Expanding the Plant Virome: Umbra-Like Viruses Use Host Proteins for Movement.

Before the very recent discovery of umbra-like viruses (ULVs), the signature defining feature of all plant RNA viruses was the encoding of specialized RNA-binding movement proteins (MPs) for transiting their RNA genomes through gated plasmodesmata to establish systemic infections. The vast majority of ULVs share umbravirus-like RNA-dependent RNA polymerases and 3'-terminal structures, but they differ by not encoding cell-to-cell and long-distance MPs and by not relying on a helper virus for trans-encapsidation and plant-to-plant transmission. The recent finding that two groups of ULVs do not necessarily encode MPs is expanding our understanding of the minimum requirements for modern plant RNA viruses. ULV CY1 from citrus uses host protein PHLOEM PROTEIN 2 (PP2) for systemic movement, and related ULVs encode a capsid protein, thereby providing an explanation for the lack of helper viruses present in many ULV-infected plants. ULVs thus resemble the first viruses that infected plants, which were likely deposited from feeding organisms and would have similarly required the use of host proteins such as PP2 to exit initially infected cells.

Moving beyond hotspots of HIV prevalence to geospatial hotspots of UNAIDS 95-95-95 targets in sub-Saharan Africa.

The HIV epidemic in sub-Saharan Africa displays a varied geographical distribution, with particular regions termed as HIV hotspots due to a higher prevalence of infection. Addressing these hotspots is essential for controlling the epidemic. However, these regions, influenced by historical factors, challenge standard interventions. Legacy effects-the lasting impact of past events-play a substantial role in the persistence of these hotspots. To address this challenge of the standard interventions, we propose a shift towards the UNAIDS 95-95-95 targets. Spatial analysis of HIV viral load and antiretroviral therapy coverage can provide a more comprehensive perspective on the epidemic's dynamics. Studies in Zambia and Zimbabwe, using this approach, have revealed disparities in HIV care metrics across regions. By focusing on the UNAIDS 95-95-95 targets, more effective control strategies can be designed, with consideration of both historical and current factors. This approach would offer a solution-oriented strategy, emphasising tailored interventions based on specific regional needs.

Spatial detection and consequences of nonrenal calcitriol production as assessed by targeted mass spectrometry imaging.

The immune benefits of vitamin D3 supplementation beyond calcium and phosphate maintenance are highly clinically debated. Kidney expression of CYP27B1 is the source of endocrine, circulating 1,25(OH)2D3 (active form of vitamin D) that maintains serum calcium and phosphate. 1,25(OH)2D3 may also be made by the CYP27B1 enzyme in non-renal cells, like immune cells, in a process driven by cellular availability of 25(OH)D3 and inflammation. Due to the endocrine nature of 1,25(OH)2D3 in circulation, it is difficult to discern between these two sources. We recently created a regulatory deletion model of Cyp27b1 (M1/M21-DIKO) where mice have normal inflammatory-regulated Cyp27b1 expression in non-renal tissues (unlike global Cyp27b1-KO), but no expression within kidney. Here, utilizing on-tissue chemical derivatization and Matrix Assisted Laser Desorption Ionization-Mass Spectrometry Imaging (MALDI-MSI), we investigated the distribution of 1,25(OH)2D3 and 25(OH)D3 in the kidney, liver, spleen, and thymus. MALDI-MSI demonstrated increased 1,25(OH)2D3 in non-renal tissues such as the spleen after vitamin D3 supplementation in M1/M21-DIKO mice. Additionally, from this we found increased Il4 and decreased Tnfa in the spleen after vitamin D3 supplementation. Taken together, these data demonstrate non-renal production of 1,25(OH)2D3 in vivo and provide a consequence of vitamin D3 supplementation and non-renal 1,25(OH)2D3 production in cytokine changes.

Molecular modeling of multi-target analogs of huperzine A and applications in Alzheimer's disease.

CONTEXT: Given the diverse pathophysiological mechanisms underlying Alzheimer's disease, it is improbable that a single targeted drug will prove successful as a therapeutic strategy. Therefore, exploring various hypotheses in drug design is imperative. The sequestration of Fe(II) and Zn(II) cations stands out as a crucial mechanism based on the mitigation of reactive oxygen species. Moreover, inhibiting acetylcholinesterase represents a pivotal strategy to enhance acetylcholine levels in the synaptic cleft. This research aims to investigate the analogs of Huperzine A, documented in scientific literature, considering of these two hypotheses. Consequently, the speciation chemistry of these structures with Fe(II) and Zn(II) was scrutinized using quantum chemistry calculations, molecular docking simulations, and theoretical predictions of pharmacokinetics properties. From the pharmacokinetic properties, only two analogs, HupA-A1 and HupA-A2, exhibited a theoretical permeability across the blood-brain barrier; on the other hand, from a thermodynamic standpoint, the enantiomers of HupA-A2 showed negligible chelation values. The enantiomers with the most favorable interaction parameters were S'R'HupA-A1 (ΔGBIND = -40.0 kcal mol-1, fitness score = 35.5) and R'R'HupA-A1 (ΔGBIND = -35.5 kcal mol-1, fitness score = 22.61), being compared with HupA (ΔGBIND = -41.75 kcal mol-1, fitness score = 39.95). From this study, some prime candidates for promising drug were S'R'HupA-A1 and R'R'HupA-A1, primarily owing to their favorable thermodynamic chelating capability and potential anticholinesterase mechanism. METHODS: Quantum chemistry calculations were carried out at B3LYP/6-31G(d) level, considering the IEF-PCM(UFF) implicit solvent model for water. The coordination compounds were assessed using the Gibbs free energy variation and hard and soft acid theory. Molecular docking calculations were conducted using the GOLD program, based on the crystal structure of the acetylcholinesterase protein (PDB code = 4EY5), where the ChemScore function was employed with the active site defined as the region within a 15-Å radius around the centroid coordinates (X = -9.557583, Y = -43.910473, Z = 31.466687). Pharmacokinetic properties were predicted using SwissADME, focusing on Lipinski's rule of five.

Complete genome sequence and phylogenetic analysis of a newly discovered fusagra-like virus infecting Carica papaya in Ecuador.

A new fusagra-like virus infecting papaya (Carica papaya L.) was genetically characterized. The genome of the virus, provisionally named "papaya sticky fruit-associated virus" (PSFaV), is a single molecule of double-stranded RNA, 9,199 nucleotides (nt) in length, containing two discontinuous open reading frames. Pairwise sequence comparisons based on complete RNA-dependent-RNA-polymerase (RdRp) sequences revealed identity of 79.4% and 83.3% at the nt and amino acid (aa) level, respectively, to babaco meleira-like virus (BabMelV), an uncharacterized virus sequence discovered in babaco (Vasconcellea x heilbornii) in Ecuador. Additional plant-associated viruses with sequence identity in the 50% range included papaya meleira virus (PMeV) isolates from Brazil. Phylogenetic analysis based on the amino acid sequences of the capsid protein (CP), RdRp, and CP-RdRp fusion protein genes placed PSFaV in a group within a well-supported clade that shares a recent ancestor with Sclerotium rolfsii RNA virus 2 and Phlebiopsis gigantea mycovirus dsRNA 2, two fungus-associated fusagraviruses. Genomic features and phylogenetic relatedness suggest that PSFaV, along with its closest relative BabMelV, represent a species of novel plant-associated virus classified within the recently established family Fusagraviridae.

Overexpression of TBX3 suppresses tumorigenesis in experimental and human cholangiocarcinoma.

TBX3 behaves as a tumor suppressor or oncoprotein across cancer. However, TBX3 function remains undetermined in intrahepatic cholangiocarcinoma (iCCA), a deadly primary liver malignancy with few systemic treatment options. This study sought to investigate the impact of TBX3 on iCCA. We found that overexpression of TBX3 strongly inhibited human iCCA cell growth. In the Akt/FBXW7ΔF mouse iCCA model, overexpression of Tbx3 reduced cholangiocarcinogenesis in vivo, while inducible genetic knockout of Tbx3 accelerated iCCA growth. RNA-seq identified MAD2L1 as a downregulated gene in TBX3-overexpressing cells, and ChIP confirmed that TBX3 binds to the MAD2L1 promoter. CRISPR-mediated knockdown of Mad2l1 significantly reduced the growth of two iCCA models in vivo. Finally, we found that TBX3 expression is upregulated in ~20% of human iCCA samples, and its high expression is associated with less proliferation and better survival. MAD2L1 expression is upregulated in most human iCCA samples and negatively correlated with TBX3 expression. Altogether, our findings suggest that overexpression of TBX3 suppresses CCA progression via repressing MAD2L1 expression.

Pathology of Squamous Cell Carcinoma of the Penis: Back to Square One.

The landscape of squamous cell carcinoma of the penis (SCC-P) has undergone a significant transformation since the new World Health Organization classification of genitourinary cancers and recent European Association of Urology/American Association of Clinical Oncology guidelines. These changes emphasize the necessity to categorize SCC-P into 2 groups based on its association with human papillomavirus (HPV) infection. This shift has major implications, considering that prior knowledge was derived from a mix of both groups. Given the distinct prognosis, treatment options, and staging systems observed for HPV-associated tumors in other body areas, the question now arises: will similar patterns emerge for SCC-P?

High-gamma and beta bursts in the Left Supramarginal Gyrus can accurately differentiate verbal memory states and performance.

The left supramarginal gyrus (LSMG) may mediate attention to memory, and gauge memory state and performance. We performed a secondary analysis of 142 verbal delayed free recall experiments, in patients with medically-refractory epilepsy with electrode contacts implanted in the LSMG. In 14 of 142 experiments (in 14 of 113 patients), the cross-validated convolutional neural networks (CNNs) that used 1-dimensional(1-D) pairs of convolved high-gamma and beta tensors, derived from the LSMG recordings, could label recalled words with an area under the receiver operating curve (AUROC) of greater than 60% [range: 60-90%]. These 14 patients were distinguished by: 1) higher amplitudes of high-gamma bursts; 2) distinct electrode placement within the LSMG; and 3) superior performance compared with a CNN that used a 1-D tensor of the broadband recordings in the LSMG. In a pilot study of 7 of these patients, we also cross-validated CNNs using paired 1-D convolved high-gamma and beta tensors, from the LSMG, to: a) distinguish word encoding epochs from free recall epochs [AUC 0.6-1]; and distinguish better performance from poor performance during delayed free recall [AUC 0.5-0.86]. These experiments show that bursts of high-gamma and beta generated in the LSMG are biomarkers of verbal memory state and performance.

Acute Administration of Calafate (Berberis microphylla) Extract Induces the Expression of Thermogenic Markers and Modulates Gut Microbiota in Mice Fed a High-Fat Chow Diet.

INTRODUCTION: Obesity, characterized by excess adipose tissue, is a major public health problem worldwide. Brown adipose tissue (BAT) and beige adipose tissue participate in thermogenesis through uncoupling protein 1 (UCP1). Polyphenols including those from Calafate (a native polyphenol-rich Patagonian berry), are considered as potential anti-obesity compounds due to their pro-thermogenic characteristics. However, polyphenols are mainly metabolized by the gut microbiota (GM) that may influence their bioactivity and bioavailability. The aim of this study was to determine the impact of dietary administration with a Calafate polyphenol-rich extract on thermogenic activity of BAT and beige adipose tissue and GM composition. METHODS: Eight-week-old C57BL6 mice (n = 30) were divided into 4 groups to receive for 24 weeks a control diet (C), a high-fat diet alone (HF), or high-fat diet supplemented with Calafate extract (HFC) or the same high-fat diet supplemented with Calafate extract but treated with antibiotics (HFCAB) from week 19-20. Administration with Calafate extract (50 mg/kg per day) was carried out for 3 weeks from week 21-23 in the HFC and HFCAB groups. After euthanasia, gene expression of thermogenic markers was analyzed in BAT and inguinal white adipose tissue (iWAT). Transmission electron microscopy was performed to assess mitochondrial morphology and cristae density in BAT. GM diversity and composition were characterized by deep sequencing with the MiSeq Illumina platform. RESULTS: Calafate extract administration had no effect on weight gain in mice fed a high-fat diet. However, it prevented alterations in mitochondrial cristae induced by HFD and increased Dio2 expression in BAT and iWAT. The intervention also influenced the GM composition, preventing changes in specific bacterial taxa induced by the high-fat diet. However, the antibiotic treatment prevented in part these effects, suggesting the implications of GM. CONCLUSION: These results suggest that the acute administration of a Calafate extract modulates the expression of thermogenic markers, prevents alterations in mitochondrial cristae and intestinal microbiota in preclinical models. The study highlights the complex interaction between polyphenols, thermogenesis, and the GM, providing valuable insights into their potential roles in the treatment of obesity-related metabolic diseases.

Proof of concept of the Universal Baby video innovation for early child development in Lima, Peru.

OBJECTIVE: Community-based video interventions offer an effective and potentially scalable early interaction coaching tool for caregivers living in low resource settings. We tested the Universal Baby (UB) video innovation; an early interaction coaching tool using video sourced and produced locally with early child development (ECD) expert supervision. METHODS: This proof-of-concept study enrolled 40 caregivers of children ages 10-18 months assigned to intervention and control groups by health establishments in Carabayllo, Lima, Peru. Mother/child dyads received 12 weekly group health education sessions with social support. Of those, 16 caregivers also received 6 UB videos featuring brain science education and local clips of responsive, reciprocal interaction, also known as "serve and return" interaction. Survey data assessed feasibility and acceptability of the intervention. We assessed improved quality of mother/child interaction using the Parenting Interactions with Children: Checklist of Observations Linked to Outcomes (PICCOLO). RESULTS: We found the program feasible. We successfully trained the local team to produce UB videos using locally-sourced footage and delivered the videos as part of a community-based intervention. We also found it to be acceptable in that participants enthusiastically received the UB videos, reporting they enjoyed being videotaped, and learned how to recognize and appropriately respond to their child's nuanced sounds and gestures. The median change in total PICCOLO scores favored the intervention group compared to the control group. CONCLUSIONS: UB offers great potential as a sustainable, potentially scalable, and culturally appropriate tool to promote equity for child development among young children living in low resource homes globally.

Endothelial Heterogeneity in the Response to Autophagy Drives Small Vessel Muscularization in Pulmonary Hypertension.

BACKGROUND: Endothelial cell (EC) apoptosis and proliferation of apoptosis-resistant cells is a hallmark of pulmonary hypertension (PH). Yet, why some ECs die and others proliferate and how this contributes to vascular remodeling is unclear. We hypothesized that this differential response may: (1) relate to different EC subsets, namely pulmonary artery (PAECs) versus microvascular ECs (MVECs); (2) be attributable to autophagic activation in both EC subtypes; and (3) cause replacement of MVECs by PAECs with subsequent distal vessel muscularization. METHODS: EC subset responses to chronic hypoxia were assessed by single-cell RNA sequencing of murine lungs. Proliferative versus apoptotic responses, activation, and role of autophagy were assessed in human and rat PAECs and MVECs, and in precision-cut lung slices of wild-type mice or mice with endothelial deficiency in the autophagy gene Atg7 (Atg7EN-KO). Abundance of PAECs versus MVECs in precapillary microvessels was assessed in lung tissue from patients with PH and animal models on the basis of structural or surface markers. RESULTS: In vitro and in vivo, PAECs proliferated in response to hypoxia, whereas MVECs underwent apoptosis. Single-cell RNA sequencing analyses support these findings in that hypoxia induced an antiapoptotic, proliferative phenotype in arterial ECs, whereas capillary ECs showed a propensity for cell death. These distinct responses were prevented in hypoxic Atg7EN-KO mice or after ATG7 silencing, yet replicated by autophagy stimulation. In lung tissue from mice, rats, or patients with PH, the abundance of PAECs in precapillary arterioles was increased, and that of MVECs reduced relative to controls, indicating replacement of microvascular by macrovascular ECs. EC replacement was prevented by genetic or pharmacological inhibition of autophagy in vivo. Conditioned medium from hypoxic PAECs yet not MVECs promoted pulmonary artery smooth muscle cell proliferation and migration in a platelet-derived growth factor-dependent manner. Autophagy inhibition attenuated PH development and distal vessel muscularization in preclinical models. CONCLUSIONS: Autophagic activation by hypoxia induces in parallel PAEC proliferation and MVEC apoptosis. These differential responses cause a progressive replacement of MVECs by PAECs in precapillary pulmonary arterioles, thus providing a macrovascular context that in turn promotes pulmonary artery smooth muscle cell proliferation and migration, ultimately driving distal vessel muscularization and the development of PH.

Use of Sotrovimab in Pregnancy: Experiences from the COVID-19 International Drug Pregnancy Registry.

INTRODUCTION: Available data regarding the safety and efficacy of sotrovimab in pregnant patients remain limited due to their exclusion from clinical trials. METHODS: The COVID-19 International Drug Pregnancy Registry (COVID-PR) was established to gather comprehensive safety data from pregnant women who have received monoclonal antibody (mAb) or antiviral treatments for mild, moderate, or severe coronavirus disease 2019 (COVID-19) during pregnancy. Participants actively contributed self-reported data concerning their COVID-19 symptoms, in addition to sociodemographic and health-related characteristics. Obstetric, neonatal, and infant outcomes were also documented, with follow-up extending up to 12 months after childbirth. RESULTS: As of 30 November 2023, sotrovimab was administered to 39 participants enrolled in the COVID-PR. At the time of this report, 26 participants had given birth, with nine deliveries performed via cesarean section. The infants' birthweight ranged from 2381 g to 4762 g, with a mean of 3439.91 g. Twenty-five infants were born at ≥37 weeks. A total of 31 adverse events (AEs) were reported by 12 participants. The most frequently reported AE was gestational hypertension, observed in three participants. COVID-19 re-infection, fatigue, gestational diabetes, headache, and morning sickness were each reported by two participants. Of the reported AEs, eight (in five participants) were classified as serious, including four AEs (prolonged labor, pre-eclampsia, polyhydramnios, premature labor) that affected pregnancy. Seven of these eight serious AEs (SAEs) were found to be unrelated to sotrovimab, with one event (urinary retention) not assessable. A total of 44 AEs were reported in 19 delivered infants or in utero fetuses. The most common were COVID-19 (n = 6 events), ear infection (n = 5 events), neonatal dyspnea (n = 3 events), and respiratory syncytial virus infection (n = 3 events). Sixteen AEs (in 11 infants/fetuses) were classified as serious, including one report each of fetal cardiac disorder, congenital ankyloglossia, persistent right umbilical vein, and congenital hydronephrosis; the latter was considered a major congenital malformation. For all assessable SAEs, causality of sotrovimab treatment was ruled out based on lack of a temporal relationship alone or in combination with absence of a plausible mechanism. CONCLUSION: A sizable proportion of sotrovimab-treated participants in the COVID-PR had underlying medical conditions associated with an increased risk of severe COVID-19. None of the assessable SAEs were considered to be related to sotrovimab treatment.

Analysis of a new negevirus-like sequence from Bemisia tabaci unveils a potential new taxon linking nelorpi- and centiviruses.

This study presents the complete genome sequence of a novel nege-like virus identified in whiteflies (Bemisia tabaci MEAM1), provisionally designated as whitefly negevirus 1 (WfNgV1). The virus possesses a single-stranded RNA genome comprising 11,848 nucleotides, organized into four open reading frames (ORFs). These ORFs encode the putative RNA-dependent-RNA-polymerase (RdRp, ORF 1), a glycoprotein (ORF 2), a structural protein with homology to those in the SP24 family, (ORF 3), and a protein of unknown function (ORF 4). Phylogenetic analysis focusing on RdRp and SP24 amino acid sequences revealed a close relationship between WfNgV1 and Bemisia tabaci negevirus 1, a negevirus sequence recently discovered in whiteflies from Israel. Both viruses form a clade sharing a most recent common ancestor with the proposed nelorpivirus and centivirus taxa. The putative glycoprotein from ORF 2 and SP24 (ORF 3) of WfNgV1 exhibit the characteristic topologies previously reported for negevirus counterparts. This marks the first reported negevirus-like sequence from whiteflies in the Americas.

Corrigendum to "Treatment of textile wastewater using the Co(II)/NaHCO3/H2O2 oxidation system" [Heliyon 9(12) December 2023 e22444].

[This corrects the article DOI: 10.1016/j.heliyon.2023.e22444.].

Amino-modified upcycled biochar achieves selective chromium removal in complex aqueous matrices.

Chromium pollution of groundwater sources is a growing global issue, which correlates with various anthropogenic activities. Remediation of both the Cr(VI) and Cr(III), via adsorption technologies, has been championed in recent years due to ease of use, minimal energy requirements, and the potential to serve as a highly sustainable remediation technology. In the present study, a biochar sorbent sourced from pineapple skins, allowed for the upcycling of agricultural waste into water purification technology. The biochar material was chemically modified, through a green amination method, to produce an efficient and selective adsorbent for the removal of both Cr(VI) and Cr(III) from complex aqueous matrices. From FTIR analysis it was evident that the chemical modification introduced new C-N and N-H bonds observed in the modified biochar along with a depletion of N-O and C-H bonds found in the pristine biochar. The amino modified biochar was found to spontaneously adsorb both forms of chromium at room temperature, with binding capacities of 46.5 mg/g of Cr(VI) and 27.1 mg/g of Cr(III). Interference studies, conducted in complex matrices, showed no change in adsorption capacity for Cr(VI) in matrices containing up to 3,000× the concentration of interfering ions. Finally, Cr(III) removal was synergized to 100% adsorption at interfering ions concentrations up to 330× of the analyte, which were suppressed at higher interference concentrations. Considering such performance, the amino modified biochar achieved selective removal for both forms of chromium, showing great potential for utilization in complex chromium pollution sources.

Molecular characterization and descriptive analysis of carbapenemase-producing Gram-negative rod infections in Bogota, Colombia.

In this study, the genetic differences and clinical impact of the carbapenemase-encoding genes among the community and healthcare-acquired infections were assessed. This retrospective, multicenter cohort study was conducted in Colombia and included patients infected with carbapenem-resistant Gram-negative rods between 2017 and 2021. Carbapenem resistance was identified by Vitek, and carbapenemase-encoding genes were identified by whole-genome sequencing (WGS) to classify the alleles and sequence types (STs). Descriptive statistics were used to determine the association of any pathogen or gene with clinical outcomes. A total of 248 patients were included, of which only 0.8% (2/248) had community-acquired infections. Regarding the identified bacteria, the most prevalent pathogens were Pseudomonas aeruginosa and Klebsiella pneumoniae. In the WGS analysis, 228 isolates passed all the quality criteria and were analyzed. The principal carbapenemase-encoding gene was blaKPC, specifically blaKPC-2 [38.6% (88/228)] and blaKPC-3 [36.4% (83/228)]. These were frequently detected in co-concurrence with blaVIM-2 and blaNDM-1 in healthcare-acquired infections. Notably, the only identified allele among community-acquired infections was blaKPC-3 [50.0% (1/2)]. In reference to the STs, 78 were identified, of which Pseudomonas aeruginosa ST111 was mainly related to blaKPC-3. Klebsiella pneumoniae ST512, ST258, ST14, and ST1082 were exclusively associated with blaKPC-3. Finally, no particular carbapenemase-encoding gene was associated with worse clinical outcomes. The most identified genes in carbapenemase-producing Gram-negative rods were blaKPC-2 and blaKPC-3, both related to gene co-occurrence and diverse STs in the healthcare environment. Patients had several systemic complications and poor clinical outcomes that were not associated with a particular gene.IMPORTANCEAntimicrobial resistance is a pandemic and a worldwide public health problem, especially carbapenem resistance in low- and middle-income countries. Limited data regarding the molecular characteristics and clinical outcomes of patients infected with these bacteria are available. Thus, our study described the carbapenemase-encoding genes among community- and healthcare-acquired infections. Notably, the co-occurrence of carbapenemase-encoding genes was frequently identified. We also found 78 distinct sequence types, of which two were novel Pseudomonas aeruginosa, which could represent challenges in treating these infections. Our study shows that in low and middle-income countries, such as Colombia, the burden of carbapenem resistance in Gram-negative rods is a concern for public health, and regardless of the allele, these infections are associated with poor clinical outcomes. Thus, studies assessing local epidemiology, prevention strategies (including trials), and underpinning genetic mechanisms are urgently needed, especially in low and middle-income countries.

Collaborative Modeling to Compare Different Breast Cancer Screening Strategies: A Decision Analysis for the US Preventive Services Task Force.

Importance: The effects of breast cancer incidence changes and advances in screening and treatment on outcomes of different screening strategies are not well known. Objective: To estimate outcomes of various mammography screening strategies. Design, Setting, and Population: Comparison of outcomes using 6 Cancer Intervention and Surveillance Modeling Network (CISNET) models and national data on breast cancer incidence, mammography performance, treatment effects, and other-cause mortality in US women without previous cancer diagnoses. Exposures: Thirty-six screening strategies with varying start ages (40, 45, 50 years) and stop ages (74, 79 years) with digital mammography or digital breast tomosynthesis (DBT) annually, biennially, or a combination of intervals. Strategies were evaluated for all women and for Black women, assuming 100% screening adherence and "real-world" treatment. Main Outcomes and Measures: Estimated lifetime benefits (breast cancer deaths averted, percent reduction in breast cancer mortality, life-years gained), harms (false-positive recalls, benign biopsies, overdiagnosis), and number of mammograms per 1000 women. Results: Biennial screening with DBT starting at age 40, 45, or 50 years until age 74 years averted a median of 8.2, 7.5, or 6.7 breast cancer deaths per 1000 women screened, respectively, vs no screening. Biennial DBT screening at age 40 to 74 years (vs no screening) was associated with a 30.0% breast cancer mortality reduction, 1376 false-positive recalls, and 14 overdiagnosed cases per 1000 women screened. Digital mammography screening benefits were similar to those for DBT but had more false-positive recalls. Annual screening increased benefits but resulted in more false-positive recalls and overdiagnosed cases. Benefit-to-harm ratios of continuing screening until age 79 years were similar or superior to stopping at age 74. In all strategies, women with higher-than-average breast cancer risk, higher breast density, and lower comorbidity level experienced greater screening benefits than other groups. Annual screening of Black women from age 40 to 49 years with biennial screening thereafter reduced breast cancer mortality disparities while maintaining similar benefit-to-harm trade-offs as for all women. Conclusions: This modeling analysis suggests that biennial mammography screening starting at age 40 years reduces breast cancer mortality and increases life-years gained per mammogram. More intensive screening for women with greater risk of breast cancer diagnosis or death can maintain similar benefit-to-harm trade-offs and reduce mortality disparities.

Substitution Effects in Aryl Halides and Amides into the Reaction Mechanism of Ullmann-Type Coupling Reactions.

In this article, we present a comprehensive computational investigation into the reaction mechanism of N-arylation of substituted aryl halides through Ullmann-type coupling reactions. Our computational findings, obtained through DFT ωB97X-D/6-311G(d,p) and ωB97X-D/LanL2DZ calculations, reveal a direct relation between the previously reported experimental reaction yields and the activation energy of haloarene activation, which constitutes the rate-limiting step in the overall coupling process. A detailed analysis of the reaction mechanism employing the Activation Strain Model indicates that the strain in the substituted iodoanilines is the primary contributor to the energy barrier, representing an average of 80% of the total strain energy. Additional analysis based on conceptual Density Functional Theory (DFT) suggests that the nucleophilicity of the nitrogen in the lactam is directly linked to the activation energies. These results provide valuable insights into the factors influencing energetic barriers and, consequently, reaction yields. These insights enable the rational modification of reactants to optimize the N-arylation process.

The Andes as a semi-permeable geographical barrier: Genetic connectivity between structured populations in a widespread spider.

Geographical barriers like mountain ranges impede genetic exchange among populations, promoting diversification. The effectiveness of these barriers in limiting gene flow varies between lineages due to each species' dispersal modes and capacities. Our understanding of how the Andes orogeny contributes to species diversification comes from well-studied vertebrates and a few arthropods and plants, neglecting organisms unable to fly or walk long distances. Some arachnids, such as Gasteracantha cancriformis, have been hypothesized to disperse long distances via ballooning (i.e. using their silk to interact with the wind). Yet, we do not know how the environment and geography shape its genetic diversity. Therefore, we tested whether the Andes contributed to the diversification of G. cancriformis acting as an absolute or semi-permeable barrier to genetic connectivity between populations of this spider at opposite sides of the mountain range. We sampled thousands of loci across the distribution of the species and implemented population genetics, phylogenetic, and landscape genetic analyses. We identified two genetically distinct groups structured by the Central Andes, and a third less structured group in the Northern Andes that shares ancestry with the previous two. This structure is largely explained by the altitude along the Andes, which decreases in some regions, possibly facilitating cross-Andean dispersal and gene flow. Our findings support that altitude in the Andes plays a major role in structuring populations in South America, but the strength of this barrier can be overcome by organisms with long-distance dispersal modes together with altitudinal depressions.

Las barreras geográficas como las cordilleras montañosas impiden el intercambio genético entre poblaciones, promoviendo la diversificación. La efectividad de estas barreras para limitar el flujo genético varía entre linajes debido a los modos y capacidades de dispersión de cada especie. Nuestra comprensión de cómo la orogenia de los Andes contribuye a la diversificación de especies proviene de vertebrados y algunos artrópodos y plantas bien estudiados, descuidando a los organismos incapaces de volar o caminar grandes distancias. Se ha hipotetizado que algunas arañas, como Gasteracantha cancriformis, se dispersan a grandes distancias mediante la técnica de "ballooning" (es decir, utilizando su seda para interactuar con el viento). Sin embargo, no sabemos cómo el entorno y la geografía han dado forma a su diversidad genética. Por lo tanto, probamos si los Andes contribuyeron a la diversificación de G. cancriformis actuando como una barrera absoluta o permeable para la conectividad genética entre poblaciones de esta araña en lados opuestos de la cordillera. Muestreamos miles de loci a través de la distribución de la especie e implementamos análisis de genética de poblaciones, filogenéticos y de genética del paisaje. Identificamos dos grupos genéticamente distintos estructurados por los Andes Centrales, y un tercer grupo menos estructurado en los Andes del Norte que comparte ascendencia con los dos anteriores. Esta estructura se explica en gran medida por la altitud a lo largo de los Andes, que disminuye en algunas regiones, posiblemente facilitando la dispersión y el flujo genético a través de los Andes. Nuestros hallazgos apoyan que la altitud en los Andes juega un papel importante en la estructuración de las poblaciones en América del Sur, pero la fuerza de esta barrera puede ser superada por organismos con modos de dispersión a larga distancia junto con depresiones altitudinales.

HIV transmission dynamics and population-wide drug resistance in rural South Africa.

Despite expanded antiretroviral therapy (ART) in South Africa, HIV-1 transmission persists. Integrase strand transfer inhibitors (INSTI) and long-acting injectables offer potential for superior viral suppression, but pre-existing drug resistance could threaten their effectiveness. In a community-based study in rural KwaZulu-Natal, prior to widespread INSTI usage, we enroled 18,025 individuals to characterise HIV-1 drug resistance and transmission networks to inform public health strategies. HIV testing and reflex viral load quantification were performed, with deep sequencing (20% variant threshold) used to detect resistance mutations. Phylogenetic and geospatial analyses characterised transmission clusters. One-third of participants were HIV-positive, with 21.7% having detectable viral loads; 62.1% of those with detectable viral loads were ART-naïve. Resistance to older reverse transcriptase (RT)-targeting drugs was found, but INSTI resistance remained low (<1%). Non-nucleoside reverse transcriptase inhibitor (NNRTI) resistance, particularly to rilpivirine (RPV) even in ART-naïve individuals, was concerning. Twenty percent of sequenced individuals belonged to transmission clusters, with geographic analysis highlighting higher clustering in peripheral and rural areas. Our findings suggest promise for INSTI-based strategies in this setting but underscore the need for RPV resistance screening before implementing long-acting cabotegravir (CAB) + RPV. The significant clustering emphasises the importance of geographically targeted interventions to effectively curb HIV-1 transmission.