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This paper proposes a mathematical model to optimally design a multi-modal global production and logistics network consisting of multiple plants, warehouses, and marketplaces. The proposed model is a mixed integer linear program (MILP), which optimally selects different facilities and warehouses required to be active in each time period to fulfil the demand of various marketplaces. The objective function is cost minimization pertaining to setup, production, inventory holding, and transportation. Along with this, the model also decides the optimal quantities to be transported among the plants, warehouses, and marketplaces. The model also optimally selects the transportation mode to be deployed. The paper then expands the proposed model to include a time-cost trade off by imposing a penalty cost for delays and compares and critiques the results of the two scenarios. The proposed MILP has been validated on a randomly generated data set consisting of 4 plants, 6 warehouses, 4 marketplaces, and 3 time periods (4P-6W-4 M-3T) using LINGO 10 optimization package. The illustration considers three modes of transportation namely, road, rail, and air. Last, the paper concludes with discussing managerial implications of the work along with suggesting some research directions for future. [ABSTRACT FROM AUTHOR]

Rust is a relatively new programming language that aims to provide memory safety at compile time. It introduces a novel ownership system that enforces the automatic deallocation of unused resources without using a garbage collector. In light of Rust's promise of safety, a natural question arises about the possible benefits of exploiting ownership to ensure the memory safety of C programs. In our previous work, we developed a formal ownership checker to verify whether a C program satisfies exclusive ownership constraints. In this paper, we further propose an ownership-based safe memory deallocation approach, named SafeMD, to fix memory leaks in the C programs that satisfy exclusive ownership defined in the prior formal ownership checker. Benefiting from the C programs satisfying exclusive ownership, SafeMD obviates alias and inter-procedural analysis. Also, the patches generated by SafeMD make the input C programs still satisfy exclusive ownership. Usually, a C program that satisfies the exclusive ownership constraints is safer than its normal version. Our evaluation shows that SafeMD is effective in fixing memory leaks of C programs that satisfy exclusive ownership. [ABSTRACT FROM AUTHOR]

We investigate the torsion-free classes satisfying the Jordan-Hölder property in the representation category of a quiver of type A. Explicitly, we use reflection functors and c-sortable elements to give a combinatorial criterion for determining such torsion-free classes. [ABSTRACT FROM AUTHOR]

Clogging of emitters is one of the main challenges for farmers using drip irrigation systems. Therefore, in the present study, solutions to reduce chemical clogging of emitters based on acid-washing methods and ultrasonic systems have been presented. The ultrasonic system, considered a type of green technology, has been proposed to mitigate emitter clogging in drip irrigation systems. In this regard, first, samples of emitters were selected from the chosen fields, and then they were grouped by measuring their discharge. Based on the measured discharge compared to the nominal discharge, the emitters were classified into five categories in terms of clogging: category 1 with 100% clogging, category 2 with 75-100% clogging, category 3 with 50-75% clogging, category 4 with 25-50% clogging, and category 5 with 0- 25% clogging. Four treatments were applied for each category: (1) acid washing at pH = 3, (2) acid washing at pH = 5, (3) ultrasonic bath cleaning, and (4) ultrasonic-acid washing. A reduction in clogging of zero-grade emitters, when placed in an ultrasonic bath for 15 minutes, was approximately 45%. Based on the analysis of variance, it can be observed that, with a Pvalue of 0.1 and an F-value of 2.81, the use of the ultrasonic method significantly affects emitter clogging at a 90% confidence level. A comparison of clogging reduction after washing shows the significant superiority of the ultrasonic method over acid washing. The results revealed that the ultrasonic washing method only reduced physical clogging, while the acid washing method reduced chemical clogging. The ultrasonic system is an environmentally friendly and green technology proposed to reduce emitter clogging in drip irrigation systems. [ABSTRACT FROM AUTHOR]

AbstractDiglycolamide (DGA) resin, a product produced by Eichrom Technologies, Inc. employs TODGA (N,N,N′,N′-tetraoctyldiglycolamide) as the active extractant, which will be used by Savannah River National Laboratory to extract trivalent actinides and lanthanides from dissolved irradiated Mark-18A targets. The final form of the extracted material will be an oxide suitable for shipment. A two-step process was developed and validated for the direct recovery of actinides and lanthanides loaded on I-grade DGA resin as nitrates by thermally drying and decomposing resin loaded with Nd(III), a surrogate for trivalent actinides and lanthanides, under inert conditions followed by calcining the resultant residue in air to provide an oxide product. A stepwise heating profile up to 385°C under argon gas flow resulted in 85% to 89% mass loss during the resin drying and decomposition step, and calcination of the resultant Nd-loaded resin residue provided an overall material mass loss of ≥ 98%. Recoveries from resin saturated with Nd(III) from 7 M and 0.35 M nitric acid subjected to this process were 30.7 mg and 27.6 mg Nd/g dry resin, respectively, representing an average of 96.1% of Nd retained in the resin bed. [ABSTRACT FROM AUTHOR]

Copyright of Cuadernos de Psicología del Deporte is the property of Cuadernos de Psicologia del Deporte and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

This special issue on spatial macroeconomics aims to bridge the divide between spatial and macroeconomics. Defined in the introduction, spatial macroeconomics explores the interactions between economic activity and geographical space. The issue comprises eleven papers authored by a total of 32 researchers. These papers were selected through a combination of solicited submissions and an open call for contributions. Four papers within this special issue delve into spatial macroeconomic theory. They cover topics such as agglomeration economies for innovation, a neoclassical spatial general equilibrium growth model, the spatial sorting of heterogeneous workers and the impact of national industrial policies in strategic industries on trade. Additionally, seven papers offer empirical studies that encompass a wide range of methodologies. These include general equilibrium models, input-output-based analyses and econometric models. The empirical research addresses various topics, such as the impact of trade on productivity, the trade-off between efficiency and equity, fiscal assistance, local and nationwide fiscal multipliers, forced human displacement during wars and the spatial diffusion effects of renewable energy resource deployment. [ABSTRACT FROM AUTHOR]

The recent so-called 'data revolution' offers unprecedented opportunities to innovate regional policies. New data sources are being widely used by the scientific community, however their uptake is far from being systematic in the policy cycle, where data innovation can improve territorial impact assessment. This paper presents a survey on the use of non-traditional data in the context of regional policy, together with a case study on real estate markets of three European countries, highlighting the perspectives and limitations of computational social science in regional analysis in terms of data quality and availability. [ABSTRACT FROM AUTHOR]

Diamond nanoparticles represent an elegant class of nanoscale materials with promising applications in nanotechnology. Solid-state NMR is a powerful technique for investigating the atomic-level structure and dynamics of nanomaterials in their natural state. The present study illustrates the application of high-resolution 13C NMR to nanomaterials characterization, and the fundamental 13C spin–lattice relaxation times highlight the spatial arrangement of surface-associated paramagnetic centers around the core sp3 carbon assembly of diamond nanoparticles, delineating the unique size-dependent physicochemical characteristics of diamond nanoparticles. [ABSTRACT FROM AUTHOR]

In this study, SiO@graphite@C@Al2O3 (SiO@G@C@A) composites are synthesized by varying the content of Al2O3, and their morphology and structure and their electrochemical performance are investigated in detail. The results indicate that the SiO/G@C@A-2 composite exhibits a specific capacity of 977.1 mA h g−1 at a current density of 0.1 A g−1 with a coulombic efficiency of 71.15%. Even after 100 cycles at a current density of 0.5 A g−1, it retains a delithiated specific capacity of 640.7 mA h g−1 and a capacity retention rate of 73.56%. Moreover, when the current density is raised to 2 A g−1, it maintains a delithiated capacity of 568.4 mA h g−1 and a capacity retention rate of 58.51%. The excellent electrochemical performance is ascribed to the synergistic effect of different components. The inclusion of graphite enhances overall conductivity while mitigating the volume expansion of the SiO. The application of asphalt pyrolytic carbon as a coating effectively isolates the SiO from the electrolyte, further reducing volume expansion and enhancing conductivity. The introduction of Al2O3 can absorb trace amounts of hydrogen fluoride (HF) generated during charge and discharge processes. Additionally, it facilitates the formation of an AlF3 film on the particle surfaces, which hinders and decelerates electrolyte dissolution into the electrode. The prepared composites exhibit promising prospects as lithium-ion battery anode materials. [ABSTRACT FROM AUTHOR]

Heteroatom doping of graphitic carbon is of high interest for tuning its physicochemical properties. Aluminum is commonly reported as a high-interest dopant, but few synthetic strategies have been reported owing to the low equilibrium solubility of Al within graphite. Herein we report several strategies to achieve metastable aluminum-substituted turbostratic graphitic carbon materials with aluminum contents up to ~ 0.5 at%, via co-pyrolysis of two molecular precursors between 800 and 1100°C. The resulting materials exhibit turbostratic graphitic structure and a previously unreported aluminum environment detectable by X-ray absorption spectroscopy (XAS), a likely signature of trigonal planar or puckered AlC3-type sites. [ABSTRACT FROM AUTHOR]

Background: The increasing number of cancer cases requires developing newer approaches to treat this disease. One approach uses natural compounds with known anticancer effects, such as tocotrienols. Many cell-based and animal-model studies found that tocotrienols possess potent anticancer activities. However, the exact molecular regulatory mechanism through which tocotrienols exert anticancer actions remains unclear. Methods: This scoping review analysed data from original research articles reporting on the anticancer effects of tocotrienols on human cancer cell lines published in the last seven years (January 2015 and September 2021) using a systematic scoping review approach. From the initial 619 research papers [ProQuest (n= 61), PubMed (n= 84), Embase (n = 148), Ovid Medline (n =53), Scopus (n = 137), Web of Science (n =136)] identified using pre-defined keywords, only 37 articles met the inclusion and exclusion criteria for this review. Human cancers commonly studied in the 37 research articles include breast, lung, prostate and colorectal cancer cell lines. Results: The analysis showed that exposing human cancer cell lines to tocotrienols triggered common anticancer mechanisms such as activation of apoptosis and inhibition of proliferation, angiogenesis and cell migration through regulation of key regulatory genes and proteins involved in these pathways. Conclusions: The findings show that tocotrienols regulate a number of biomarkers that induce cell death and regulate cell cycle in various types of human cancer cells. Further targeted studies are required to map the definite pathways by which T3 exerts their action and to better understand the cellular actions and the regulatory pathways.

BackgroundGermline variants in the DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2) cause Lynch syndrome, an autosomal dominant hereditary cancer susceptibility syndrome. The risk for endometrial cancer is significantly higher in women with MSH6 pathogenic/likely pathogenic (P/LP) variants compared with that for MLH1 or MSH2 variants.MethodsThe proband was tested via a clinical testing, Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT). RT-PCR was performed using patient's blood DNA and cDNA was analyzed by DNA sequencing and a cloning approach.ResultsWe report a 56-year-old female with endometrial cancer who carries a germline variant, MSH6 c.4001G > C, located at the last nucleotide of exon 9. While the pathogenicity of this variant was previously unknown, functional studies demonstrated that this variant completely abolished normal splicing and caused exon 9 skipping, which is expected to lead to a prematurely truncated or abnormal protein.ConclusionOur results indicate that this variant likely contributes to cancer predisposition through disruption of normal splicing, and is classified as likely pathogenic.

Summary: Variations in arbuscular mycorrhizae (AM) effects on plant growth (MGR) are commonly assumed to result from cost : benefit balances, with C as the cost and, most frequently, P as the benefit. The trade‐balance model (TBM) adopts these assumptions and hypothesizes that mycorrhizal benefit depends on C : N : P stoichiometry. Although widely accepted, the TBM has not been experimentally tested.We isolated the parameters included in the TBM and tested these assumptions using it as framework. Oryza sativa plants were supplied with different N : P ratios at low light level, establishing different C : P and C : N exchange rates, and C, N or P limitation. MGR and effects on nutrient uptake, %M, ERM, photosynthesis and shoot starch were measured.C distribution to AM fungi played no role in MGR, and N was essential for all AM effects, including on P nutrition. C distribution to AM and MGR varied with the limiting nutrient (N or P), and evidence of extensive interplay between N and P was observed.The TBM was not confirmed. The results agreed with the exchange of surplus resources and source–sink regulation of resource distribution among plants and AMF. Rather than depending on exchange rates, resource exchange may simply obey both symbiont needs, not requiring further regulation. [ABSTRACT FROM AUTHOR]

Despite extensive studies on how environmental factors influence plant and soil nutrient distribution and stoichiometry, how the intertidal zone affects plant and soil distribution, and stoichiometry remains unclear. Therefore, this study analyzed the leaf and soil organic carbon (C), nitrogen (N), and phosphorus (P) concentrations and stoichiometry in mangrove forest wetlands in South China. The results demonstrated that leaf and soil phosphorus concentrations were significantly different in different plants and intertidal zones. The average leaf N:P ratio was 12.85 and was mainly nitrogen-limited. Soil organic carbon at 0-10 cm was higher in the mid- and low intertidal zones, while the opposite was true for the high intertidal zone. The nitrogen concentration at 0-10 cm was less than that at <30-40 cm in both the high and mid-intertidal zones, while the opposite was true for the low intertidal zone. The phosphorus concentration varied similarly to that of carbon. The C:N ratios at both 0-10 cm and 30-40 cm were the highest in the high intertidal zone and decreased with decreasing elevation. Contrastingly, the C:P and N:P ratios did not differ much among the three intertidal zones and between the 0-10-cm and 30-40-cm profiles. The soil C:N ratios significantly correlated with the leaf carbon, phosphorus, and C:P ratio. Overall, the results demonstrated that the soil stoichiometry responded differently to different plant communities and intertidal zones. These differences might be attributed to variations in the environmental conditions of plant communities. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Both humoral and cellular immunity can be significantly influenced by the immunological responses to vaccination, and both responses are essential. Vaccination is the most consistent, safe, and cost-efficient practice for controlling the COVID-19 pandemic. PATIENTS AND METHODS: Blood samples were collected from participants who received two vaccine doses of COVID-19 Pfizer/BioNTech (BNT162b2) before and on days 7 and 10 after the first and second immunization. We evaluated some hematological and immunological markers responses to the 1st and 2nd doses of the BNT162b2 mRNA (Pfizer/BioNtech) vaccine. RESULTS: In healthy subjects' neutrophil and WBC counts significantly increased compared to those after the first dose. The results of all first-group participant categories demonstrated no discernible variations in lymphocyte counts. There was no change in IgM or IgG in all second- group cohorts, except for a considerable rise in IgG levels in people with a history of coronavirus infection following the second dosage compared to baseline. After the second dose, CD4+ T-cell and CD8+ T-cell levels rose in all groups compared to before the immunization and after the first dosage. Data demonstrated a sub-stantial rise in neutrophil-lymphocyte ratio (NLR) after the second dose of the vaccine. Individuals who had previously had COVID-19 disease experienced a considerable increase in C3 and C4 levels after the first and second dosages compared to baseline. Additionally, compared to their levels after the first dosage, C4 levels increased significantly following the second dosage. Interleukin (IL)-6, IL-15, macrophage colony-stimulating factor (M-CSF), granulocyte colony stimulating factor (G-CSF), interferon gamma-induced protein 10 (IP-10/CXCL10), and macrophage inflammatory protein-1 alpha (MIP-1α/CCL3) levels were increased after boost correlated with Spike antibody levels, supporting their utility as indicators of successful humoral immunity development in response to vaccination. CONCLUSIONS: We can conclude that the Pfizer/BioNTech vaccine produced a more potent T-cell response than humoral ones. [ABSTRACT FROM AUTHOR]

Field Experiment to validate the Biointensive IPM (BIPM) package on black rice variety "Kola Chaul" revealed that BIPM package consisting seedlings root dip with Pseudomonas fluorescens @ 2% solution; application of organic manure MUKTA @ 2 t ha-1; application of Beauveria bassiana @ 1013 spores ha-1 against sucking pests, use of bird perch (10 ha-1), 6 releases of Trichogramma japonicum @ 50,000 ha-1 at 10 days interval starting from 30 days after treatment (DAT) for stem borer and leaf folder infestation along with need based application of botanicals NSKE 5% (5 l/ l-1) could suppress the major rice pests and produce higher grain yield as compared to the farmer's practice (FP). Maximum grain yield of 3124.8 kg ha-1 and 3139.10 kg ha-1 was recorded in BIPM field as compared to 2882.6 kg ha-1 and 2897.20 kg ha-1 in farmers practice plot during 2020-21 and 2021-22, respectively. Thus, BIPM practice was observed to be superior to FP with higher benefit: cost ratio. [ABSTRACT FROM AUTHOR]

The death of C. Richard Conti, MD, MACC in February 2022 marked the passing of a global leader in cardiology who played a pivotal role in the history of the American College of Cardiology and the College's outreach to the People's Republic of China.

A sequential chlorination and electrochemical reduction process is demonstrated to convert Na–doped iridium oxide nanoparticles into useful IrIIICl 6 3− (aq) serving as the precursor for the fabrication of bio–stimulating electrode. The Na–doped iridium oxide nanoparticles are treated in 35 wt% hydrochloric acid at 70 °C for 18 h to form IrIVCl 6 2− (aq) with pH of 0.3, so the latter could be readily reduced to IrIIICl 6 3− (aq) at a potentiostatic mode of 0.6 V (vs. SCE). The oxidation state and the nature of complexing ligands for the regenerated IrIIICl 6 3− and IrIVCl 6 2−, as well as commercially available IrIIICl 6 3− are validated by X–ray Absorption Spectroscopy. UV–Vis profiles of regenerated IrIVCl 6 2− (aq) are recorded and the absorbance at 487 nm signal is benchmarked against that of standard IrIVCl 6 2− (aq) to obtain the effective regeneration ratio of 68.6%. X–ray diffraction patterns of Na–doped iridium oxide nanoparticles before and after the annealing treatment indicate the amorphous structure facilitates the chlorination step. The regenerated IrIIICl 6 3− is reused to synthesize Na–doped iridium oxide thin film serving as a bio–stimulating electrode for implantable bio–electronics. The regenerated Na–doped iridium oxide thin film reveals a charge-storage capacity of 0.32 mC/cm2-nm and impressive stability that are comparable to those of fresh Na–doped iridium oxide thin film derived from commercially available IrIIICl 6 3−. [ABSTRACT FROM AUTHOR]

Copyright of Science & Technology of Food Industry is the property of Science & Technology of Food Industry Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Specification languages for runtime verification are commonly rooted in formal languages, such as temporal logic, automata, or regular expressions. We argue that, for practical purposes, specification languages for monitoring should allow language features similar to those found in general purpose programming languages, in addition to providing specialized monitoring constructs. Using a realistic and large event-log, we compare two such programming-oriented monitoring language systems to a temporal logic-based monitoring system that was previously evaluated on the same log. The first programming-oriented language is a library in Scala developed for runtime verification. The other language is a scripting language, originally developed for fast static code analysis. We formulate the same reasonably complex properties as in the temporal logic case, using both methods, and compare the efficiency with which they can be checked against the large event log, and the ease with which the properties can be formulated. [ABSTRACT FROM AUTHOR]

Luvic Greyzemic Phaeozems have been farmed for centuries in Western Ukraine. We investigate their stocks of major nutrients and stoichiometry under arable crops receiving conventional NPK fertilisation and an unfertilised control. Total carbon stocks increase only with parallel increases in total N, P, Ca and Mg. Likewise, total N increases along with parallel increases in total Ca and Mg, P and Ca, P and C. Under winter barley, application of the background fertilisation (N23P60K60) + N97 (urea) before sowing, with or without nitrapyrin as a nitrogen stabiliser, improved the status of C, N, Ca and Mg to P in the 0–20 cm soil layer. The best ratio of total C, N, Ca and Mg to P and the best C:N, C:P, N:P, and Ca:N ratios were achieved with the background fertilisation plus nitrapyrin and urea or ammonium nitrate. The system cannot hold onto nutrients, nitrogen in particular, applied in excess of the harmonic stoichiometry. [ABSTRACT FROM AUTHOR]

Our cost of illness study aimed to provide an estimate of the burden related to systemic lupus erythematosus (SLE) in the Mexican context. Our model was used to simulate the resource utilization and economic consequences over a period of 5 years for patients with SLE in Mexico. The model simulated four health states—three phenotypes of SLE, including mild, moderate, and severe states, and death. Clinical parameters were retrieved from the literature. Resource utilization in our model represents the most common practice in the Mexican healthcare system. These include disease management, transient events (e.g. infections, flares, and complications due to SLE-related organ damage), and indirect costs. Direct non-medical costs were not considered. One-way sensitivity analysis was performed. The number of targeted Mexican SLE patients was 57,754. The numbers of SLE patients diagnosed with mild, moderate, and severe phenotypes were 8,230, 44,291, and 5,233, respectively. Disease management costs, including the treatment of each phenotype and disease follow-up, were MXN 4 billion ($ 415 million); the costs of transient events (infections, flares, and consequences of SLE-related organ damage) were MXN 5 billion ($ 478 million). Productivity loss costs among adult employed Mexican patients with SLE were estimated at MXN 17 billion ($ 1.6 billion). The total SLE cost in Mexico over 5 years from the payer and societal perspectives is estimated at MXN 9 billion ($ 893 million) and 26 billion ($ 2.5 billion), respectively. Over 5 years, the costs per patient per year from the payer and societal perspectives were MXN 32,131($ 3,095) and MXN 91,661($ 8,830), respectively. The findings pointed out the substantial economic burden associated with SLE, including the costs of disease progression and SLE transient events, such as flare-ups, infections, and organ damage, in addition to productivity loss due to work capacity impairment. [ABSTRACT FROM AUTHOR]

Our study aims to provide an enhanced comprehension of systemic lupus erythematosus (SLE) burden in United Arab Emirates (UAE), over a five-year period from payer and societal perspective. A Markov model was established to simulate the economic consequences of SLE among UAE population. It included four health states: i) the three phenotypes of SLE, representing mild, moderate, and severe states, and ii) death. Clinical parameters were retrieved from previous literature and validated using the Delphi panel—the most common clinical practice within the Emirati healthcare system. We calculated the disease management, transient events, and indirect costs by macro costing. One-way sensitivity analysis was conducted. The estimated number of SLE patients in our study was 13,359. The number of SLE patients with mild, moderate, and severe phenotypes was 3,914, 8,109, and 1,336, respectively. Disease management costs, including treatment of each phenotype and disease follow-up, were AED 2 billion ($0.89 billion), whereas the costs of transient events (infections, flares, and consequences of SLE-related organ damage) were AED 1 billion ($0.44 billion). The productivity loss costs among adult-employed patients with SLE in the UAE were estimated at AED 7 billion ($3.1 billion). The total SLE cost over five years from payer and societal perspectives is estimated at AED 3 ($1.3 billion) and 10 billion ($4.4 billion), respectively. Additionally, the costs per patient per year from the payer and societal perspectives were AED 45,960 ($20,610) and AED 148,468 ($66,578), respectively. Our findings demonstrate that the burden of SLE in the UAE is enormous, mainly because of the costly complications and productivity loss. More awareness should be created to limit the progression of SLE and reduce the occurrence of flares, necessitating further economic evaluations of novel treatments that could help reduce the economic consequences of SLE in the UAE. [ABSTRACT FROM AUTHOR]

SLE imposes a significant morbidity and mortality as well as a substantial burden on the healthcare system. The model aimed to measure the cost-effectiveness of anifrolumab implementation against belimumab as an add-on-therapy to the standard of care (SoC) over a lifetime horizon for Emirati patients. A microsimulation model was used to assess the cost-effectiveness of anifrolumab against belimumab (IV/SC) as an add-on therapy to SoC in a hypothetical cohort of adult Emirati patients with systemic lupus erythematosus (SLE) over a lifetime horizon. The clinical data was captured from published clinical trials as; TULIP-1, TULIP-2, BLISS-52, BLISS-76 and BLISS‐SC. Health utility scores were constructed according to a linear regression model from the pooled data of the two TULIP Phase III trials of anifrolumab. Our model captures direct SLE-related medical costs from the Dubai Health Authority. Sensitivity analyses were conducted to assess model uncertainty. Using BICLA as a response criterion in the Johns Hopkins cohort, anifrolumab was found to be more effective than belimumab (IV/SC; the incremental discounted QALY of anifrolumab against belimumab was 0.42). The incremental cost-effectiveness ratio (ICER) of anifrolumab against belimumab IV and belimumab SC were AED 466,371 ($209,135) and AED 252,612 ($113,279), respectively, these ICERs are below the cost-effectiveness threshold in the United Arab Emirates (UAE) (three times gross domestic product capita; AED 592,278). In the Toronto lupus cohort, the ICER of anifrolumab against belimumab IV and belimumab SC were AED 491,403 ($220,360) and AED 276,642 ($124,055), respectively (anifrolumab was a cost-effective option vs. belimumab IV and belimumab SC). The addition of anifrolumab to SoC is a cost-effective option versus belimumab for the treatment of adult patients with active, autoantibody-positive SLE, despite being allocated to SoC. Cost-effectiveness was demonstrated by a reduction in complications and organ damage, which reflected costs and outcomes. [ABSTRACT FROM AUTHOR]

Our cost-of-illness (COI) model adopted both payer and societal perspectives over a time horizon of 5 years to measure the economic burden of systemic lupus erythematosus (SLE) in Taiwan. A prevalence-based model was established to estimate the economic consequences of SLE after diagnosis in Taiwan. The model included four health states: (i) the three phenotypes representing mild, moderate, and severe SLE, and (ii) death. The inputs were obtained from a literature review of all the clinical trials and validated using a Delphi panel. The Delphi panel's insights included commonly used treatment strategies for patients with SLE within the Taiwanese healthcare system. The costs mentioned in this model are disease management, monitoring, transient event, and indirect costs. One-way sensitivity analyses were conducted to assess the model uncertainty. The number of patients with SLE in our COI model was 20,189. At diagnosis, the number of SLE patients with mild, moderate, and severe phenotypes was 5,916, 12,255, and 2019, respectively. The total SLE cost in Taiwan over 5 years from both payer and societal perspectives was estimated at TWD 3.9 and 47 billion, respectively. The costs per patient per year from the payer and societal perspective were TWD 38,775 ($2,758) and TWD 466,119 ($33,152), respectively. The findings demonstrated that the burden of SLE in Taiwan over a time horizon of 5 years is substantially high, mainly due to the consequences of economic loss as it affects women and men during their working age, in addition to the costs of SLE management and its consequences, such as flares, infection, and organ damage. Therefore, more attention should be paid to limiting the progression of SLE and the occurrence of flares, and further economic evaluations are necessary to assess novel treatment strategies that could control the disease. [ABSTRACT FROM AUTHOR]

Our cost-of-illness (COI) model adopted the perspective of both payer and society over a time horizon of 5 years to measure the economic burden of systemic lupus erythematosus (SLE) in Malaysia. Our COI model utilized a prevalence-based model to estimate the costs and economic consequences of SLE in Malaysia. The clinical parameters were obtained from published literature and validated using the Delphi panel. Direct and indirect medical costs were measured, including disease management, transient events, and indirect costs. One-way sensitivity analysis was also performed. The number of target Malaysian patients with SLE in the COI model was 18,121. At diagnosis, the numbers of SLE patients with mild, moderate, and severe phenotypes were 2,582, 13,897, and 1,642, respectively. The total SLE cost in Malaysia over 5 years from both payer and society perspectives was estimated at MYR 678 million and 2 billion, respectively. The results showed a considerable cost burden due to productivity losses resulting from SLE-related morbidity and mortality. Over a 5-year time horizon, the costs per patient per year from the payer and society perspectives were MYR 7,484 ($4766) and 24,281($15,465), respectively. Our study demonstrated the substantial economic burden of SLE in Malaysia over a time horizon of 5 years. It affects adults of working age, in addition to the costs of SLE management and its consequences, such as flares, infection, and organ damage. Our COI model indicated that disease management costs among patients with higher disease severity were higher than those among patients with a mild phenotype. Hence, more attetion should be paid to limiting the progression of SLE and the occurrence of flares, with the need for further economic evaluation of novel treatments that could lead to better outcomes. [ABSTRACT FROM AUTHOR]

Our cost-of-illness (COI) model adopted payer and societal perspectives over five years to measure the economic burden of Systemic Lupus Erythematosus (SLE) in Colombia. A prevalence-based model was constructed to estimate costs and economic consequences for SLE patients in Colombia. The model included four health states: three phenotypes of SLE representing mild, moderate, and severe states and death. The clinical inputs were captured from the published literature and validated by the Delphi panel. Our model measured direct medical and indirect costs, including disease management, transient events, and indirect costs. One-way sensitivity analysis was also performed. The number of Colombian SLE patients was 37,498. The number of SLE patients with mild, moderate, and severe phenotypes was 5343, 28757 and 3,397, respectively. SLE-patients with moderate (Colombian pesos; COP 146 billion) and severe phenotypes (COP276 billion) incurred higher costs than those with mild phenotypes (COP2 billion), over 5 years. The total SLE cost in Colombia over five years from the payer and societal perspectives was estimated to be COP 915 billion and 8 trillion, respectively. The costs per patient per year from the payer and societal perspectives were COP 4,881,902 ($3,510) and COP 46,637,054 ($33,528), respectively. The burden of SLE in Colombia over five years is substantially high, mainly due to the consequences of economic loss because it affects women and men of working age, in addition to the costs of SLE management and its consequences, such as flares, infection, and organ damage. Our COI indicated that disease management costs among patients with moderate and severe SLE were substantially higher than those among patients with a mild phenotype. Therefore, more attention should be paid to limiting the progression of SLE and the occurrence of flares, with the need for further economic evaluation of novel treatment strategies that help in disease control. [ABSTRACT FROM AUTHOR]

Titanium carbide has attracted widespread attention due to its excellent properties. This study investigates the process of carbon thermally reducing TiO2 to prepare TiC through a combination of thermodynamic analysis and experiments. The effects of temperature, TiO2/C molar ratio, and time on the phase transformation and morphology evolution of the products are investigated. The synthesis of titanium carbide involves the main reduction path of TiO2–Magnéli–Ti3O5–Ti2O3–TiCxO1−x. With the increase in reaction temperature and TiC content, the microstructure transitions from a smooth disc-like structure to a loose and porous layered structure, while the particle size decreases significantly. The carburisation rate of the reduced product is more affected by temperature, according to chemical analysis. The carburisation rate increased from 18.37% to 36.09% for 2 h–10 h of holding time at 1400 °C, and from 51.43% to 77.57% for 2 h–10 h of holding time at 1500 °C. The quantification of the carburisation rate provides a valuable reference for the preparation of titanium carbide by TiO2. [ABSTRACT FROM AUTHOR]

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Nitrogen (N) fixation is a fundamental mechanism by which N enters streams. Yet, because of modern N saturation, it is difficult to study the importance of N-fixation to stream nutrient budgets. Here, we utilized relatively simple and pristine McMurdo Dry Valley streams to investigate the role of N-fixing Nostoc abundance, streamwater dissolved inorganic N (DIN) concentration, and distance from the source glacier in regulating the elemental and isotopic composition of three microbial mat types (black, orange, and green) at the landscape scale. We found Nostoc-based black mats were the most enriched in δ15N, and δ15N signatures of mats increased where Nostoc was abundant, but did not surpass the atmospheric standard (δ15N ≈ 0‰). Furthermore, green and orange mat δ15N signatures became more depleted with increasing DIN, indicating that mats utilize glacial meltwater-sourced N when available. The distance from the source glacier explained limited variability in mat δ15N across sites, indicating the influence of individual stream characteristics on N spiraling. To further explore longitudinal N spiraling processes generating observed δ15Ν patterns, we developed a simple steady-state mathematical model. Analysis of plausible scenarios with this model confirmed that streams both have the capacity to remove allochthonous DIN over the plausible range of inputs, and that internal N sources are required to account for δ15N signatures and observed DIN concentrations at stream outlets. Collectively, these data and modeling results demonstrate that N-fixation exerts substantial influence within and across these streams, and is presumably dependent upon interconnected organic matter reserves, mineralization rates, and geomorphology. [ABSTRACT FROM AUTHOR]

Due to the rapid growth of the global economy, energy consumption has been steadily increasing, leading to increasing issues such as energy shortages and environmental concerns. Biomass energy, a critical renewable energy source, plays a vital role in advancing low-carbon energy development and resource sustainability. In this study, experiments were conducted to study the migration of C, H, and N elements of corn straw during the microwave heating process, and the effects of residence time, heating temperature, and microwave power were also investigated. The results showed that when the temperature rose, both the proportion of C and H elements fluctuated slightly. Specifically, when the temperature rose from 75 °C to 275 °C, there was a 1.02% increase in the proportion of the C element and a 0.25% decrease in the proportion of the H element. Residence time appeared to be a significant factor influencing the changes in C, H, and N elements. For a 40 min residence time, the proportion of the C element increased from 31.77% to 35.36%, while the proportion of the H element decreased from 4.50% to 3.83%. When there was an increase in the microwave power between 160 W and 200 W, higher temperatures were reached in the samples, leading to the carbonization process of corn straw being more complete. Consequently, the proportion of the C element rose with extended residence time, whereas the proportion of the H element decreased as the residence time increased. [ABSTRACT FROM AUTHOR]

BackgroundAlthough many large, randomized controlled trials (RCT) have been conducted on antibiotic therapy for patients with primary C. difficile infections (CDI), few RCTs have been performed for patients with recurrent CDI (rCDI). In addition, fecal microbial transplant (FMT) is neither FDA-approved or guideline-recommended for patients with pauci-rCDI (first or second recurrences). Therefore, a rigorous RCT of sufficient size was designed to determine the optimal treatment among three antibiotic regimens in current practice for treatment of pauci-rCDI.MethodsVA Cooperative Studies Program (CSP) #596 is a prospective, double-blind, multi-center clinical trial of veteran patients with pauci-rCDI comparing fidaxomicin (FDX) 200 mg twice daily for 10 days and vancomycin (VAN) 125 mg four times daily for 10 days followed by a 3-week vancomycin taper and pulse (VAN-T/P) regimen to a standard course of VAN 125 mg four times daily for 10 days. The primary endpoint is sustained clinical response at day 59, with sustained response measured as a diarrhea composite outcome (D-COM) that includes symptom resolution during treatment (before day 10) without recurrence of diarrhea or other clinically important outcomes through day 59.DiscussionCSP study 596 is designed to compare three current antibiotic treatments for recurrent CDI that are in clinical practice, but which lack high-quality evidence to support strong guideline recommendations. The design of the study which included a pilot phase initiated at six sites with expansion to 24 sites is described along with protocol modifications based on early trial experience and clinical realities including the COVID-19 pandemic.Trial registrationThis study is registered with clinicaltrials.gov (Identifier: NCT02667418).

The auxin-inducible degradation system in C. elegans allows for spatial and temporal control of protein degradation via heterologous expression of a single Arabidopsis thaliana F-box protein, transport inhibitor response 1 (AtTIR1). In this system, exogenous auxin (Indole-3-acetic acid; IAA) enhances the ability of AtTIR1 to function as a substrate recognition component that adapts engineered degron-tagged proteins to the endogenous C. elegans E3 ubiquitin ligases complex [SKR-1/2-CUL-1-F-box (SCF)], targeting them for degradation by the proteosome. While this system has been employed to dissect the developmental functions of many C. elegans proteins, we have found that several auxin-inducible degron (AID)-tagged proteins are constitutively degraded by AtTIR1 in the absence of auxin, leading to undesired loss-of-function phenotypes. In this manuscript, we adapt an orthogonal auxin derivative/mutant AtTIR1 pair [C. elegans AID version 2 (C.e.AIDv2)] that transforms the specificity of allosteric regulation of TIR1 from IAA to one that is dependent on an auxin derivative harboring a bulky aryl group (5-Ph-IAA). We find that a mutant AtTIR1(F79G) allele that alters the ligand-binding interface of TIR1 dramatically reduces ligand-independent degradation of multiple AID*-tagged proteins. In addition to solving the ectopic degradation problem for some AID-targets, the addition of 5-Ph-IAA to culture media of animals expressing AtTIR1(F79G) leads to more penetrant loss-of-function phenotypes for AID*-tagged proteins than those elicited by the AtTIR1-IAA pairing at similar auxin analog concentrations. The improved specificity and efficacy afforded by the mutant AtTIR1(F79G) allele expand the utility of the AID system and broaden the number of proteins that can be effectively targeted with it.

Toxin A (TcdA) and toxin B (TcdB) are two key virulence factors secreted by Clostridioides difficile, which is listed as an urgent threat by the CDC. These two large homologous exotoxins are mainly responsible for diseases associated with C. difficile infection (CDI) with symptoms ranging from diarrhea to life threatening pseudomembranous colitis. Single-domain camelid antibodies (VHHs) AH3 and AA6 are two potent antitoxins against TcdA, which when combined with two TcdB-targeting VHHs showed effective protection against both primary and recurrent CDI in animal models. Here, we report the co-crystal structures of AH3 and AA6 when they form complexes with the glucosyltransferase domain (GTD) and a fragment of the delivery and receptor-binding domain (DRBD) of TcdA, respectively. Based on these structures, we find that AH3 binding enhances the overall stability of the GTD and interferes with its unfolding at acidic pH, and AA6 may inhibit the pH-dependent conformational changes in the DRBD that is necessary for pore formation of TcdA. These studies reveal two functionally critical epitopes on TcdA and shed new insights into neutralizing mechanisms and potential development of epitope-focused vaccines against TcdA.

Microsporidia are ubiquitous obligate intracellular pathogens of animals. These parasites often infect hosts through an oral route, but little is known about the function of host intestinal proteins that facilitate microsporidia invasion. To identify such factors necessary for infection by Nematocida parisii, a natural microsporidian pathogen of Caenorhabditis elegans, we performed a forward genetic screen to identify mutant animals that have a Fitness Advantage with Nematocida (Fawn). We isolated four fawn mutants that are resistant to Nematocida infection and contain mutations in T14E8.4, which we renamed aaim-1 (Antibacterial and Aids invasion by Microsporidia). Expression of AAIM-1 in the intestine of aaim-1 animals restores N. parisii infectivity and this rescue of infectivity is dependent upon AAIM-1 secretion. N. parisii spores in aaim-1 animals are improperly oriented in the intestinal lumen, leading to reduced levels of parasite invasion. Conversely, aaim-1 mutants display both increased colonization and susceptibility to the bacterial pathogen Pseudomonas aeruginosa and overexpression ofaaim-1 reduces P. aeruginosa colonization. Competitive fitness assays show that aaim-1 mutants are favored in the presence of N. parisii but disadvantaged on P. aeruginosa compared to wild-type animals. Together, this work demonstrates how microsporidia exploits a secreted protein to promote host invasion. Our results also suggest evolutionary trade-offs may exist to optimizing host defense against multiple classes of pathogens.

TMEM132D is a human gene identified with multiple risk alleles for panic disorders, anxiety and major depressive disorders. Defining a conserved family of transmembrane proteins, TMEM132D and its homologs are still of unknown molecular functions. By generating loss-of-function mutants of the sole TMEM132 ortholog in C. elegans, we identify abnormal morphologic phenotypes in the dopaminergic PDE neurons. Using a yeast two-hybrid screen, we find that NAP1 directly interacts with the cytoplasmic domain of human TMEM132D, and mutations in C. elegans tmem-132 that disrupt interaction with NAP1 cause similar morphologic defects in the PDE neurons. NAP1 is a component of the WAVE regulatory complex (WRC) that controls F-actin cytoskeletal dynamics. Decreasing activity of WRC rescues the PDE defects in tmem-132 mutants, whereas gain-of-function of TMEM132D in mammalian cells inhibits WRC, leading to decreased abundance of select WRC components, impaired actin nucleation and cell motility. We propose that metazoan TMEM132 family proteins play evolutionarily conserved roles in regulating NAP1 protein homologs to restrict inappropriate WRC activity, cytoskeletal and morphologic changes in the cell.

BackgroundMutations in LMNA, encoding lamin A/C, lead to a variety of diseases known as laminopathies including dilated cardiomyopathy (DCM) and skeletal abnormalities. Though previous studies have investigated the dysregulation of gene expression in cells from patients with DCM, the role of epigenetic (gene regulatory) mechanisms, such as DNA methylation, has not been thoroughly investigated. Furthermore, the impact of family-specific LMNA mutations on DNA methylation is unknown. Here, we performed reduced representation bisulfite sequencing on ten pairs of fibroblasts and their induced pluripotent stem cell (iPSC) derivatives from two families with DCM due to distinct LMNA mutations, one of which also induces brachydactyly.ResultsFamily-specific differentially methylated regions (DMRs) were identified by comparing the DNA methylation landscape of patient and control samples. Fibroblast DMRs were found to enrich for distal regulatory features and transcriptionally repressed chromatin and to associate with genes related to phenotypes found in tissues affected by laminopathies. These DMRs, in combination with transcriptome-wide expression data and lamina-associated domain (LAD) organization, revealed the presence of inter-family epimutation hotspots near differentially expressed genes, most of which were located outside LADs redistributed in LMNA-related DCM. Comparison of DMRs found in fibroblasts and iPSCs identified regions where epimutations were persistent across both cell types. Finally, a network of aberrantly methylated disease-associated genes revealed a potential molecular link between pathways involved in bone and heart development.ConclusionsOur results identified both shared and mutation-specific laminopathy epimutation landscapes that were consistent with lamin A/C mutation-mediated epigenetic aberrancies that arose in somatic and early developmental cell stages.