Evolution of Linoleic Acid Biosynthesis Paved the Way for Ecological Success of Termites.

Termites are dominant animals of tropical terrestrial ecosystems. Their success is due to their eusocial organization as well as their ability to digest dead plant tissues. While being extremely abundant, the termite diet is poor in crucial nutrients, such as fatty acids. Linoleic acid (LA) is a precursor for many vital biomolecules, and most animals depend on its dietary supply. Termites count among the exceptions known to produce LA de novo, presumably via the action of an unknown Δ12 fatty acyl desaturase (FAD) introducing the second double bond into monounsaturated oleic acid. Here, we search for the evolutionary origin of LA biosynthesis in termites. To this end, we compile the repertoire of FAD homologs from 57 species of termites and their closest relatives, the cockroaches, analyze FAD phylogeny, and identify a potential Δ12 FAD branch, which arose through duplication of a likely Δ9 FAD. We functionally characterize both paralogs and identify the Δ9 activity in the ancestral FAD-A1a and the Δ12 activity responsible for LA biosynthesis in FAD-A1b. Through the combination of homology modeling and site-directed mutagenesis, we pinpoint structural features possibly contributing to the distinct functions, regiospecificities, and substrate preferences of the two enzymes. We confirm the presence of both paralogs in all 36 studied species of the Blattoidea lineage (Blattidae, Lamproblattidae, Cryptocercidae, and termites) and conclude that we identified an evolutionary event important for the ecological success of termites, which took place in their cockroach ancestors roughly 160 My and remained conserved throughout termite diversification into 3,000 extant species.

Model-based population pharmacokinetic and exposure response analyses for safety and efficacy of nivolumab as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer.

AIMS: Nivolumab is approved as adjuvant treatment in subjects with resected oesophageal or gastroesophageal junction cancer (EC/GEJC) based on results from the pivotal CheckMate 577 trial. We present a model-based clinical pharmacology profiling and benefit-risk assessment of nivolumab as adjuvant treatment in subjects with resected EC/GEJC supporting a less frequent dosing regimen. METHODS: Population pharmacokinetic (popPK) analysis was conducted to characterize nivolumab pharmacokinetics (PK) using clinical data from 1493 subjects from seven monotherapy clinical studies across multiple solid tumours. The exposure-response (E-R) analyses included data from 756 patients from CheckMate 577. E-R relationships for efficacy and safety were characterized by evaluating the relationship between nivolumab exposure and disease-free survival (DFS) for efficacy; and time to first occurrence of Grade ≥2 immune-mediated adverse events (Gr2 + IMAEs) for safety. RESULTS: Nivolumab exposure was found to be associated with both DFS and risk of Gr2 + IMAEs. However, the hazard ratios (HRs) (95% confidence interval [CI]) at the 5th and 95th percentiles of nivolumab exposure were similar for DFS and Gr2 + IMAEs, indicating flat E-R relationships within the exposure range produced by the studied regimen. Model-predicted probability of DFS and Gr2 + IMAEs were similar between the two regimens of 240 mg every 2 weeks or 480 mg every 4 weeks for 16 weeks followed by 480 mg Q4W up to 1 year. CONCLUSIONS: The analyses demonstrated a flat E-R relationship over the range of exposures produced by the studied regimen and supported the approval of an alternative dosing regimen with less frequent dosing in patients with adjuvant EC/GEJC.

Lateral Pelvic Nodal Management and Patterns of Failure in Patients Receiving Short-Course Radiation for Locally Advanced Rectal Cancer.

BACKGROUND: Management of lateral pelvic lymph nodes in locally advanced rectal cancer is controversial, with limited data indicating the optimal approach. In addition, no data exist regarding the treatment of lateral nodes in the setting of short-course radiation and nonoperative intent. OBJECTIVE: To evaluate a novel approach incorporating simultaneous integrated boost to suspicious lateral nodes. DESIGN: A retrospective study. SETTING: This study was conducted at a large tertiary referral center. PATIENTS: Patients treated with radiation therapy and consolidation chemotherapy were included. All primary tumors underwent biopsy confirmation and disease staging with pelvic MRI. INTERVENTIONS: Primary tumors were biopsy proven and staged with pelvic MRI. A subset of lateral pelvic lymph node patients received a simultaneous integrated boost of 35 Gy in 5 fractions. Then, chemotherapy was administered, with the majority receiving modified folinic acid, fluorouracil, and oxaliplatin. Clinical partial response required total mesorectal excision. MAIN OUTCOME MEASURES: Patterns of failure and survival analyses by subgroup were assessed. Outcomes based on receipt of radiation were compared across node status. RESULTS: Between January 2017 and January 2022, 155 patients were treated with short-course chemotherapy, with 121 included in the final analysis. Forty-nine percent of patients underwent nonoperative management. The median follow-up was 36 months and the median age was 58 years. Thirty-eight patients (26%) had positive lateral pelvic lymph nodes. Comparing lateral node status, progression-free survival was significantly worse for patients with positive disease ( p < 0.001), with a trend for worse overall survival. Receipt of nodal boost in patients with lateral nodes resulted in meaningful locoregional control. Nodal boost did not contribute to additional acute or late GI toxicity. LIMITATIONS: Limitations include retrospective nature and lack of lateral node pathology; however, a thorough radiographic review was performed. CONCLUSIONS: Lateral node-positive rectal cancer is correlated with worse oncologic outcomes and higher locoregional failure. Boost to clinically positive lateral nodes is a safe approach in the setting of short course radiation and in those receiving nonoperative intent. See Video Abstract. MANEJO DE LOS GANGLIOS PLVICOS LATERALES Y PATRONES DE FALLA EN PACIENTES QUE RECIBEN RADIACIN DE CICLO CORTO PARA EL CNCER DE RECTO LOCALMENTE AVANZADO: ANTECEDENTES:El manejo de los ganglios linfáticos pélvicos laterales en el cáncer de recto localmente avanzado es controvertido, con datos limitados que indiquen el abordaje óptimo. Además, no existen datos sobre el tratamiento de los ganglios linfáticos laterales en el contexto de la radiación de curso corto y la intención no operatoria.OBJETIVO:Evaluamos un enfoque novedoso que incorpora sobreimpresión integrada simultánea (SIB) a los linfonodos laterales sospechosos.DISEÑO:Este fue un estudio retrospectivo.ESCENARIO:Este estudio se realizó en un gran centro de referencia terciario.PACIENTES:Se incluyeron pacientes tratados con radiación y quimioterapia de consolidación. Todos los tumores primarios se confirmaron mediante biopsia y la enfermedad se estadificó con resonancia magnética pélvica.INTERVENCIONES:Los tumores primarios se confirmaron mediante biopsia y se estadificaron con RM pélvica. Un subconjunto de pacientes con linfonodos pélvicos laterales (LPLN) recibió SIB a 35 Gy en 5 fracciones. Luego, se administró quimioterapia y la mayoría recibió mFOLFOX. La respuesta clínica parcial requirió la escisión total del mesorrecto.PRINCIPALES MEDIDAS DE RESULTADO:Se evaluaron los patrones de fracaso y los análisis de supervivencia por subgrupo. Los resultados basados en el esquema de radiación se compararon según el estado de los ganglios.RESULTADOS:Entre enero de 2017 y enero de 2022, 155 pacientes fueron tratados con ciclo corto y quimioterapia con 121 incluidos en el análisis final. El 49% se sometió a manejo no operatorio. La mediana de seguimiento fue de 36 meses y la mediana de edad fue de 58 años. 38 pacientes (26%) tuvieron LPLN positivos. Comparando el estado de los ganglios laterales, la supervivencia libre de progresión fue significativamente peor para los pacientes con LPLN positiva ( p < 0,001) con una tendencia a una peor supervivencia global. La recepción de refuerzo nodal en pacientes con nodos laterales dio como resultado un control locorregional significativo. La sobreimpresión ganglionar no contribuyó a la toxicidad GI aguda o tardía adicional.LIMITACIONES:Las limitaciones incluyeron la naturaleza retrospectiva y la falta de patología de los ganglios linfáticos laterales; sin embargo, se realizó una revisión radiográfica exhaustiva.CONCLUSIONES:El cáncer de recto con ganglio lateral positivo se correlaciona con peores resultados oncológicos y mayor fracaso locorregional. La sobreimpresión a los ganglios laterales clínicamente positivos es un enfoque seguro en el contexto de un curso corto y en aquellos que siguen un manejo no operatorio. (Traducción-Dr. Felipe Bellolio ).

Visual predictive check of longitudinal models and dropout.

Visual predictive checks (VPC) are commonly used to evaluate pharmacometrics models. However their performance may be hampered if patients with worse outcomes drop out earlier, as often occurs in clinical trials, especially in oncology. While methods accounting for dropouts have appeared in literature, they vary in assumptions, flexibility, and performance, and the differences between them are not widely understood. This manuscript aims to elucidate which methods can be used to handle VPC with dropout and when, along with a more informative VPC approach using confidence intervals. Additionally, we propose constructing the confidence interval based on the observed data instead of the simulated data. The theoretical framework for incorporating dropout in VPCs is developed and applied to propose two approaches: full and conditional. The full approach is implemented using a parametric time-to-event model, while the conditional approach is implemented using both parametric and Cox proportional-hazard (CPH) models. The practical performances of these approaches are illustrated with an application to the tumor growth dynamics (TGD) modeling of data from two cancer clinical trials of nivolumab and docetaxel, where patients were followed until disease progression. The dataset consisted of 3504 tumor size measurements from 855 subjects, which were described by a TGD model. The dropout of subjects was described by a Weibull or CPH model. Simulated datasets were also used to further illustrate the properties of the VPC methods. The results showed that the more familiar full approach might not provide meaningful improvement for TGD model evaluation over the naive approach of not adjusting for dropout, and could be outperformed by the conditional approach using either the Weibull model or the Cox proportional hazard model. Overall, including confidence intervals in VPC should improve interpretation, the conditional approach was shown to be more generally applicable when dropout occurs, and the nonparametric approach could provide additional robustness.

Antennal Transcriptome Screening and Identification of Chemosensory Proteins in the Double-Spine European Spruce Bark Beetle, Ips duplicatus (Coleoptera: Scolytinae).

The northern bark beetle, Ips duplicatus, is an emerging economic pest, reportedly infesting various species of spruce (Picea spp.), pine (Pinus spp.), and larch (Larix spp.) in Central Europe. Recent climate changes and inconsistent forest management practices have led to the rapid spread of this species, leaving the current monitoring strategies inefficient. As understanding the molecular components of pheromone detection is key to developing novel control strategies, we generated antennal transcriptomes from males and females of this species and annotated the chemosensory proteins. We identified putative candidates for 69 odorant receptors (ORs), 50 ionotropic receptors (IRs), 25 gustatory receptors (GRs), 27 odorant-binding proteins (OBPs), including a tetramer-OBP, 9 chemosensory proteins (CSPs), and 6 sensory neuron membrane proteins (SNMPs). However, no sex-specific chemosensory genes were detected. The phylogenetic analysis revealed conserved orthology in bark beetle chemosensory proteins, especially with a major forest pest and co-habitant, Ips typographus. Recent large-scale functional studies in I. typographus chemoreceptors add greater significance to the orthologous sequences reported here. Nevertheless, identifying chemosensory genes in I. duplicatus is valuable to understanding the chemosensory system and its evolution in bark beetles (Coleoptera) and, generally, insects.

Exploring the Rhizospheric Microbial Communities under Long-Term Precipitation Regime in Norway Spruce Seed Orchard.

The rhizosphere is the hotspot for microbial enzyme activities and contributes to carbon cycling. Precipitation is an important component of global climate change that can profoundly alter belowground microbial communities. However, the impact of precipitation on conifer rhizospheric microbial populations has not been investigated in detail. In the present study, using high-throughput amplicon sequencing, we investigated the impact of precipitation on the rhizospheric soil microbial communities in two Norway Spruce clonal seed orchards, Lipová Lhota (L-site) and Prenet (P-site). P-site has received nearly double the precipitation than L-site for the last three decades. P-site documented higher soil water content with a significantly higher abundance of Aluminium (Al), Iron (Fe), Phosphorous (P), and Sulphur (S) than L-site. Rhizospheric soil metabolite profiling revealed an increased abundance of acids, carbohydrates, fatty acids, and alcohols in P-site. There was variance in the relative abundance of distinct microbiomes between the sites. A higher abundance of Proteobacteria, Acidobacteriota, Ascomycota, and Mortiellomycota was observed in P-site receiving high precipitation, while Bacteroidota, Actinobacteria, Chloroflexi, Firmicutes, Gemmatimonadota, and Basidiomycota were prevalent in L-site. The higher clustering coefficient of the microbial network in P-site suggested that the microbial community structure is highly interconnected and tends to cluster closely. The current study unveils the impact of precipitation variations on the spruce rhizospheric microbial association and opens new avenues for understanding the impact of global change on conifer rizospheric microbial associations.

Genome-Wide Transcriptomic and Metabolomic Analyses Unveiling the Defence Mechanisms of Populus tremula against Sucking and Chewing Insect Herbivores.

Plants and insects coevolved as an evolutionarily successful and enduring association. The molecular arms race led to evolutionary novelties regarding unique mechanisms of defence and detoxification in plants and insects. While insects adopt mechanisms to conquer host defence, trees develop well-orchestrated and species-specific defence strategies against insect herbivory. However, current knowledge on the molecular underpinnings of fine-tuned tree defence responses against different herbivore insects is still restricted. In the current study, using a multi-omics approach, we unveiled the defence response of Populus tremula against aphids (Chaitophorus populialbae) and spongy moths (Lymantria dispar) herbivory. Comparative differential gene expression (DGE) analyses revealed that around 272 and 1203 transcripts were differentially regulated in P. tremula after moth and aphid herbivory compared to uninfested controls. Interestingly, 5716 transcripts were differentially regulated in P. tremula between aphids and moth infestation. Further investigation showed that defence-related stress hormones and their lipid precursors, transcription factors, and signalling molecules were over-expressed, whereas the growth-related counterparts were suppressed in P. tremula after aphid and moth herbivory. Metabolomics analysis documented that around 37% of all significantly abundant metabolites were associated with biochemical pathways related to tree growth and defence. However, the metabolic profiles of aphid and moth-fed trees were quite distinct, indicating species-specific response optimization. After identifying the suitable reference genes in P. tremula, the omics data were further validated using RT-qPCR. Nevertheless, our findings documented species-specific fine-tuning of the defence response of P. tremula, showing conservation on resource allocation for defence overgrowth under aphid and moth herbivory. Such findings can be exploited to enhance our current understanding of molecular orchestration of tree responses against herbivory and aid in developing insect pest resistance P. tremula varieties.

Insights into the Detoxification of Spruce Monoterpenes by the Eurasian Spruce Bark Beetle.

Plant defence mechanisms, including physical barriers like toughened bark and chemical defences like allelochemicals, are essential for protecting them against pests. Trees allocate non-structural carbohydrates (NSCs) to produce secondary metabolites like monoterpenes, which increase during biotic stress to fend off pests like the Eurasian spruce bark beetle, ESBB (Ips typographus). Despite these defences, the ESBB infests Norway spruce, causing significant ecological damage by exploiting weakened trees and using pheromones for aggregation. However, the mechanism of sensing and resistance towards host allelochemicals in ESBB is poorly understood. We hypothesised that the exposure of ESBB to spruce allelochemicals, especially monoterpenes, leads to an upsurge in the important detoxification genes like P450s, GSTs, UGTs, and transporters, and at the same time, genes responsible for development must be compromised. The current study demonstrates that exposure to monoterpenes like R-limonene and sabiene effectively elevated detoxification enzyme activities. The differential gene expression (DGE) analysis revealed 294 differentially expressed (DE) detoxification genes in response to R-limonene and 426 DE detoxification genes in response to sabiene treatments, with 209 common genes between the treatments. Amongst these, genes from the cytochrome P450 family 4 and 6 genes (CP4 and CP6), esterases, glutathione S-transferases family 1 (GSTT1), UDP-glucuronosyltransferase 2B genes (UDB), and glucose synthesis-related dehydrogenases were highly upregulated. We further validated 19 genes using RT-qPCR. Additionally, we observed similar high expression levels of detoxification genes across different monoterpene treatments, including myrcene and α-pinene, suggesting a conserved detoxification mechanism in ESBB, which demands further investigation. These findings highlight the potential for molecular target-based beetle management strategies targeting these key detoxification genes.

Mycophenolate Mofetil with Steroid, a Reasonable Alternative to Current First-line Therapy, for Idiopathic Membranous Nephropathy in Resource-constrained Settings: A Randomized, Open-label Study.

BACKGROUND: The modified Ponticelli regimen (mPR) is a first-line therapy in patients with idiopathic membranous nephropathy (IMN); however, it has a less favorable safety profile. Though mycophenolate mofetil (MMF) + steroid (S) is not recommended by Kidney Disease Improving Global Outcomes guidelines, it can be used as an alternative to mPR due to higher tolerability and steroid-sparing effect. Thus, we compared the safety and effectiveness of MMF + S and mPR regimens in patients with IMN. METHODS: This randomized, open-label study enrolled patients with adult-onset nephrotic syndrome (NS) and biopsy-proven IMN. Forty-two patients were allocated to MMF + S group (MMF 1 gm twice daily + oral prednisolone 0.5 mg/kg/day; n = 21) and mPR group [methylprednisolone (1 gm intravenous) for 3 days followed by alternating monthly cycles of oral prednisolone (0.5 mg/kg/day) for the next 27 days and cyclophosphamide (2 mg/kg/day) for 6 months; n = 21]. The primary outcome measure was change in urinary protein creatinine ratio (UPCR). RESULTS: At 6 months, both groups demonstrated a significant increase in serum albumin levels and estimated glomerular filtration rate (eGFR) (both p-values <0.0001) as well as a decrease in 24-hour proteinuria (MMF + S group: p-value = 0.003, and mPR group: p-value <0.0001) and UPCR (both p-values <0.0001). However, the groups did not differ in any of these parameters at any of the monthly follow-up visits. Moreover, the groups did not differ significantly in terms of the composite remission rates (61.91% for MMF + S group and 71.43% for mPR group). CONCLUSION: MMF + S and mPR had comparable tolerability and effectiveness, with MMF-associated advantage of reduced steroid exposure.

Circulating renin-angiotensin systems mediated feedback controls over the mean-arterial pressure.

The renin-angiotensin systems play pivotal role in cardiovascular physiology through its effects on regulating blood pressure and electrolyte homeostasis. Components of circulating RAS (cRAS) that include precursor angiotensinogen, two critical enzymes (renin and angiotensin-converting enzyme, ACE), their bioactive products, angiotensin- I, II together with its receptors (AT1R and AT2R) essentially determine this homeostasis. Most classical studies, however, showed the deleterious role of cRAS in elevating the blood pressure. Contemporary discovery of non-canonical components of the RAS has challenged this classic hypothesis that it can only exert deleterious effects on the cardiovascular systems. Using the classic cRAS model, we have designed in-silico experiments to test the hypothesis that AT2R-mediated feedback effects play pivotal role for maintaining the normal variation of the mean-arterial pressure (MAP).Beside the AT2R-mediation of downstream singling pathways consisting of several non-canonical RAS components, this study first time illustrated AT2R mediated feedback controls over the blood pressure regulation: one that impedes AT1R activity, and the other that downregulates renin. It has been shown that relatively stronger suppression of renin activity significantly contributes in maintaining the normal MAP and that tight AT2R-mediated regulation is relaxed in hyper-and hypotension. This control mechanism is noted to be robustly maintained with the MAP variations through an established linear steady-state relationship among renin, angiotensin I and angiotensin II. This examination suggests that AT2R-mediated downregulation of renin activities potentially counteracts the AT1R-mediated deleterious actions of Ang II. This study, therefore, provides a solid ground for considering different AT2 receptor adaptor protein and direct agonism at AT2R that can cause greater effects along with contemporary approaches of blocking AT1R mediation to attenuate hypertension or other cardiovascular disorders.

Silicon nanoparticles: Synthesis, uptake and their role in mitigation of biotic stress.

In the current scenario of global warming and climate change, plants face many biotic stresses, which restrain growth, development and productivity. Nanotechnology is gaining precedence over other means to deal with biotic and abiotic constraints for sustainable agriculture. One of nature's most beneficial metalloids, silicon (Si) shows ameliorative effect against environmental challenges. Silicon/Silica nanoparticles (Si/SiO2NPs) have gained special attention due to their significant chemical and optoelectronic capabilities. Its mesoporous nature, easy availability and least biological toxicity has made it very attractive to researchers. Si/SiO2NPs can be synthesised by chemical, physical and biological methods and supplied to plants by foliar, soil, or seed priming. Upon uptake and translocation, Si/SiO2NPs reach their destined cells and cause optimum growth, development and tolerance against environmental stresses as well as pest attack and pathogen infection. Using Si/SiO2NPs as a supplement can be an eco-friendly and cost-effective option for sustainable agriculture as they facilitate the delivery of nutrients, assist plants to mitigate biotic stress and enhances plant resistance. This review aims to present an overview of the methods of formulation of Si/SiO2NPs, their application, uptake, translocation and emphasize the role of Si/SiO2NPs in boosting growth and development of plants as well as their conventional advantage as fertilizers with special consideration on their mitigating effects towards biotic stress.

Nanoparticle-Shielded dsRNA Delivery for Enhancing RNAi Efficiency in Cotton Spotted Bollworm Earias vittella (Lepidoptera: Nolidae).

The spotted bollworm Earias vittella (Lepidoptera: Nolidae) is a polyphagous pest with enormous economic significance, primarily affecting cotton and okra. However, the lack of gene sequence information on this pest has a significant constraint on molecular investigations and the formulation of superior pest management strategies. An RNA-seq-based transcriptome study was conducted to alleviate such limitations, and de novo assembly was performed to obtain transcript sequences of this pest. Reference gene identification across E. vittella developmental stages and RNAi treatments were conducted using its sequence information, which resulted in identifying transcription elongation factor (TEF), V-type proton ATPase (V-ATPase), and Glyceraldehyde -3-phosphate dehydrogenase (GAPDH) as the most suitable reference genes for normalization in RT-qPCR-based gene expression studies. The present study also identified important developmental, RNAi pathway, and RNAi target genes and performed life-stage developmental expression analysis using RT-qPCR to select the optimal targets for RNAi. We found that naked dsRNA degradation in the E. vittella hemolymph is the primary reason for poor RNAi. A total of six genes including Juvenile hormone methyl transferase (JHAMT), Chitin synthase (CHS), Aminopeptidase (AMN), Cadherin (CAD), Alpha-amylase (AMY), and V-type proton ATPase (V-ATPase) were selected and knocked down significantly with three different nanoparticles encapsulated dsRNA conjugates, i.e., Chitosan-dsRNA, carbon quantum dots-dsRNA (CQD-dsRNA), and Lipofectamine-dsRNA conjugate. These results demonstrate that feeding nanoparticle-shielded dsRNA silences target genes and suggests that nanoparticle-based RNAi can efficiently manage this pest.

Changes in the associations between malaria incidence and climatic factors across malaria endemic countries in Africa and Asia-Pacific region.

Empirical evidence supporting the associations between malaria incidence and climatic factors has remained controversial, buffering the progress in the Global Malaria Program that aims to eliminate 90% of the world malaria burden by 2030. This study has aimed to evaluate the nature and extent at which these relations are maintained across all the malaria endemic countries of Africa and Asia-Pacific region. We have utilized the last two decades of malaria incidence, annual minimum temperature, and annual precipitation time series data (2000-2020) for the two most malaria-impacted regions. These data were fitted in the generalized linear model and the mixed effects model. The results showed that there exists a large heterogeneity in malaria incidence across the countries, and between the regions. Last two decadal tendencies showed significant reductions in the disease burden in almost all the countries in the Asia Pacific, with several exceptions or relatively slowed reductions in the Africa. We found significant changes in the positive linear associations between malaria incidence, annual minimum temperature, and annual precipitation across African countries. Many Asia-Pacific countries namely Bangladesh, Bhutan, Indonesia, South Korea, Nepal, Thailand, Vietnam showed negative effects in the associations with the annual precipitation. This study indicates that increasing temperature within the range of 12-30 °C can generate positive effects on malaria incidence, but the nature and extent of precipitation effects vary across countries and at a large regional scale.

Pesticide resistance in arthropods: Ecology matters too.

Pesticide resistance development is an example of rapid contemporary evolution that poses immense challenges for agriculture. It typically evolves due to the strong directional selection that pesticide treatments exert on herbivorous arthropods. However, recent research suggests that some species are more prone to evolve pesticide resistance than others due to their evolutionary history and standing genetic variation. Generalist species might develop pesticide resistance especially rapidly due to pre-adaptation to handle a wide array of plant allelochemicals. Moreover, research has shown that adaptation to novel host plants could lead to increased pesticide resistance. Exploring such cross-resistance between host plant range evolution and pesticide resistance development from an ecological perspective is needed to understand its causes and consequences better. Much research has, however, been devoted to the molecular mechanisms underlying pesticide resistance while both the ecological contexts that could facilitate resistance evolution and the ecological consequences of cross-resistance have been under-studied. Here, we take an eco-evolutionary approach and discuss circumstances that may facilitate cross-resistance in arthropods and the consequences cross-resistance may have for plant-arthropod interactions in both target and non-target species and species interactions. Furthermore, we suggest future research avenues and practical implications of an increased ecological understanding of pesticide resistance evolution.

Neurovascular complications in adults with Neurofibromatosis type 1: A national referral center experience.

Neurofibromatosis type 1 (NF1) is associated with a range of vascular abnormalities. To assess the frequency, clinical and imaging spectrum of vascular complications in an adult cohort of NF1 patients, we reviewed 2068 adult NF1 patient records seen in our service between 2009 and 2019, to determine presence of vascular abnormalities, age at detection, associated symptoms and management. A literature review of the range of vascular abnormalities associated with NF1 was also undertaken. 1234 patients had magnetic resonance imaging cranial imaging. The frequency of vascular abnormalities associated with NF1 patients who had cranial imaging in this cohort was 3.5% (n = 43), the majority (n = 26, 60%) were symptomatic. Stroke and cerebral arterial stenosis were the commonest vascular complication. Eight patients (0.65%) had more than one type of vascular abnormality. One death due to a vascular complication was identified and significant morbidity resulted from other complications. We conclude that clinicians caring for patients with NF1 need to be cognizant that rapid onset of new neurological symptoms or signs may be the result of a vascular complication of NF1 and require urgent investigation and management, ideally within specialist teams who have experience of managing vascular complications of NF1.

Total Neoadjuvant Therapy With Short-Course Radiation: US Experience of a Neoadjuvant Rectal Cancer Therapy.

BACKGROUND: Short-course radiation followed by chemotherapy as total neoadjuvant therapy has been investigated primarily in Europe and Australia with increasing global acceptance. There are limited data on this regimen's use in the United States, however, potentially delaying implementation. OBJECTIVE: This study aimed to compare clinical performance and oncologic outcomes of 2 rectal cancer neoadjuvant treatment modalities: short-course total neoadjuvant therapy versus standard chemoradiation. DESIGN: This is a retrospective cohort study. SETTING: This study was performed at a National Cancer Institute-designated cancer center. PATIENTS: A total of 413 patients had locally advanced rectal cancers diagnosed from June 2009 to May 2018 and received either short-course total neoadjuvant therapy or standard chemoradiation. INTERVENTIONS: There were 187 patients treated with short-course total neoadjuvant therapy (5 × 5 Gy radiation followed by consolidation oxaliplatin-based chemotherapy) compared with 226 chemoradiation recipients (approximately 50.4 Gy radiation in 28 fractions with concurrent fluorouracil equivalent). MAIN OUTCOME MEASURES: Primary end points were tumor downstaging, measured by complete response and "low" neoadjuvant rectal score rates, and progression-free survival. Secondary analyses included treatment characteristics and completion, sphincter preservation, and recurrence rates. RESULTS: Short-course total neoadjuvant therapy was associated with higher rates of complete response (26.2% vs 17.3%; p = 0.03) and "low" neoadjuvant rectal scores (40.1% vs 25.7%; p < 0.01) despite a higher burden of node-positive disease (78.6% vs 68.9%; p = 0.03). Short-course recipients also completed trimodal treatment more frequently (88.4% vs 50.4%; p < 0.01) and had fewer months with temporary stomas (4.8 vs 7.0; p < 0.01). Both regimens achieved comparable local control (local recurrence: 2.7% short-course total neoadjuvant therapy vs 2.2% chemoradiation, p = 0.76) and 2-year progression-free survival (88.2% short-course total neoadjuvant therapy (95% CI, 82.9-93.5) vs 85.6% chemoradiation (95% CI, 80.5-90.7)). LIMITATIONS: Retrospective design, unbalanced disease severity, and variable dosing of neoadjuvant consolidation chemotherapy were limitations of this study. CONCLUSIONS: Short-course total neoadjuvant therapy was associated with improved downstaging and similar progression-free survival compared with chemoradiation. These results were achieved with shortened radiation courses, improved treatment completion, and less time with diverting ostomies. Short-course total neoadjuvant therapy is an optimal regimen for locally advanced rectal cancer. See Video Abstract at http://links.lww.com/DCR/B724.TERAPIA NEOADYUVANTE TOTAL CON RADIACIÓN DE CORTA DURACIÓN: EXPERIENCIA ESTADOUNIDENSE DE UNA TERAPIA NEOADYUVANTE CONTRA EL CÁNCER DE RECTO. ANTECEDENTES: La radiación de corta duración seguida de quimioterapia como terapia neoadyuvante total se ha investigado principalmente en Europa y Australia con una aceptación mundial cada vez mayor. Sin embargo, datos limitados sobre el uso de este régimen en los Estados Unidos, han potencialmente retrasando su implementación. OBJETIVO: Comparar el desempeño clínico y los resultados oncológicos de dos modalidades de tratamiento neoadyuvante del cáncer de recto: terapia neoadyuvante total de corta duración versus quimioradiación. estándar. DISEO: Cohorte retrospectivo. AJUSTE: Centro oncológico designado por el NCI. PACIENTES: Un total de 413 cánceres rectales localmente avanzados diagnosticados entre junio de 2009 y mayo de 2018 que recibieron cualquiera de los regímenes neoadyuvantes. INTERVENCIONES: Hubo 187 pacientes tratados con terapia neoadyuvante total de ciclo corto (radiación 5 × 5 Gy seguida de quimioterapia de consolidación basada en oxaliplatino) en comparación con 226 pacientes de quimiorradiación (aproximadamente 50,4 Gy de radiación en 28 fracciones con equivalente de fluorouracilo concurrente). PRINCIPALES MEDIDAS DE RESULTADO: Los criterios primarios de valoración fueron la disminución del estadio del tumor, medido por la respuesta completa y las tasas de puntuación rectal neoadyuvante "baja", y la supervivencia libre de progresión. Los análisis secundarios incluyeron las características del tratamiento y las tasas de finalización, conservación del esfínter y recurrencia. RESULTADOS: La terapia neoadyuvante total de corta duración, se asoció con tasas más altas de respuesta completa (26,2% versus 17,3%, p = 0,03) y puntuaciones rectales neoadyuvantes "bajas" (40,1% versus 25,7%, p < 0,01) a pesar de una mayor carga de enfermedad con ganglios positivos (78,6% versus 68,9%, p = 0,03). Los pacientes de ciclo corto también completaron el tratamiento trimodal con mayor frecuencia (88,4% versus 50,4%, p < 0,01) y tuvieron menos meses con estomas temporales (4,8 versus 7,0, p < 0,01). Ambos regímenes lograron un control local comparable (recidiva local: 2,7% de SC-TNT versus 2,2% de TRC, p = 0,76) y supervivencia libre de progresión a 2 años (88,2% de SC-TNT [IC: 82,9 - 93,5] versus 85,6% CRT [CI: 80,5 - 90,7]). LIMITACIONES: Diseño retrospectivo, gravedad de la enfermedad desequilibrada y dosificación variable de quimioterapia neoadyuvante de consolidación. CONCLUSIONES: La terapia neoadyuvante total de ciclo corto se asoció con una mejora en la reducción del estadio y una supervivencia libre de progresión similar en comparación con la quimioradiación. Estos resultados se lograron con ciclos de radiación más cortos, tratamientos mejor finalizados y menos tiempo en ostomías de derivación. La terapia neoadyuvante total de corta duración es un régimen óptimo para el cáncer de recto localmente avanzado. Consulte Video Resumen en http://links.lww.com/DCR/B724. (Traducción- Dr. Fidel Ruiz Healy).

Privacy Preserving Multi-Party Key Exchange Protocol for Wireless Mesh Networks.

Presently, lightweight devices such as mobile phones, notepads, and laptops are widely used to access the Internet throughout the world; however, a problem of privacy preservation and authentication delay occurs during handover operation when these devices change their position from a home mesh access point (HMAP) to a foreign mesh access point (FMAP). Authentication during handover is mostly performed through ticket-based techniques, which permit the user to authenticate itself to the foreign mesh access point; therefore, a secure communication method should be formed between the mesh entities to exchange the tickets. In two existing protocols, this ticket was not secured at all and exchanged in a plaintext format. We propose a protocol for handover authentication with privacy preservation of the transfer ticket via the Diffie-Hellman method. Through experimental results, our proposed protocol achieves privacy preservation with minimum authentication delay during handover operation.

Road-map of pre-clinical treatment for Visceral Leishmaniasis.

Visceral leishmaniasis (VL) or Kala-azar, is the most lethal form of leishmaniasis, is still prevalent in many countries where it is endemic. It is a threat to human life caused by protozoan parasite Leishmania donovani. The severity of the disease is further increased as the treated individuals might have a chance of developing Post Kala-azar Dermal Leishmaniasis (PKDL) in the long run. Moreover, several countries have reported high number of HIV-VL co-infected patients. Therefore, there is a dire need for the development of efficient diagnostic methods and drugs in order to combat the disease and to control the spread of disease. At present, the treatment for VL entirely relies on therapeutic drugs as no vaccine is available yet. Ever since 1900s a series of drugs have been invented and used for treatment of VL; but the need for one such cost-effective treatment that would completely cure the disease with minimal side-effects, low relapse rate with high efficacy and less toxicity remains yet to be fulfilled. Therefore, identifying novel compounds is very crucial to develop potent antileishmanial agents. Thus, this review enlists several instances of drug development, including the pharmacokinetic and pharmacodynamic properties of antileishmanial drugs, different experimental animal models used to investigate the disease progression and to analyze treatment dosage and pharmacological aspect of drugs. Furthermore, the existing gap in drug development and future measures to improve the process are also discussed in this review.

How to Cope with the Challenges of Environmental Stresses in the Era of Global Climate Change: An Update on ROS Stave off in Plants.

With the advent of human civilization and anthropogenic activities in the shade of urbanization and global climate change, plants are exposed to a complex set of abiotic stresses. These stresses affect plants' growth, development, and yield and cause enormous crop losses worldwide. In this alarming scenario of global climate conditions, plants respond to such stresses through a highly balanced and finely tuned interaction between signaling molecules. The abiotic stresses initiate the quick release of reactive oxygen species (ROS) as toxic by-products of altered aerobic metabolism during different stress conditions at the cellular level. ROS includes both free oxygen radicals {superoxide (O2•-) and hydroxyl (OH-)} as well as non-radicals [hydrogen peroxide (H2O2) and singlet oxygen (1O2)]. ROS can be generated and scavenged in different cell organelles and cytoplasm depending on the type of stimulus. At high concentrations, ROS cause lipid peroxidation, DNA damage, protein oxidation, and necrosis, but at low to moderate concentrations, they play a crucial role as secondary messengers in intracellular signaling cascades. Because of their concentration-dependent dual role, a huge number of molecules tightly control the level of ROS in cells. The plants have evolved antioxidants and scavenging machinery equipped with different enzymes to maintain the equilibrium between the production and detoxification of ROS generated during stress. In this present article, we have focused on current insights on generation and scavenging of ROS during abiotic stresses. Moreover, the article will act as a knowledge base for new and pivotal studies on ROS generation and scavenging.

Benefit-risk assessment of nivolumab 240 mg flat dose relative to 3 mg/kg Q2W regimen in Japanese patients with advanced cancers.

Nivolumab 3 mg/kg every 2 weeks (Q2W) has been approved in Japan for various cancers; however, use of a flat dose is expected to simplify dosing and administration. A quantitative clinical pharmacology approach was used to assess the benefit-risk profile of nivolumab 240 mg Q2W relative to the approved dose of nivolumab 3 mg/kg Q2W in Japanese patients. Three exposure-response safety analyses were performed for adverse events that led to discontinuation/death, were grade 3 or higher, and were immune-mediated and grade 2 or higher for Japanese patients diagnosed with one of multiple tumor types. Exposure-response analyses of efficacy were evaluated for overall survival and objective response rate. Exposures of nivolumab 240 mg Q2W were 37% higher than those of nivolumab 3 mg/kg Q2W in Japanese patients across the tumor types analyzed. Predicted safety profiles at the two doses differed by less than 2% across tumor types for adverse events leading to discontinuation/death, adverse events of grade 3 or higher, or immune-mediated adverse events of grade 2 or higher. In addition, the predicted 1-year and 2-year overall survival rates, the mean overall survival and the objective response rates were comparable between the doses regardless of the tumor type analyzed. Overall, these results demonstrated that the benefit-risk of nivolumab 240 mg Q2W was comparable to that of the previously approved 3 mg/kg Q2W dosing regimen, and was the basis for the approval of the 240 mg Q2W as an alternative dosing regimen for treatment in Japanese patients across multiple tumor types.