Pseudouridine synthase 7 is an opportunistic enzyme that binds and modifies substrates with diverse sequences and structures.

Pseudouridine (Ψ) is a ubiquitous RNA modification incorporated by pseudouridine synthase (Pus) enzymes into hundreds of noncoding and protein-coding RNA substrates. Here, we determined the contributions of substrate structure and protein sequence to binding and catalysis by pseudouridine synthase 7 (Pus7), one of the principal messenger RNA (mRNA) modifying enzymes. Pus7 is distinct among the eukaryotic Pus proteins because it modifies a wider variety of substrates and shares limited homology with other Pus family members. We solved the crystal structure of Saccharomyces cerevisiae Pus7, detailing the architecture of the eukaryotic-specific insertions thought to be responsible for the expanded substrate scope of Pus7. Additionally, we identified an insertion domain in the protein that fine-tunes Pus7 activity both in vitro and in cells. These data demonstrate that Pus7 preferentially binds substrates possessing the previously identified UGUAR (R = purine) consensus sequence and that RNA secondary structure is not a strong requirement for Pus7-binding. In contrast, the rate constants and extent of Ψ incorporation are more influenced by RNA structure, with Pus7 modifying UGUAR sequences in less-structured contexts more efficiently both in vitro and in cells. Although less-structured substrates were preferred, Pus7 fully modified every transfer RNA, mRNA, and nonnatural RNA containing the consensus recognition sequence that we tested. Our findings suggest that Pus7 is a promiscuous enzyme and lead us to propose that factors beyond inherent enzyme properties (e.g., enzyme localization, RNA structure, and competition with other RNA-binding proteins) largely dictate Pus7 substrate selection.

Occupational Injuries in the US Nursing Homes.

BACKGROUND: Workplace injuries adversely affect worker well-being and may worsen staffing shortages and turnover in nursing homes. A better understanding of the trends in injuries in nursing homes including organizational factors associated with injuries can help improve our efforts in addressing worker injuries. OBJECTIVE: To summarize the trends in injuries and organizational correlates of injuries in US nursing homes. RESEARCH DESIGN: We combine national injury tracking data from the Occupational Safety and Health Administration (2016-2019) with nursing home characteristics from Nursing Home Compare. Our outcomes include the proportion of nursing homes reporting any injuries, the mean number of injuries, and the mean number of injuries or illnesses with days away from work, or job transfer or restriction, or both (DART). We descriptively summarize trends in injuries over time. We also estimate the association between nursing home characteristics and injuries using multivariable regressions. RESULTS: We find that approximately 93% of nursing homes reported at least 1 occupational injury in any given year. Injuries had a substantial impact on productivity with 4.1 DART injuries per 100 full-time employees in 2019. Higher bed size, occupancy, RN staffing, and chain ownership are associated with increased DART rates whereas higher overall nursing home star ratings and for-profit status are associated with decreased DART rates. CONCLUSIONS: A high proportion of nursing homes report occupational injuries that can affect staff well-being, productivity, and quality of care. Injury prevention policies should target the types of injuries occurring in nursing homes and OSHA should monitor nursing homes reporting high and repeated injuries.

Use of Intergovernmental Transfers-based Medicaid Supplemental Payments to Boost Nursing Home Finances: Evidence From Indiana Nursing Homes.

BACKGROUND: Indiana provides intergovernmental transfers-based supplemental payment to nursing homes owned/operated by the nonstate governmental organization (NSGO) but NSGOs may divert substantial supplemental payments away from participating nursing homes. OBJECTIVE: The aim of this study was to estimate the effect of participation in the intergovernmental transfers-based Medicaid supplemental payment program on nursing home revenue and expenditures. RESEARCH DESIGN: Difference-in-differences regressions using Callaway and Sant'Anna method accounting for treatment effect heterogeneity across groups and over time. SUBJECTS: All 410 Medicare and Medicaid-certified nursing homes in Indiana from 2009 to 2017 with nonmissing data (N=3170). MEASURES: The key independent variable is a binary variable indicating NSGO ownership. Outcome variables include total revenue, total operating, clinical, hotel, and administrative expenses as well as profit margins extracted from Medicare Cost Report. Control variables include facility and resident characteristics from Nursing Home Compare and LTCfocus data. RESULTS: Supplemental payments increased nursing home revenues by about $0.58 million on average but payments were larger in later years. On a per-person per day basis, nursing home revenue increased by $21.9 dollars with an increase in administrative ($11.3), and hotel ($6.9) expenses but a decrease in clinical ($4.67) expenses. CONCLUSIONS: NSGO-owned/operated nursing homes received only a fraction of the total supplemental payments on average, but we observed increased payments to nursing homes in later years. Participating nursing homes did not increase clinical expenses. Our findings raise questions on the transparency of the financing arrangements between NSGOs and nursing homes and the need to link supplemental payments to clinical expenses.

Cerebrolysin Attenuates Exacerbation of Neuropathic Pain, Blood-spinal Cord Barrier Breakdown and Cord Pathology Following Chronic Intoxication of Engineered Ag, Cu or Al (50-60 nm) Nanoparticles.

Neuropathic pain is associated with abnormal sensations and/or pain induced by non-painful stimuli, i.e., allodynia causing burning or cold sensation, pinching of pins and needles like feeling, numbness, aching or itching. However, no suitable therapy exists to treat these pain syndromes. Our laboratory explored novel potential therapeutic strategies using a suitable composition of neurotrophic factors and active peptide fragments-Cerebrolysin (Ever Neuro Pharma, Austria) in alleviating neuropathic pain induced spinal cord pathology in a rat model. Neuropathic pain was produced by constrictions of L-5 spinal sensory nerves for 2-10 weeks period. In one group of rats cerebrolysin (2.5 or 5 ml/kg, i.v.) was administered once daily after 2 weeks until sacrifice (4, 8 and 10 weeks). Ag, Cu and Al NPs (50 mg/kg, i.p.) were delivered once daily for 1 week. Pain assessment using mechanical (Von Frey) or thermal (Hot-Plate) nociceptive showed hyperalgesia from 2 weeks until 10 weeks progressively that was exacerbated following Ag, Cu and Al NPs intoxication in nerve lesioned groups. Leakage of Evans blue and radioiodine across the blood-spinal cord barrier (BSCB) is seen from 4 to 10 weeks in the rostral and caudal cord segments associated with edema formation and cell injury. Immunohistochemistry of albumin and GFAP exhibited a close parallelism with BSCB leakage that was aggravated by NPs following nerve lesion. Light microscopy using Nissl stain exhibited profound neuronal damages in the cord. Transmission electron microcopy (TEM) show myelin vesiculation and synaptic damages in the cord that were exacerbated following NPs intoxication. Using ELISA spinal tissue exhibited increased albumin, glial fibrillary acidic protein (GFAP), myelin basic protein (MBP) and heat shock protein (HSP 72kD) upregulation together with cytokines TNF-α, IL-4, IL-6, IL-10 levels in nerve lesion that was exacerbated following NPs intoxication. Cerebrolysin treatment significantly reduced hyperalgesia and attenuated BSCB disruption, edema formation and cellular changes in nerve lesioned group. The levels of cytokines were also restored near normal levels with cerebrolysin treatment. Albumin, GFAP, MABP and HSP were also reduced in cerebrolysin treated group and thwarted neuronal damages, myelin vesiculation and cell injuries. These neuroprotective effects of cerebrolysin with higher doses were also effective in nerve lesioned rats with NPs intoxication. These observations suggest that cerebrolysin actively protects spinal cord pathology and hyperalgesia following nerve lesion and its exacerbation with metal NPs, not reported earlier.

Whole genome sequencing of spotted stem borer, Chilo partellus, reveals multiple genes encoding enzymes for detoxification of insecticides.

Spotted stem borer, Chilo partellus, is the most important constraint for increasing the production and productivity of maize and sorghum, the two major coarse cereals in Asia and Africa. The levels of resistance to this pest in the cultivated germplasm are low to moderate, and hence, farmers have to use insecticides for effective control of this pest. However, there is no information on the detoxification mechanisms in C. partellus, which is one of the constraints for deployment of appropriate insecticides to control this pest. The ability to detoxify insecticides varies across insect populations, and hence, we sequenced different populations of C. partellus to identify and understand detoxification mechanisms to devise appropriate strategies for deployment of different insecticides for controlling this pest. Larval samples were sequenced from three different cohorts of C. partellus using the Illumina HiSeq 2500 platform. The data were subjected to identify putative genes that are involved in detoxification on insecticides in our cohort insect species. These studies resulted in identification of 64 cytochrome P450 genes (CYP450s), and 36 glutathione S-transferases genes (GSTs) encoding metabolic detoxification enzymes, primarily responsible for xenobiotic metabolism in insects. A total of 183 circadian genes with > 80% homolog and 11 olfactory receptor genes that mediate chemical cues were found in the C. partellus genome. Also, target receptors related to insecticide action, 4 acetylcholinesterase (AChE), 14 γ-aminobutyric acid (GABA), and 15 nicotinic acetylcholine (nAChR) receptors were detected. This is the first report of whole genome sequencing of C. partellus useful for understanding mode of action of different insecticides, and mechanisms of detoxification and designing target-specific insecticides to develop appropriate strategies to control C. partellus for sustainable crop production.

Prevalence of Traumatic Injuries to Primary Anterior Teeth among Children aged 2-6 Years in National Capital Region of Delhi, India.

AIMS: The aim of this study was to assess subject wise and tooth wise distribution and prevalence of traumatic injuries to the anterior teeth of 2- to 6-year-old children. MATERIALS AND METHODS: A cross-sectional survey was performed. Primary maxillary and mandibular anterior teeth of 1,800 children aged between 2 years and 6 years, who attended 20 pre-schools in National Capital Region Delhi, India, were examined by a single examiner, and a questionnaire was filled in person by the parent/guardian. Andreasen's classification was used to classify the traumatic injuries. The Chi-square test was used to statistically analyze the variation in traumatic dental injuries (TDIs) with age and gender. Multiple logistic regression was used to determine the influence of independent variables on the occurrence of TDIs. RESULTS: The prevalence of TDIs was 17%. Significant and highly significant differences were found between boys and girls for cause and location of trauma (p < 0.05) and tooth type involved (p < 0.001) with boys being more prone to such injuries. The commonest cause of injury was due to falls and the location was playground. The teeth most commonly affected were the maxillary central incisors (36.9%) followed by maxillary lateral incisors (3.3%), and the least affected were the maxillary and mandibular canines (0.3%). CONCLUSION: The prevalence of traumatic injuries to the anterior teeth in 2- to 6-year-old children in National Capital Region of Delhi, India, was 17%. There is a need to run educational programs to increase parents' awareness of the risks of dental trauma and emphasize preventive measures. CLINICAL SIGNIFICANCE: Parents should be made aware of the widespread prevalence, risk factors, and consequences of trauma to primary dentition, so that they can seek appropriate care timely. The time elapsed between injury and dental care is of utmost importance.

Carbon material produced by hydrothermal carbonisation of food waste as an electrode material for supercapacitor application: A circular economy approach.

This study aims to use landfill leachate (LL) as an aqueous medium during hydrothermal carbonisation (HTC) of food waste to produce hydrochar (FWH-LL-C), which could be used as an electrode material in energy storage devices. The structural properties and electrochemical performance of the hydrochar were compared to that obtained using distilled water as a reaction medium (FWH-DW-C). The results showed that there is a difference in Brunauer-Emmett-Teller (BET) surface area of FWH-LL-C (220 m2 gm-1) and FWH-DW-C (319 m2 gm-1). The electrochemical properties were comparable, with FWH-LL-C having 227 F g-1 specific capacitance at 1 A g-1 current density and FWH-DW-C having 235 F g-1 specific capacitance at 1 A g-1 current density. Furthermore, at a power density of 634 W kg-1, FWH-DW-C achieved the highest energy density of 14.4 Wh kg-1. The energy retention capacity of the electrode was 98% which indicate that the material has an excellent energy storage capacity. The findings suggested that LL could be used as an alternative source of aqueous media during the HTC of food waste to produce hydrochar which could be used as an effective electrode material in supercapacitors.

Aggregation-Enhanced Photoluminescence and Photoacoustics of Atomically Precise Gold Nanoclusters in Lipid Nanodiscs (NANO2).

The authors designed a structurally stable nano-in-nano (NANO2) system highly capable of bioimaging via an aggregation-enhanced NIR excited emission and photoacoustic response achieved based on atomically precise gold nanoclusters protected by linear thiolated ligands [Au25(SC n H2n+1)18, n = 4-16] encapsulated in discoidal phospholipid bicelles through a one-pot synthesis. The detailed morphological characterization of NANO2 is conducted using cryogenic transmission electron microscopy, small/wide angle X-ray scattering with the support of molecular dynamics simulations, providing information on the location of Au nanoclusters in NANO2. The photoluminescence observed for NANO2 is 20-60 times more intense than that of the free Au nanoclusters, with both excitation and emission wavelengths in the near-infrared range, and the photoacoustic signal is more than tripled. The authors attribute this newly discovered aggregation-enhanced photoluminescence and photoacoustic signals to the restriction of intramolecular motion of the clusters' ligands. With the advantages of biocompatibility and high cellular uptake, NANO2 is potentially applicable for both in vitro and in vivo imaging, as the authors demonstrate with NIR excited emission from in vitro A549 human lung and the KB human cervical cancer cells.

First Year of Skilled Nursing Facility Value-based Purchasing Program Penalizes Facilities With Poorer Financial Performance.

BACKGROUND: The Skilled Nursing Facility Value-based Purchasing Program (SNF-VBP) incentivizes facilities to coordinate care, improve quality, and lower hospital readmissions. However, SNF-VBP may unintentionally punish facilities with lower profit margins struggling to invest resources to lower readmissions. OBJECTIVE: The objective of this study was to estimate the SNF-VBP penalty amounts by skilled nursing facility (SNF) profit margin quintiles and examine whether facilities with lower profit margins are more likely to be penalized by SNF-VBP. RESEARCH DESIGN: We combined the first round of SNF-VBP performance data with SNF profit margins and characteristics data. Our outcome variables included estimated penalty amount and a binary measure for whether facilities were penalized by the SNF-VBP. We categorized SNFs into 5 profit margin quintiles and examined the relationship between profit margins and SNF-VBP performance using descriptive and regression analysis. RESULTS: The average profit margins for SNFs in the lowest profit margin quintile was -14.4% compared with the average profit margin of 11.1% for SNFs in the highest profit margin quintile. In adjusted regressions, SNFs in the lowest profit margin quintile had 17% higher odds of being penalized under SNF-VBP compared with facilities in the highest profit margin quintile. The average penalty for SNFs in the lowest profit margin quintile was $22,312. CONCLUSIONS: SNFs in the lowest profit margins are more likely to be penalized by the SNF-VBP, and these losses can exacerbate quality problems in SNFs with lower quality. Alternative approaches to measuring and rewarding SNFs under SNF-VBP or programs to assist struggling SNFs is warranted, particularly considering the coronavirus disease 2019 pandemic, which requires resources for prevention and management.

Label-free quantitative proteomics of Sorghum bicolor reveals the proteins strengthening plant defense against insect pest Chilo partellus.

BACKGROUND: Spotted stem borer- Chilo partellus - a Lepidopteran insect pest of Sorghum bicolor is responsible for major economic losses. It is an oligophagous pest, which bores through the plant stem, causing 'deadheart' and hampering the development of the main cob. We applied a label-free quantitative proteomics approach on three genotypes of S. bicolor with differential resistance/ susceptibility to insect pests, intending to identify the S. bicolor's systemic protein complement contributing to C. partellus tolerance. METHODS: The proteomes of S. bicolor with variable resistance to insect pests, ICSV700, IS2205 (resistant) and Swarna (susceptible) were investigated and compared using label-free quantitative proteomics to identify putative leaf proteins contributing to resistance to C. partellus. RESULTS: The multivariate analysis on a total of 967 proteins led to the identification of proteins correlating with insect resistance/susceptibility of S. bicolor. Upon C. partellus infestation S. bicolor responded by suppression of protein and amino acid biosynthesis, and induction of proteins involved in maintaining photosynthesis and responding to stresses. The gene ontology analysis revealed that C. partellus-responsive proteins in resistant S. bicolor genotypes were mainly involved in stress and defense, small molecule biosynthesis, amino acid metabolism, catalytic and translation regulation activities. At steady-state, the resistant S. bicolor genotypes displayed at least two-fold higher numbers of unique proteins than the susceptible genotype Swarna, mostly involved in catalytic activities. Gene expression analysis of selected candidates was performed on S. bicolor by artificial induction to mimic C. partellus infestation. CONCLUSION: The collection of identified proteins differentially expressed in resistant S. bicolor, are interesting candidates for further elucidation of their role in defense against insect pests.

Molecular Binding Mechanism and Pharmacology Comparative Analysis of Noscapine for Repurposing against SARS-CoV-2 Protease.

Originating in the city of Wuhan in China in December 2019, COVID-19 has emerged now as a global health emergency with a high number of deaths worldwide. COVID-19 is caused by a novel coronavirus, referred to as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), resulting in pandemic conditions around the globe. We are in the battleground to fight against the virus by rapidly developing therapeutic strategies in tackling SARS-CoV-2 and saving human lives from COVID-19. Scientists are evaluating several known drugs either for the pathogen or the host; however, many of them are reported to be associated with side effects. In the present study, we report the molecular binding mechanisms of the natural alkaloid, noscapine, for repurposing against the main protease of SARS-CoV-2, a key enzyme involved in its reproduction. We performed the molecular dynamics (MD) simulation in an explicit solvent to investigate the molecular mechanisms of noscapine for stable binding and conformational changes to the main protease (Mpro) of SARS-CoV-2. The drug repurposing study revealed the high potential of noscapine and proximal binding to the Mpro enzyme in a comparative binding pattern analyzed with chloroquine, ribavirin, and favipiravir. Noscapine binds closely to binding pocket-3 of the Mpro enzyme and depicted stable binding with RMSD 0.1-1.9 Å and RMSF profile peak conformational fluctuations at 202-306 residues, and a Rg score ranging from 21.9 to 22.4 Å. The MM/PB (GB) SA calculation landscape revealed the most significant contribution in terms of binding energy with ΔPB -19.08 and ΔGB -27.17 kcal/mol. The electrostatic energy distribution in MM energy was obtained to be -71.16 kcal/mol and depicted high free energy decomposition (electrostatic energy) at 155-306 residues (binding pocket-3) of Mpro by a MM force field. Moreover, the dynamical residue cross-correlation map also stated that the high pairwise correlation occurred at binding residues 200-306 of the Mpro enzyme (binding pocket-3) with noscapine. Principal component analysis depicted the enhanced movement of protein atoms with a high number of static hydrogen bonds. The obtained binding results of noscapine were also well correlated with the pharmacokinetic parameters of antiviral drugs.

Challenges, opportunities, and innovations for effective solid waste management during and post COVID-19 pandemic.

The crisis brought upon by the COVID-19 pandemic has altered global waste generation dynamics and therefore has necessitated special attention. The unexpected fluctuations in waste composition and quantity also require a dynamic response from policymakers. This study highlights the challenges faced by the solid waste management sector during the pandemic and the underlying opportunities to fill existing loopholes in the system. The study presents specific cases for biomedical waste, plastic waste, and food waste management - all of which have been a major cause of concern during this crisis. Further, without active citizen participation and cooperation, commingled virus-laden biomedical waste with the regular solid waste stream pose significant negative health and safety issues to sanitation workers. Single-use plastic usage is set to bounce back due to growing concerns of hygiene, particularly from products used for personal protection and healthcare purposes. It is expected that household food waste generation may reduce due to increased conscious buying of more non-perishable items during lockdown and due to concerns of food shortage. However, there is a chance of increase in food waste from the broken supply chains such as food items getting stuck on road due to restriction in vehicle movements, lack of workers in the warehouse for handling the food products, etc. The study also stresses the need for building localized resilient supply chains to counter such situations during future pandemics. While offering innovative solutions to existing waste management challenges, the study also suggests some key recommendations to the policymakers to help handle probable future pandemics if any holistically.

Quantifying the drivers of urban expansion in Nepal.

The Tarai region of Nepal is regarded as the food bowl of Nepal, and yet urban areas have increased in size at an average annual rate of 12% for the 30 years since 1988/1989, largely at the expense of prime agricultural land. Nepal is recognized internationally as highly sensitive to food security with 40% of its population undernourished. To aid future planning and reduce potential further loss of agricultural land and consequent increased food insecurity, we here investigated the previously unknown factors underlying this rapid urban expansion. We achieved this through analyses of land use and land cover (LULC) data, population, and climatic data, in association with focus group discussions and questionnaire surveys. We found that socioeconomic factors were perceived to have made the highest (62%) contribution to urbanization, particularly migration-led population growth and the economic opportunities offered by urban areas, followed by political factors (14.5%), physical factors (12%), and planning and policy factors (11.5%). In addition, climate and physiographic features make the area attractive for urban development along with favorable government plans and policies. Accelerated urban expansion during this period was particularly driven by mass migration due to political upheaval in the country resulting in rapid population and urban center growth. Of the total 293 urban centers in the country, the Tarai region includes 150 (51.2%) of which 77 (26.3%) are located in province 2 alone and accommodate 17.2% of Nepal's households. This increasing urbanization trend is expected to continue in the future due to current socioeconomic and demographic factors. We hope our results which show what has driven past urbanization will aid future urban planning and management of the Tarai as well as other similar regions elsewhere in the world. We also identified that such rapid urban growth is largely at the cost of populations in rural areas with rural depopulation resulting in agriculture being abandoned in some areas. Given Nepal's sensitivity to food security and lower food production, this will be an increasing problem for the future.

Ayurveda and Epigenetics.

Ayurveda is a comprehensive, natural health care system that originated in the ancient Vedic times of India. Epigenetics refers to the external modification of DNA that turns genes on and off, affecting gene expression. This occurs without changes in the basic structure of the DNA. This gene expression can have transgenerational effects. The major factors that cause epigenetic changes are lifestyle and behavior, diet and digestion, stress, and environmental factors. Ayurveda addresses these factors, thereby affecting the Deha (body) Prakriti (psychophysiological constitution), which corresponds to the phenotype, and indirectly the Janma (birth) Prakriti, which corresponds to the genotype. Thus, it is proposed that epigenetics is an important mechanism of Ayurveda. This correlation and understanding will lead to better communication and understanding with the current medical system, and lead to better integration of both sciences in the management of optimal health. In addition, research on Ayurvedic modalities affecting gene expression will further increase correlation and understanding between the current medical system and Ayurveda.

Imidacloprid impedes mitochondrial function and induces oxidative stress in cotton bollworm, Helicoverpa armigera larvae (Hubner: Noctuidae).

Neonicotinoids have high agonistic affinity to insect nicotinic acetylcholine receptors (nAChR) and are frequently used as insecticides against most devastating lepidopteran insect pests. Imidacloprid influenced dose-dependent decline in the state III and IV respiration, respiration control index (RCI), and P/O ratios, in vitro and in vivo. The bioassay indicated its LD50 value to be 531.24 µM. The insecticide exhibited a dose-dependent inhibition on F0F1-ATPase and complex IV activity. At 600 µM, the insecticide inhibited 83.62 and 27.13% of F0F1-ATPase and complex IV activity, respectively, and induced the release of 0.26 nmoles/min/mg protein of cytochrome c. A significant dose- and time-dependent increase in oxidative stress was observed; at 600 µM, the insecticide correspondingly induced lipid peroxidation, LDH activity, and accumulation of H2O2 content by 83.33, 31.51 and 223.66%. The stress was the maximum at 48 h of insecticide treatment (91.58, 35.28, and 189.80%, respectively). In contrast, catalase and superoxide dismutase were reduced in a dose- and time-dependent manner in imidacloprid-fed larvae. The results therefore suggest that imidacloprid impedes mitochondrial function and induces oxidative stress in H. armigera, which contributes to reduced growth of the larvae along with its neurotoxic effect.

Growth of wormlike micelles of surfactant induced by embedded polymer: role of polymer chain length.

Incorporation of polymer chains into wormlike surfactant micelles, which find a large range of applications, offers the opportunity to modify their structure and properties. In this paper, using spectroscopic, scattering and rheological techniques and computer simulations, we study the incorporation of poly(4-vinylpyridine) of two different molecular weights (MWs) into entangled networks of wormlike surfactant micelles of potassium oleate. Using NMR-spectroscopy we show that, independent of its MW, the polymer incorporates into the core-corona interface of the surfactant micelles. According to SANS data, the polymer does not alter the micelle structure or the micelle radius, but diminishes the packing density of the surfactant. At the same time, rheology reveals a stark difference between the surfactant networks with embedded polymers of different MWs. Networks with the higher-MW polymer possess larger viscosity and a longer relaxation time, which we attribute to the larger length of the hybrid micelles. Moreover, we demonstrate that in an intermediate concentration range the higher-MW polymer is able to link neighbouring surfactant micelles together, which has never been previously observed. However, with a further increase in polymer content the micelles become smaller due to the high breaking susceptibility of the boundaries of polymer-containing sections, leading to the stabilization of micellar end-caps by the embedded macromolecules. This process is more prominent in the case of the shorter polymer. Our finding that an increased MW of macromolecules permits the formation of longer hybrid micelles and enhances their rheological properties is of obvious importance for the fundamental understanding of polymer-surfactant interactions and the development of new industrial formulations based on hybrid polymer-wormlike surfactant micelles.

State insurance mandates and off-label use of chemotherapy.

Access to cancer drugs used off-label is important to cancer patients but may drive up healthcare costs with little evidence of clinical benefit. We hypothesized that state health insurance mandates for private insurers to provide coverage for off-label use of cancer drugs cause higher rates of off-label use. We used Truven MarketScan data from 1999 to 2007 on utilization of 35 infused chemotherapy drugs in private health plans in the United States, covering the period when eight states implemented off-label coverage laws. We studied trends in off-label use of drugs, distinguishing between appropriate and inappropriate off-label use according to drug compendia, and estimated difference-in-difference regressions of the effect of state laws on off-label use. We estimate 41% of utilization was off-label, including 17% of use conservatively defined as inappropriate. Trends show gradual declines in off-label use over time. We also find no discernable effect of state laws mandating coverage of off-label use of cancer drugs on utilization patterns under multiple empirical specifications. Our conclusion is that policymakers should consider shifting away from mandating coverage as a way to ensure access to drugs off-label and towards incentivizing adherence to clinical practice guidelines to improve the quality and value of off-label use.

Malpractice Environment vs Direct Litigation: What Drives Nursing Home Exit?

An ongoing concern about medical malpractice litigation is that it may induce provider exit, potentially affecting consumer welfare. The nursing home sector is subject to substantial litigation activity but remains generally understudied in terms of the effects of litigation, due perhaps to a paucity of readily available data. In this article, we estimate the association between litigation and nursing home exit (closure or change in ownership), separating the impact of malpractice environment from direct litigation. We use 2 main data sources for this study: Westlaw's Adverse Filings database (1997-2005) and Online Survey, Certification and Reporting data sets (1997-2005). We use probit models with state and year fixed effects to examine the relationship between litigation and the probability of nursing home closure or change in ownership with and without adjustment for malpractice environment. We examine the relationship on average and also stratify by profit status, chain membership, and market competition. We find that direct litigation against a nursing home has a nonsignificant effect on the probability of closure or change in ownership within the subsequent 2 years. In contrast, the broader malpractice environment has a significant effect on change in ownership, even for nursing homes that have not been sued, but not on closure. Effects are stronger among for-profit and chain facilities and those in more competitive markets. A high-risk malpractice environment is associated with change of ownership of nursing homes regardless of whether they have been directly sued, indicating that it is too blunt an instrument for weeding out low-quality nursing homes.

Alkaline serine proteases from Helicoverpa armigera: potential candidates for industrial applications.

We characterized trypsin- and chymotrypsin-like serine alkaline proteases from cotton bollworm, Helicoverpa armigera, for their probable potential application as additives in various bio-formulations. Purification was achieved by using hydroxylapatite, DEAE sephadex and CM sephadex columns, which resulted in increased enzyme activity by 13.76- and 14.05-fold for trypsin and chymotrypsin, respectively. Michaelis-Menten constants (Km ) for substrates of trypsin and chymotrypsin, BApNA and SAAPFpNA, were found to be 1.25 and 0.085 mM, correspondingly. Fluorescent zymogram analysis indicated the presence of five trypsin bands with molecular masses of ∼21, 25, 38, 40, and 66 kDa and two chymotrypsin bands with molecular masses of ∼29 and 34 kDa in SDS-PAGE. The optimum pH was 10.0 and optimum temperature was 50°C for proteolytic activity for the purified proteases. The proteases were inhibited by synthetic inhibitors such as PMSF, aprotonin, leupeptin, pefabloc, and antipain. TLCK and TPCK inhibited about 94 and 90% of trypsin and chymotrypsin activity, respectively, while EDTA, EGTA, E64, pepstatin, idoacetamide, and bestatin did not affect the enzymes. The purified enzymes exhibited high stability and compatibility with metal ions; oxidizing, reducing, and bleaching agents; organic solvents; and commercial detergents. Short life cycles, voracious feeding behavior, and production of multiple forms of proteases in the midgut with rapid catalytic activity and chemostability can serve H. armigera as an excellent alternative source of industrially important proteases for use as additives in stain removers, detergents, and other bio-formulations. Identification of enzymes with essential industrial properties from insect species could be a bioresource.

Evaluation of flubendiamide-induced mitochondrial dysfunction and metabolic changes in Helicoverpa armigera (Hubner).

Phthalic acid diamide insecticides are the most effective insecticides used against most of the lepidopteran pests including Helicoverpa armigera, a polyphagous pest posing threat to several crops worldwide. The present studies were undertaken to understand different target sites and their interaction with insect ryanodine receptors (RyR). Bioassays indicated that flubendiamide inhibited the larval growth in dose-dependent manner with LD50 value of 0.72 µM, and at 0.8 µM larval growth decreased by about 88%. Flubendiamide accelerated the Ca2+ -ATPase activity in dose-dependent trend, and at 0.8 µM, the activity was increased by 77.47%. Flubendiamide impedes mitochondrial function by interfering with complex I and F0 F1 -ATPase activity, and at 0.8 µM the inhibition was found to be about 92% and 50%, respectively. In vitro incubation of larval mitochondria with flubendiamide induced the efflux of cytochrome c, indicating the mitochondrial toxicity of the insecticide. Flubendiamide inhibited lactate dehydrogenase and the accumulation of H2 O2 , thereby preventing the cells from lipid peroxidation compared to control larvae. At 0.8 µM the LDH, H2 O2 content and lipid peroxidation was inhibited by 98.44, 70.81, and 70.81%, respectively. Cytochrome P450, general esterases, AChE, and antioxidant enzymes (catalase and superoxide dismutase) exhibited a dose-dependent increasing trend, whereas alkaline phosphatase and the midgut proteases, except amino peptidase, exhibited dose-dependent inhibition in insecticide-fed larvae. The results suggest that flubendiamide induced the harmful effects on the growth and development of H. armigera larvae by inducing mitochondrial dysfunction and inhibition of midgut proteases, along with its interaction with RyR.