Search

We explore the interplay of New Physics (NP) effects in (g− 2)ℓ and h→ℓ+ℓ− within the Standard Model Effective Field Theory (SMEFT) framework, including one-loop Renormalization Group (RG) evolution of the Wilson coefficients as well as matching to the observables below the electroweak symmetry breaking scale. We include both the leading dimension six chirality flipping operators including a Higgs and SU(2)L gauge bosons as well as four-fermion scalar and tensor operators, forming a closed operator set under the SMEFT RG equations. We compare present and future experimental sensitivity to different representative benchmark scenarios. We also consider two simple UV completions, a Two Higgs Doublet Model and a single scalar LeptoQuark extension of the SM, and show how tree level matching to SMEFT followed by the one-loop RG evolution down to the electroweak scale can reproduce with high accuracy the (g−2)ℓ and h→ℓ+ℓ− contributions obtained by the complete one- and even two-loop calculations in the full models. [ABSTRACT FROM AUTHOR]

Background: Historically, vector control, including entomological monitoring, has been a field dominated by men. Each year, the U.S. President's Malaria Initiative (PMI) VectorLink project hires 50,000 to 70,000 seasonal workers across the countries in which it works to implement vector control activities, creating an economic opportunity for both men and women. Remaining barriers to women's employment in vector control include social and cultural norms regarding acceptability of formal employment for women, perceptions that women are not fit to serve as spray operators, and a historical context of male-dominated fields such as entomology., Methods: We use PMI VectorLink project data from Madagascar, Rwanda, and Zambia for 2019-2021 and key informant interviews with project staff in these countries to examine levels of female employment, effectiveness and efficiency of female versus male malaria spray operators, and strategies to expand the role of women in vector control., Results: The percentage of female seasonal employees ranges from 25% in Madagascar to 32% in Rwanda and 45% in Zambia. The percentage of women in leadership positions ranges from 32% in Madagascar and Rwanda to 38% in Zambia. Men and women are equally effective and efficient as spray operators. Best practices for recruiting and retaining women in vector control include engaging community leaders in recruitment, implementing affirmative action hiring policies, mentoring women to progress to leadership positions, and ensuring equitable, safe, and attractive workplaces., Discussion: As vector control programs transition away from donor funding and are increasingly government led, sustaining gains in female empowerment is critical. Country programs should work closely with national, regional, district, and local leaders to demonstrate the importance of hiring women in vector control-including leadership positions-and the impact on female economic empowerment, community well-being, and success of vector control programs., (© Shiras et al.)

The usage of disposable face mask to control the spread of COVID-19 disease has led to the alarming generation of a huge amount of plastic waste in a short span of time. On other hand, face masks are made of high-quality thermoplastic polymers that could be recovered and converted into valuable products. The aim of this study is to investigate a complementary approach for the recycling of face mask in lab-scale plants: the mechanical recycling of the filter in polypropylene (PP) and the chemical recycling of the whole face mask. For this purpose, a new designed surgical face mask was chemically and physically characterized. The results shows that the face mask was composed of 92.3 wt% high grade PP (filter), very similar to virgin PP but with a high melt volume index (MVI, 385 cm 3 /10 min) due to its non-woven manufacturing. The PP from face mask was mixed with recycled virgin PP in order to obtain a MVI suitable for the extrusion process and recycled as filament for 3D printing. This filament was used to print a specimen with a very similar visual quality of that printed with a commercial PP filament. Simultaneously, the whole face mask underwent a pyrolysis process to produce new feedstocks or fuels. Low-cost catalysts derived from coal fly ash (CFA) were employed to enhance the production of light hydrocarbons. In particular, the synthetized acid X zeolite (HX/CFA) improved the yield of light fractions up to 91 wt% (79 wt% for thermal pyrolysis) and the quality of the light oil with the 85% of C 6 -C 10 (55% for thermal pyrolysis). Furthermore, HX/CFA decreased the degradation temperature of PP to 384 °C versus 458 °C of thermal cracking., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Purpose: To assess the preclinical efficacy, clinical safety and efficacy, and MTD of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC)., Experimental Design: Preclinical activity was tested in patient-derived xenograft (PDX) models of PDAC. In the open-label, phase I clinical study, the dose-escalation cohort received oral palbociclib initially at 75 mg/day (range, 50‒125 mg/day; modified 3+3 design; 3/1 schedule); intravenous nab-paclitaxel was administered weekly for 3 weeks/28-day cycle at 100‒125 mg/m 2 . The modified dose-regimen cohorts received palbociclib 75 mg/day (3/1 schedule or continuously) plus nab-paclitaxel (biweekly 125 or 100 mg/m 2 , respectively). The prespecified efficacy threshold was 12-month survival probability of ≥65% at the MTD., Results: Palbociclib plus nab-paclitaxel was more effective than gemcitabine plus nab-paclitaxel in three of four PDX models tested; the combination was not inferior to paclitaxel plus gemcitabine. In the clinical trial, 76 patients (80% received prior treatment for advanced disease) were enrolled. Four dose-limiting toxicities were observed [mucositis ( n = 1), neutropenia ( n = 2), febrile neutropenia ( n = 1)]. The MTD was palbociclib 100 mg for 21 of every 28 days and nab-paclitaxel 125 mg/m 2 weekly for 3 weeks in a 28-day cycle. Among all patients, the most common all-causality any-grade adverse events were neutropenia (76.3%), asthenia/fatigue (52.6%), nausea (42.1%), and anemia (40.8%). At the MTD ( n = 27), the 12-month survival probability was 50% (95% confidence interval, 29.9-67.2)., Conclusions: This study showed the tolerability and antitumor activity of palbociclib plus nab-paclitaxel treatment in patients with PDAC; however, the prespecified efficacy threshold was not met., Trial Registration: Pfizer Inc (NCT02501902)., Significance: In this article, the combination of palbociclib, a CDK4/6 inhibitor, and nab-paclitaxel in advanced pancreatic cancer evaluates an important drug combination using translational science. In addition, the work presented combines preclinical and clinical data along with pharmacokinetic and pharmacodynamic assessments to find alternative treatments for this patient population., Competing Interests: M. Hidalgo reports grants from Pfizer during the conduct of the study; personal fees and other from BMS, InxMed, Champions; personal fees from MinKi, Velavigo, Oncomatrix; other from Nelum outside the submitted work; and M. Hidalgo is an independant director in BMS. R. Garcia-Carbonero reports personal fees from AAA, Advanz Pharma, Amgen, Bayer, BMS, HMP, Ipsen, Merck, Midatech, MSD, Novartis, Pharma Mar, Pierre Fabre, Servier and grants from BMS, MSD, Pfizer outside the submitted work. W.A. Messersmith reports other from Pfizer during the conduct of the study. I. Garrido-Laguna reports personal fees from SOTIO, Kanaph, Jazz, OncXer; grants from Novartis (to institution), Bayer (to institution), Bristol Myers-Squibb (to institution), Pfizer (to institution), MedImmune (to institution), Lilly (to institution), Incyte (to institution), GlaxoSmithKline (to institution), Tolero Pharmaceuticals (to institution), BridgeBio Pharma (to institution), Jacobio (to institution), Repare Therapeutics (to institution), and Sumitomo Dainippon Pharma Oncology (to institution) outside the submitted work. E. Borazanci reports other from Pfizer during the conduct of the study; other from BMS, Minneamrita Therapeutics, Merck, Helix Biopharma, and Biontech outside the submitted work; and reports consultancy with Vivacitus (self), TD2 (self), and Nanology (self). M. Malumbres reports grants and personal fees from Pfizer and grants from Eli Lilly outside the submitted work. D.J. Shields is an employee of Pfizer Inc. and holds shares in the company. J.E. Grossman reports other from Agenus outside the submitted work. X. Huang reports personal fees from Pfizer, Inc outside the submitted work. J.-F. Martini reports personal fees from Pfizer Inc and other from Pfizer Inc outside the submitted work. Y. Yu reports other from Pfizer Inc. outside the submitted work. K. Kern reports other from Pfizer Inc outside the submitted work. T. Macarulla reports personal fees from Ability Pharmaceuticals SL, Amgen, Aptitude Health, Basilea Pharma, Baxter, BioLineRX Ltd, Celgene, Eisai, Ellipses, Genzyme, Hirslanden/GITZ, Imedex, Ipsen Bioscience, Inc, Janssen, Lilly, Marketing Farmacéutico & Investigación Clínica, S.L, MDS, Medscape, Novocure, Paraxel, PPD Development, Polaris, QED Therapeutics, Roche Farma, Scilink Comunicación Científica SC, Surface Oncology, and Zymeworks; personal fees and other from AstraZeneca, Incyte, Sanofi-Aventis, Servier outside the submitted work. No disclosures were reported by the other authors., (© 2022 The Authors; Published by the American Association for Cancer Research.)

Outbreaks of disease in settings affected by crises grow rapidly due to late detection and weakened public health systems. Where surveillance is underfunctioning, community-based surveillance can contribute to rapid outbreak detection and response, a core capacity of the International Health Regulations. We reviewed articles describing the potential for community-based surveillance to detect diseases of epidemic potential, outbreaks, and mortality among populations affected by crises. Surveillance objectives have included the early warning of outbreaks, active case finding during outbreaks, case finding for eradication programmes, and mortality surveillance. Community-based surveillance can provide sensitive and timely detection, identify valid signals for diseases with salient symptoms, and provide continuity in remote areas during cycles of insecurity. Effectiveness appears to be mediated by operational requirements for continuous supervision of large community networks, verification of a large number of signals, and integration of community-based surveillance within the routine investigation and response infrastructure. Similar to all community health systems, community-based surveillance requires simple design, reliable supervision, and early and routine monitoring and evaluation to ensure data validity. Research priorities include the evaluation of syndromic case definitions, electronic data collection for community members, sentinel site designs, and statistical techniques to counterbalance false positive signals., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Indoor residual spraying (IRS) is a key tool for controlling and eliminating malaria by targeting vectors. To support the development of effective intervention strategies it is important to understand the impact of vector control tools on malaria incidence and on the spread of insecticide resistance. In 2006, the World Health Organization (WHO) stated that countries should report on coverage and impact of IRS, yet IRS coverage data are still sparse and unspecific. Here, the subnational coverage of IRS across sub-Saharan Africa for the four main insecticide classes from 1997 to 2017 were estimated., Methods: Data on IRS deployment were collated from a variety of sources, including the President's Malaria Initiative spray reports and National Malaria Control Programme reports, for all 46 malaria-endemic countries in sub-Saharan Africa from 1997 to 2017. The data were mapped to the applicable administrative divisions and the proportion of households sprayed for each of the four main insecticide classes; carbamates, organochlorines, organophosphates and pyrethroids was calculated., Results: The number of countries implementing IRS increased considerably over time, although the focal nature of deployment means the number of people protected remains low. From 1997 to 2010, DDT and pyrethroids were commonly used, then partly replaced by carbamates from 2011 and by organophosphates from 2013. IRS deployment since the publication of resistance management guidelines has typically avoided overlap between pyrethroid IRS and ITN use. However, annual rotations of insecticide classes with differing modes of action are not routinely used., Conclusion: This study highlights the gaps between policy and practice, emphasizing the continuing potential of IRS to drive resistance. The data presented here can improve studies on the impact of IRS on malaria incidence and help to guide future malaria control efforts.

The key event in the choice of repair pathways for DNA double-strand breaks (DSBs) is the initial processing of ends. Non-homologous end joining (NHEJ) involves limited processing, but homology-dependent repair (HDR) requires extensive resection of the 5' strand. How cells decide if an end is channeled to resection or NHEJ is not well understood. We hypothesize that the structure of ends is a major determinant and tested this hypothesis with model DNA substrates in Xenopus egg extracts. While ends with normal nucleotides are efficiently channeled to NHEJ, ends with damaged nucleotides or bulky adducts are channeled to resection. Resection is dependent on Mre11, but its nuclease activity is critical only for ends with 5' bulky adducts. CtIP is absolutely required for activating the nuclease-dependent mechanism of Mre11 but not the nuclease-independent mechanism. Together, these findings suggest that the structure of ends is a major determinant for the pathway choice of DSB repair and the Mre11 nuclease dependency of resection., (© The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Topoisomerase 2 (Top2) is an essential enzyme responsible for manipulating DNA topology during replication, transcription, chromosome organization and chromosome segregation. It acts by nicking both strands of DNA and then passes another DNA molecule through the break. The 5' end of each nick is covalently linked to the tyrosine in the active center of each of the two subunits of Top2 (Top2cc). In this configuration, the two sides of the nicked DNA are held together by the strong protein-protein interactions between the two subunits of Top2, allowing the nicks to be faithfully resealed in situ. Top2ccs are normally transient, but can be trapped by cancer drugs, such as etoposide, and subsequently processed into DSBs in cells. If not properly repaired, these DSBs would lead to genome instability and cell death. Here, I review the current understanding of the mechanisms by which DSBs are induced by etoposide, the unique features of such DSBs and how they are repaired. Implications for the improvement of cancer therapy will be discussed.

DNA double-strand breaks (DSBs) with 5' adducts are frequently formed from many nucleic acid processing enzymes, in particular DNA topoisomerase 2 (TOP2). The key intermediate of TOP2 catalysis is the covalent complex (TOP2cc), consisting of two TOP2 subunits covalently linked to the 5' ends of the nicked DNA. In cells, TOP2ccs can be trapped by cancer drugs such as etoposide and then converted into DNA double-strand breaks (DSBs) that carry adducts at the 5' end. The repair of such DSBs is critical to the survival of cells, but the underlying mechanism is still not well understood. We found that etoposide-induced DSBs are efficiently resected into 3' single-stranded DNA in cells and the major nuclease for resection is the DNA2 protein. DNA substrates carrying model 5' adducts were efficiently resected in Xenopus egg extracts and immunodepletion of Xenopus DNA2 also strongly inhibited resection. These results suggest that DNA2-mediated resection is a major mechanism for the repair of DSBs with 5' adducts., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The CRISPR-Cas9 system uses guide RNAs to direct the Cas9 endonuclease to cleave target sequences. It can, in theory, target essentially any sequence in a genome, but the efficiency of the predicted guide RNAs varies dramatically. If no targeted cells are obtained, it is also difficult to know why the experiment fails. We have developed a transient transfection based method to enrich successfully targeted cells by co-targeting the hypoxanthine phosphoribosyltransferase (HPRT) gene. Cells are transfected with two guide RNAs that target respectively HPRT and the gene of interest. HPRT targeted cells are selected by resistance to 6-thioguanine (6-TG) and then examined for potential alterations to the gene targeted by the co-transfected guide RNA. Alterations of many genes, such as AAVS1, Exo1 and Trex1, are highly enriched in the 6-TG resistant cells. This method works in both HCT116 cells and U2OS cells and can easily be scaled up to process multiple guide RNAs. When co-targeting fails, it is straightforward to determine whether the target gene is essential or the guide RNA is ineffective. HPRT co-targeting thus provides a simple, efficient and scalable way to enrich gene targeting events and to identify the cause of failure., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

The first step of homology-dependent repair of DNA double-strand breaks (DSBs) is the resection of the 5' strand to generate 3' ss-DNA. Of the two major nucleases responsible for resection, EXO1 has intrinsic 5'->3' directionality, but DNA2 does not. DNA2 acts with RecQ helicases such as the Werner syndrome protein (WRN) and the heterotrimeric eukaryotic ss-DNA binding protein RPA. We have found that the N-terminus of the RPA large subunit (RPA1N) interacts with both WRN and DNA2 and is essential for stimulating WRN's 3'->5' helicase activity and DNA2's 5'->3' ss-DNA exonuclease activity. A mutant RPA complex that lacks RPA1N is unable to support resection in Xenopus egg extracts and human cells. Furthermore, relocating RPA1N to the middle subunit but not to the small subunit causes severe defects in stimulating DNA2 and WRN and in supporting resection. Together, these findings suggest that RPA1N and its spatial position are critical for restricting the directionality of the WRN-DNA2 resection pathway., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Etoposide is a DNA topoisomerase 2-targeting drug widely used for the treatment of cancer. The cytoxicity of etoposide correlates with the generation of DNA double-strand breaks (DSBs), but the mechanism of how it induces DSBs in cells is still poorly understood. Catalytically, etoposide inhibits the re-ligation reaction of Top2 after it nicks the two strands of DNA, trapping it in a cleavable complex consisting of two Top2 subunits covalently linked to the 5' ends of DNA (Top2cc). Top2cc is not directly recognized as a true DSB by cells because the two subunits interact strongly with each other to hold the two ends of DNA together. In this study we have investigated the cellular mechanisms that convert Top2ccs into true DSBs. Our data suggest that there are two mechanisms, one dependent on active replication and the other dependent on proteolysis and transcription. The relative contribution of each mechanism is affected by the concentration of etoposide. We also find that Top2α is the major isoform mediating the replication-dependent mechanism and both Top2α and Top2 mediate the transcription-dependent mechanism. These findings are potentially of great significance to the improvement of etoposide's efficacy in cancer therapy.

Cyclobutane pyrimidine dimer (CPD) photolyases are structure specific DNA-repair enzymes that specialize in the repair of CPDs, the major photoproducts that are formed upon irradiation of DNA with ultraviolet light. The purified enzyme binds a flavin adenine dinucleotide (FAD), which is in the neutral radical semiquinone (FADH(*)) form. The CPDs are repaired by a light-driven, electron transfer from the anionic hydroquinone (FADH(-)) singlet excited state to the CPD, which is followed by reductive cleavage of the cyclobutane ring and subsequent monomerization of the pyrimidine bases. CPDs formed between two adjacent thymidine bases (T< >T) are repaired with greater efficiency than those formed between two adjacent cytidine bases (C< >C). In this paper, we investigate the changes in Escherichia coli photolyase that are induced upon binding to DNA containing C< >C lesions using resonance Raman, UV-vis absorption, and transient absorption spectroscopies, spectroelectrochemistry, and computational chemistry. The binding of photolyase to a C< >C lesion modifies the energy levels of FADH(*), the rate of charge recombination between FADH(-) and Trp(306)(*), and protein-FADH(*) interactions differently than binding to a T< >T lesion. However, the reduction potential of the FADH(-)/FADH(*) couple is modified in the same way with both substrates. Our calculations show that the permanent electric dipole moment of C< >C is stronger (12.1 D) and oriented differently than that of T< >T (8.7 D). The possible role of the electric dipole moment of the CPD in modifying the physicochemical properties of photolyase as well as in affecting CPD repair will be discussed.