Recombination of H3+ Ions in the Afterglow of a He-Ar-H2 Plasma

Recombination of H3+ with electrons was studied in a low temperature plasma in helium. The plasma recombination rate is driven by two body, H3+ + e, and three-body, H3+ + e + He, processes with the rate coefficients 7.5x10^{-8}cm3/s and 2.8x10^{-25}cm6/s correspondingly at 260K. The two-body rate coefficient is in excellent agreement with results from storage ring experiments and theoretical calculations. We suggest that the three-body recombination involves formation of highly excited Rydberg neutral H3 followed by an l- or m- changing collision with He. Plasma electron spectroscopy indicates the presence of H3.Comment: 4 figure

Surveillance for Malaria Elimination in Swaziland: A National Cross-Sectional Study Using Pooled PCR and Serology

BACKGROUND: To guide malaria elimination efforts in Swaziland and other countries, accurate assessments of transmission are critical. Pooled-PCR has potential to efficiently improve sensitivity to detect infections; serology may clarify temporal and spatial trends in exposure. METHODOLOGY/PRINCIPAL FINDINGS: Using a stratified two-stage cluster, cross-sectional design, subjects were recruited from the malaria endemic region of Swaziland. Blood was collected for rapid diagnostic testing (RDT), pooled PCR, and ELISA detecting antibodies to Plasmodium falciparum surface antigens. Of 4330 participants tested, three were RDT-positive yet false positives by PCR. Pooled PCR led to the identification of one P. falciparum and one P. malariae infection among RDT-negative participants. The P. falciparum-infected participant reported recent travel to Mozambique. Compared to performing individual testing on thousands of samples, PCR pooling reduced labor and consumable costs by 95.5%. Seropositivity was associated with age ≥20 years (11·7% vs 1·9%, P<0.001), recent travel to Mozambique (OR 4.4 [95% CI 1.0-19.0]) and residence in southeast Swaziland (RR 3.78, P<0.001). CONCLUSIONS: The prevalence of malaria infection and recent exposure in Swaziland are extremely low, suggesting elimination is feasible. Future efforts should address imported malaria and target remaining foci of transmission. Pooled PCR and ELISA are valuable surveillance tools for guiding elimination efforts

Genomic insights to SAR86, an abundant and uncultivated marine bacterial lineage

Bacteria in the 16S rRNA clade SAR86 are among the most abundant uncultivated constituents of microbial assemblages in the surface ocean for which little genomic information is currently available. Bioinformatic techniques were used to assemble two nearly complete genomes from marine metagenomes and single-cell sequencing provided two more partial genomes. Recruitment of metagenomic data shows that these SAR86 genomes substantially increase our knowledge of non-photosynthetic bacteria in the surface ocean. Phylogenomic analyses establish SAR86 as a basal and divergent lineage of γ-proteobacteria, and the individual genomes display a temperature-dependent distribution. Modestly sized at 1.25–1.7 Mbp, the SAR86 genomes lack several pathways for amino-acid and vitamin synthesis as well as sulfate reduction, trends commonly observed in other abundant marine microbes. SAR86 appears to be an aerobic chemoheterotroph with the potential for proteorhodopsin-based ATP generation, though the apparent lack of a retinal biosynthesis pathway may require it to scavenge exogenously-derived pigments to utilize proteorhodopsin. The genomes contain an expanded capacity for the degradation of lipids and carbohydrates acquired using a wealth of tonB-dependent outer membrane receptors. Like the abundant planktonic marine bacterial clade SAR11, SAR86 exhibits metabolic streamlining, but also a distinct carbon compound specialization, possibly avoiding competition

Subcortical brain volume, regional cortical thickness, and cortical surface area across disorders: findings from the ENIGMA ADHD, ASD, and OCD Working Groups

Objective Attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), and obsessive-compulsive disorder (OCD) are common neurodevelopmental disorders that frequently co-occur. We aimed to directly compare all three disorders. The ENIGMA consortium is ideally positioned to investigate structural brain alterations across these disorders. Methods Structural T1-weighted whole-brain MRI of controls (n=5,827) and patients with ADHD (n=2,271), ASD (n=1,777), and OCD (n=2,323) from 151 cohorts worldwide were analyzed using standardized processing protocols. We examined subcortical volume, cortical thickness and surface area differences within a mega-analytical framework, pooling measures extracted from each cohort. Analyses were performed separately for children, adolescents, and adults using linear mixed-effects models adjusting for age, sex and site (and ICV for subcortical and surface area measures). Results We found no shared alterations among all three disorders, while shared alterations between any two disorders did not survive multiple comparisons correction. Children with ADHD compared to those with OCD had smaller hippocampal volumes, possibly influenced by IQ. Children and adolescents with ADHD also had smaller ICV than controls and those with OCD or ASD. Adults with ASD showed thicker frontal cortices compared to adult controls and other clinical groups. No OCD-specific alterations across different age-groups and surface area alterations among all disorders in childhood and adulthood were observed. Conclusion Our findings suggest robust but subtle alterations across different age-groups among ADHD, ASD, and OCD. ADHD-specific ICV and hippocampal alterations in children and adolescents, and ASD-specific cortical thickness alterations in the frontal cortex in adults support previous work emphasizing neurodevelopmental alterations in these disorders

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Discovery and Design of Next Generation Inhibitors Targeting the HER2/HER3 heterodimer and K-Ras

Targeted inhibitors of driving oncogenes impose a selective pressure that benefits those cells who can most quickly and efficiently bypass the insult. While much attention, particularly in the kinase inhibitor field, has focused on the selective outgrowth of cells harboring mutations that directly impact the inhibitors ability to bind a much more rapid innate resistance mechanism often exists that it is revealed by the presence of the inhibitor. In chapter 1 we found that growth factor driven resistance to current clinical HER2 inhibitors was due to the inability of the inhibitors to directly target the active state of the kinase. We used this information to design a screen for an inhibitor of the active HER2/HER3 complex resulting in the identification of one hit scaffold. Optimization of our small molecule hit resulted in a HER2 inhibitor that was insensitive the presence of growth factor and also capable of targeting the mutationally activated form of HER2. In chapter 2 we used the existing known biology of K-Ras’s ability to bypass first generation farnesyltransferase inhibitors to design an inhibitor that would simultaneously block K-Ras cellular localization and its ability to bypass inhibition. The resulting inhibitor was found to block K-Ras localization in cells, and when combined with statins, was found to inhibit oncogenic K-Ras signaling and proliferation

Local and regional diversity of frog communities along an extensive rainforest elevation gradient in Papua New Guinea

&lt;p&gt;Rainforests on high tropical mountains are globally important species diversity hotspots. We studied amphibians along an extensive rainforest elevation gradient on Mt. Wilhelm (4,509 m) in Papua New Guinea. We established eight sites at 500 m elevation increments between 200 and 3,700 m a.s.l. and related their community composition to the known species pool of New Guinea island. We recorded 3,390 frogs from 55 species, which is three times more species than at any local community along the elevation gradient. Species diversity peaked at 1,700 m a.s.l. for Mt. Wilhelm communities, and at 500–1,100 m a.s.l. in the broader New Guinea fauna, probably reflecting increasing speciation and decreasing dispersal rates with increasing elevation. The beta diversity between frog communities was high and increased with increasing elevation. The change in frog community composition across 500 m elevation corresponded to the change over 200 km distance within lowland forests. A majority of frog species were distributed over narrow &lt;500 m elevational ranges, at Mt Wilhelm and the New Guinea fauna more broadly. We did not detect Rapoport's pattern of wider elevation range for species at higher elevations than for lowland species, for Mt. Wilhelm communities or the New Guinea fauna. The high beta diversity patterns along elevation gradients generated by rapid species turnover with narrow elevation ranges make frog communities vulnerable to change in the environment, including climate change.&lt;/p&gt;&lt;p&gt;Funding provided by: Association of Zoos and Aquariums&lt;br&gt;Crossref Funder Registry ID: https://ror.org/00t354q81&lt;br&gt;Award Number: &lt;/p&gt;&lt;p&gt;Funding provided by: Christensen Fund&lt;br&gt;Crossref Funder Registry ID: https://ror.org/01dtadb22&lt;br&gt;Award Number: &lt;/p&gt;&lt;p&gt;Funding provided by: Government of the Czech Republic&lt;br&gt;Crossref Funder Registry ID: https://ror.org/027acbb13&lt;br&gt;Award Number: 19-28126X&lt;/p&gt;&lt;p&gt;Funding provided by: Darwin Initiative&lt;br&gt;Crossref Funder Registry ID: https://ror.org/024hyk965&lt;br&gt;Award Number: 22-002&lt;/p&gt;&lt;p&gt;Funding provided by: Papa New Guinea Mama Graun Conservation Trust Fund*&lt;br&gt;Crossref Funder Registry ID: &lt;br&gt;Award Number: PC 10-3 -010&lt;/p&gt;&lt;p&gt;Funding provided by: Conservation Endowment Fund*&lt;br&gt;Crossref Funder Registry ID: &lt;br&gt;Award Number: 08-857&lt;/p&gt

Farnesyltransferase-Mediated Delivery of a Covalent Inhibitor Overcomes Alternative Prenylation to Mislocalize K‑Ras

Mutationally activated Ras is one of the most common oncogenic drivers found across all malignancies, and its selective inhibition has long been a goal in both pharma and academia. One of the oldest and most validated methods to inhibit overactive Ras signaling is by interfering with its post-translational processing and subsequent cellular localization. Previous attempts to target Ras processing led to the development of farnesyltransferase inhibitors, which can inhibit H-Ras localization but not K-Ras due to its ability to bypass farnesyltransterase inhibition through alternative prenylation by geranylgeranyltransferase. Here, we present the creation of a neo-substrate for farnesyltransferase that prevents the alternative prenlation by geranylgeranyltransferase and mislocalizes oncogenic K-Ras in cells

Predator pressure, herbivore abundance and plant damage along a subtropical altitudinal gradient

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