat auto-immun du diabete du type I. Le but de cette etude de recherche a ete d'identifier ces facteurs chez le receveur et le donneur pour optimiser la prise de greffe afin d'inverser le rapport risque/benefice associe a la TMO. Cet article revoit l'etat actuel des connaissances en ce qui l'action du chimisme de la CSH sur le diabete.
Two Sides of a Coin: Optimizing the Schedule of MapReduce Jobs to Minimize Their Makespan and Improve Cluster Performance

Large-scale MapReduce clusters that routinely process petabytes of unstructured and semi-structured data represent a new entity in the changing landscape of clouds. A key challenge is to increase the utilization of these MapReduce clusters. In this work, we consider a subset of the production workload that consists of MapReduce jobs with no dependencies. We observe that the order in which these jobs are executed can have a significant impact on their overall completion time and the cluster resource utilization. Our goal is to automate the design of a job schedule that minimizes the completion time (makespan) of such a set of MapReduce jobs. We offer a novel abstraction framework and a heuristic, called BalancedPools, that efficiently utilizes performance properties of MapReduce jobs in a given workload for constructing an optimized job schedule. Simulations performed over a realistic workload demonstrate that 15%-38% makespan improvements are achievable by simply processing the jobs in the right order.
The radiation quality factor as an Ornstein–Uhlenbeck process

Abstract Radiation protection strategies for extended or deep space missions rely on accurate and robust estimates of exposure dose and corresponding risk to crew health, systems functions, and mission safety in general. Simulation and modeling of dose and risk associated with such exposures are, to various degrees, made difficult by the inherent complexity and variability in characterizing the radiation environment, its passage and interaction with matter, and its biological effects. One of the more important contributors to the overall uncertainty in dose or risk assessment is the empirical variability in the radiation quality factor, Q, which is typically used to differentiate such effects. Motivated in part by recent Monte-Carlo based simulations of this variability, we propose and demonstrate a stochastic dynamic model for Q based on the Ornstein–Uhlenbeck process. The proposed model’s probability density function is a Gaussian in Q and with a linearly (in the logarithm of the LET variable) growing variance, but with rather complex scaling properties. The model’s density function is shown to be quite sensitive to any functional parameterization of the mean (deterministic) behavior of the quality factor with a discontinuous first derivative in LET. The proposed linear stochastic model is also shown to be insensitive, however, to the precise functional form of the deterministic Q.
Inhomogeneous nucleation of quark-gluon plasma in high energy nuclear collisions

We estimate the probability that a hard nucleon-nucleon collision is able to nucleate a seed of quark-gluon plasma in the surrounding hot and dense hadronic matter formed during a central collision of two large nuclei at AGS energies. The probability of producing at least one such seed is on the order of 1--100 %. We investigate the influence of quark-gluon plasma formation on the observed multiplicity distribution and find that it may lead to noticeable structure in the form of a bump or shoulder.
Isolation of ecdysteroids fromVitex strickeri using RLCC and recycling HPLC

Abstract Six phytoecdysteroids were efficiently isolated from the root bark of Vitex strickeri using a combination of rotation locular countercurrent chromatography (RLCC) and recycling high performance liquid chromatography (R-HPLC). They were identified as 20-hydroxyecdysone, ajugasterone C, abutasterone, 11α-hydroxyecdysone, 20-hydroxyecdysone-20,22-monoacetonide and ajugasterone C-20,22-monoacetonide by means of spectroscopic data. This is the first report of 11α-hydroxyecdysone and ajugasterone C-20,22-monoacetonide isolated from a natural source.
Acceptability of self-collection sampling for HPV-DNA testing in low-resource settings: a mixed methods approach

Vaginal self-sampling with HPV-DNA tests is a promising primary screening method for cervical cancer. However, women’s experiences, concerns and the acceptability of such tests in low-resource settings remain unknown. In India, Nicaragua, and Uganda, a mixed-method design was used to collect data from surveys (N = 3,863), qualitative interviews (N = 72; 20 providers and 52 women) and focus groups (N = 30 women) on women’s and providers’ experiences with self-sampling, women’s opinions of sampling at home, and their future needs. Among surveyed women, 90% provided a self- collected sample. Of these, 75% reported it was easy, although 52% were initially concerned about hurting themselves and 24% were worried about not getting a good sample. Most surveyed women preferred self-sampling (78%). However it was not clear if they responded to the privacy of self-sampling or the convenience of avoiding a pelvic examination, or both. In follow-up interviews, most women reported that they didn’t mind self-sampling, but many preferred to have a provider collect the vaginal sample. Most women also preferred clinic-based screening (as opposed to home-based self-sampling), because the sample could be collected by a provider, women could receive treatment if needed, and the clinic was sanitary and provided privacy. Self-sampling acceptability was higher when providers prepared women through education, allowed women to examine the collection brush, and were present during the self-collection process. Among survey respondents, aids that would facilitate self-sampling in the future were: staff help (53%), additional images in the illustrated instructions (31%), and a chance to practice beforehand with a doll/model (26%). Self-and vaginal-sampling are widely acceptable among women in low-resource settings. Providers have a unique opportunity to educate and prepare women for self-sampling and be flexible in accommodating women’s preference for self-sampling.
Reactions of Gas-Phase Salts: Substitutions and Eliminations in Complexes Containing a Dianion and a Tetraalklylammonium Cation

Electrospray ionization has been used to generate gas-phase complexes of a dianion (4-carboxy-4‘-sulfodiphenylacetylene) with a series of tetraalkylammonium cations. The salt complexes are stable within a quadrupole ion trap but readily react during collision-activated dissociation to give substitution and elimination products (alkylation or protonation of the carboxylate with the loss of a trialkylamine). Ab initio calculations at the MP2/6-31+G(d,p)//MP2/6-31+G(d) level are presented for the corresponding reactions of a model system, acetate + ethyltrimethylammonium.
Wind-induced mechanical stimulation increases pest resistance in common bean

The activation of the phenylpropanoid pathway in plants by environmental stimuli is one of the most universal biochemical stress responses known. Induction of enzymes such as phenylalanine ammonia-lyase and peroxidase and the accumulation of such phenolics as lignin can occur in response to insect and pathogen attack, exposure to oxidizing pollutants, and mechanical stimulation, and are thought to function in the resistance of plants to damage by these stresses. I investigated whether induction of components of this generalized stress response by wind-induced mechanical stimulation could influence the resistance to pests of common bean. In greenhouse studies, exposure of 7- to 10-day-old bean seedlings to daily periods of fan-produced wind led to increased activities of peroxidase and cinnamyl alcohol-dehydrogenase and enhanced the accumulation of lignin in primary leaves of these plants. Egg production and population growth of two-spotted spider mites were reduced when offered leaves of mechanically-stimulated plants in leaf-disk and whole-plant bioassays. Infection by anthracnose after inoculation in a detached-leaf bioassay was also reduced in leaves of mechanically-stimulated plants. The consistent positive association between the enhanced activity of the lignin branch of the phenylpropanoid pathway and enhanced resistance to pests found in leaves of mechanically-stimulated plants illustrates one way in which exposure of plants to environmental stimuli that activate a generalized stress response (e.g., wind) can influence the interactions of those plants with other environmental stimuli (e.g., pests).
Using Rotating Skill Stations to Fill Out a Simulation Day

Abstract Planning and implementing skill stations is an important factor in keeping students engaged during a simulated clinical day. A systematic approach to development and scheduling skill stations is vital to simulation success.
Consistency of incidence, survival, and prevalence data on myocardial infarction from various studies

Abstract Comparisons in levels of heart disease in different studies have been restricted to the same type of measure, such as incidence in each of two population groups. In this paper comparisons were made among different types of measures to see whether they were consistent with the estimates of the prevalence of myocardial infarction yielded by the Health Examination Survey Program. The analysis suggests that estimates of incidence among females from the Framingham Heart Study are lower than one would expect. The technique used was essentially that of a life table and may be of value where comparisons of this type are required.
Development of innervation to the ventricular myocardium of the rabbit

Abstract Catecholamine histochemistry and electron microscopy were used to study the development of innervation to the ventricular myocardium of rabbits from the 22nd day of gestation to 35 days postnatally. Special attention was directed to the first morphologic appearance of nerve fibers and terminals and the closeness of juxtaposition of terminals with myocardial cells. In animals treated with α-methylnorepinephrine fluorescent adrenergic fibers were first evident in the ventricles on the 24th day of gestation. Ultrastructurally adrenergic and cholinergic terminals were also evident on the 24th day of gestation and such terminals had close relationships with cardiac muscle cells. During the next few weeks the density of innervation increased and reached the adult pattern by 35 days postpartum. In many instances adrenergic and cholinergic fibers were evident in the same nerve bundle and were closely apposed without any intervening Schwann cell cytoplasm. Such a relationship could allow peripheral interaction between these fibers in the myocardium.
Carbide phases on iron-based Fischer-Tropsch synthesis catalysts part II: Some reaction studies

In Part I we have examined some aspects of the characterization and specific reactivity of iron catalysts for synthesis applications, with particular attention to the role of the iron carbide phases that are formed. In this part we continue this examination, but with more attention to reactivity and selectivity than to characterization, and with more attention to iron alloy formulations. However, the role of carbide formation is still an important overall factor in looking at results obtained.
The effect of ventilation on emission rates of wood finishing materials

Abstract The rate of emission of organic compounds from building materials varies according to: type of material, material loading (area of material/volume of room), compound emitted, temperature, humidity, and ventilation rate. For some compounds and materials (e.g., formaldehyde from particleboard), the relationship between emission rate and these variables is well established. For most materials and compounds, however, such relationships are unavailable. Research, using small test chambers, is being conducted by the U.S. Environmental Protection Agency (EPA) to develop data on emission rates from a variety of building materials. This paper presents selected results from the EPA studies. Emphasis is placed on the effect of ventilation (air changes/h) and material loading on the emission rate for selected organics and total measured organics. Test data for three wood finishing materials (i.e., stain, polyurethane, and wax) are presented. The data are analyzed to show the effect of ventilation on the emission characteristics of each material.
Ecomorphological pattern in Bermuda birds: The influence of competition and implications for nature preserves

Previous ecomorphological studies of introduced land birds on oceanic islands have revealed several patterns consistent with the hypothesis that interspecific competition influenced the assembly process of that community. We extend one of these analyses to Bermuda, which differs from the previous islands in its size, latitude and isolation from the mainland. We tested for the presence of morphological overdispersion in surviving introduced passeriforms. Despite a possible predominance of random events in the assembly process due to Bermuda's small size and the presence of migrant species, the surviving passeriforms were morphologically overdispersed. The presence of this pattern supports the hypothesis that the assembly of the Bermuda passeriform community has been influenced by interspecific competition. This marks the third distinct community of island land birds in which this competitive pattern has been identified. This is particularly interesting because certain attributes of Bermuda and its avifauna make it more equivalent to communities in mainland refuges than avian assemblages on islands studied previously. This suggests that interspecific competition may have important effects on the structure of refuge communities.
On the enrichment of hydrophobic organic compounds in fog droplets

Abstract The unusual degree of enrichment of hydrophobic organics in fogwater droplets reported by several investigators can be interpreted as a result of (a) the effects of temperature correction on the reported enrichment factors, (b) the effects of colloidal organic matter (both filterable and non-filterable) in fog water and (c) the effects of the large air-water interfacial adsorption of neutral hydrophobic organics on the tiny fog droplets. The enrichment factor was directly correlated to the hydrophobicity (or the activity coefficient in water) of the compounds, as indicated by their octanol-water partition constants. Compounds with large octanol-water partition coefficients (high activity coefficients in water) showed the largest enrichment. Available experimental data on the adsorption of hydrophobic compounds at the air-water interface and on colloidal organic carbon were used to show that the large specific air-water interfacial areas of fog droplets contribute significantly to the enrichment factor.
The stable evolutionary fixation of a bifunctional tyrosine-pathway protein in enteric bacteria☆

The bifunctional T-protein (chorismate mutase-T: cyclohexadienyl dehydrogenase) of l-tyrosine biosynthesis was found to be present in all genera making up the enteric bacteria. The dehydrogenase component of the T-protein was active with both prephenate and l-arogenate, showing it to be a cyclohexadienyl dehydrogenase. The dehydrogenase component, but not the mutase component, of the T-protein was feedback-inhibited by l-tyrosine. Unlike some other bifunctional proteins, the T-protein has evolved recently and is not ubiquitous. However, once the biochemical specialization of bifunctionality becomes established, the results indicate that such character states are strongly conserved through evolutionary time. Thus, bifunctional proteins can provide particularly reliable markers for small (recent origin), intermediate, and large (ancient origin) phylogenetic clusters.