A Blueprint for Characterizing Senescence.

Given the heterogeneity of senescent cells, our knowledge of both the drivers and consequences of cellular senescence in tissues and organs remains limited, as is our understanding of how this process could be harnessed for human health. Here we identified five broad areas that would help propel the field forward.

Carbon implications of marginal oils from market-derived demand shocks.

Expanded use of novel oil extraction technologies has increased the variability of petroleum resources and diversified the carbon footprint of the global oil supply1. Past life-cycle assessment (LCA) studies overlooked upstream emission heterogeneity by assuming that a decline in oil demand will displace average crude oil2. We explore the life-cycle greenhouse gas emissions impacts of marginal crude sources, identifying the upstream carbon intensity (CI) of the producers most sensitive to an oil demand decline (for example, due to a shift to alternative vehicles). We link econometric models of production profitability of 1,933 oilfields (~90% of the 2015 world supply) with their production CI. Then, we examine their response to a decline in demand under three oil market structures. According to our estimates, small demand shocks have different upstream CI implications than large shocks. Irrespective of the market structure, small shocks (-2.5% demand) displace mostly heavy crudes with ~25-54% higher CI than that of the global average. However, this imbalance diminishes as the shocks become bigger and if producers with market power coordinate their response to a demand decline. The carbon emissions benefits of reduction in oil demand are systematically dependent on the magnitude of demand drop and the global oil market structure.

Mimicking lightning-induced electrochemistry on the early Earth.

To test the hypothesis that an abiotic Earth and its inert atmosphere could form chemically reactive carbon- and nitrogen-containing compounds, we designed a plasma electrochemical setup to mimic lightning-induced electrochemistry under steady-state conditions of the early Earth. Air-gap electrochemical reactions at air-water-ground interfaces lead to remarkable yields, with up to 40 moles of carbon dioxide being reduced into carbon monoxide and formic acid, and 3 moles of gaseous nitrogen being fixed into nitrate, nitrite, and ammonium ions, per mole of transmitted electrons. Interfaces enable reactants (e.g., minerals) that may have been on land, in lakes, and in oceans to participate in radical and redox reactions, leading to higher yields compared to gas-phase-only reactions. Cloud-to-ground lightning strikes could have generated high concentrations of reactive molecules locally, establishing diverse feedstocks for early life to emerge and survive globally.

The RNA helicase Mtr4p modulates polyadenylation in the TRAMP complex.

Many steps in nuclear RNA processing, surveillance, and degradation require TRAMP, a complex containing the poly(A) polymerase Trf4p, the Zn-knuckle protein Air2p, and the RNA helicase Mtr4p. TRAMP polyadenylates RNAs designated for decay or trimming by the nuclear exosome. It has been unclear how polyadenylation by TRAMP differs from polyadenylation by conventional poly(A) polymerase, which produces poly(A) tails that stabilize RNAs. Using reconstituted S. cerevisiae TRAMP, we show that TRAMP inherently suppresses poly(A) addition after only 3-4 adenosines. This poly(A) tail length restriction is controlled by Mtr4p. The helicase detects the number of 3'-terminal adenosines and, over several adenylation steps, elicits precisely tuned adjustments of ATP affinities and rate constants for adenylation and TRAMP dissociation. Our data establish Mtr4p as a critical regulator of polyadenylation by TRAMP and reveal that an RNA helicase can control the activity of another enzyme in a highly complex fashion and in response to features in RNA.

Impact of the Hunga Tonga volcanic eruption on stratospheric composition.

The explosive eruption of the Hunga Tonga-Hunga Ha'apai (HTHH) volcano on 15 January 2022 injected more water vapor into the stratosphere and to higher altitudes than ever observed in the satellite era. Here, the evolution of the stratospherically injected water vapor is examined as a function of latitude, altitude, and time in the year following the eruption (February to December 2022), and perturbations to stratospheric chemical composition resulting from the increased sulfate aerosols and water vapor are identified and analyzed. The average calculated mass distribution of elevated water vapor between hemispheres is approximately 78% Southern Hemisphere (SH) and 22% Northern Hemisphere in 2022. Significant changes in stratospheric composition following the HTHH eruption are identified using observations from the Aura Microwave Limb Sounder satellite instrument. The dominant features in the monthly mean vertical profiles averaged over 15° latitude ranges are decreases in O3 (-14%) and HCl (-22%) at SH midlatitudes and increases in ClO (>100%) and HNO3 (43%) in the tropics, with peak pressure-level perturbations listed. Anomalies in column ozone from 1.2-100 hPa due to the HTHH eruption include widespread O3 reductions in SH midlatitudes and O3 increases in the tropics, with peak anomalies in 15° latitude-binned, monthly averages of approximately -7% and +5%, respectively, occurring in austral spring. Using a 3-dimensional chemistry-climate-aerosol model and observational tracer correlations, changes in stratospheric composition are found to be due to both dynamical and chemical factors.

A ChIP-exo screen of 887 Protein Capture Reagents Program transcription factor antibodies in human cells.

Antibodies offer a powerful means to interrogate specific proteins in a complex milieu. However, antibody availability and reliability can be problematic, whereas epitope tagging can be impractical in many cases. To address these limitations, the Protein Capture Reagents Program (PCRP) generated over a thousand renewable monoclonal antibodies (mAbs) against human presumptive chromatin proteins. However, these reagents have not been widely field-tested. We therefore performed a screen to test their ability to enrich genomic regions via chromatin immunoprecipitation (ChIP) and a variety of orthogonal assays. Eight hundred eighty-seven unique antibodies against 681 unique human transcription factors (TFs) were assayed by ultra-high-resolution ChIP-exo/seq, generating approximately 1200 ChIP-exo data sets, primarily in a single pass in one cell type (K562). Subsets of PCRP mAbs were further tested in ChIP-seq, CUT&RUN, STORM super-resolution microscopy, immunoblots, and protein binding microarray (PBM) experiments. About 5% of the tested antibodies displayed high-confidence target (i.e., cognate antigen) enrichment across at least one assay and are strong candidates for additional validation. An additional 34% produced ChIP-exo data that were distinct from background and thus warrant further testing. The remaining 61% were not substantially different from background, and likely require consideration of a much broader survey of cell types and/or assay optimizations. We show and discuss the metrics and challenges to antibody validation in chromatin-based assays.

A novel strategy to map a locus associated with flowering time in canola (Brassica napus L.).

Flowering time is an important agronomic trait for canola breeders, as it provides growers with options for minimizing exposure to heat stress during flowering and to more effectively utilize soil moisture. Plants have evolved various systems to control seasonal rhythms in reproductive phenology including an internal circadian clock that responds to environmental signals. In this study, we used canola cultivar 'Westar' as a recurrent parent and canola cultivar 'Surpass 400' as the donor parent to generate a chromosome segment substitution line (CSSL) and to map a flowering time locus on chromosome A10 using molecular marker-assisted selection. This CSSL contains an introgressed 4.6 mega-bases (Mb) segment (between 13 and 17.6 Mb) of Surpass 400, which substantially delayed flowering compared with Westar. To map flowering time gene(s) within this locus, eight introgression lines (ILs) were developed carrying a series of different lengths of introgressed chromosome A10 segments using five co-dominant polymorphic markers located at 13.5, 14.0, 14.5, 15.0, 15.5, and 16.0 Mb. Eight ILs were crossed with Westar reciprocally and flowering time of resultant 16 F1 hybrids and parents were evaluated in a greenhouse (2021 and 2022). Four ILs (IL005, IL017, IL035, and IL013) showed delayed flowering compared to Westar (P < 0.0001), and their reciprocal crosses displayed a phenotype intermediate in flowering time of both homozygote parents. These results indicated that flowering time is partial or incomplete dominance, and the flowering time locus mapped within a 1 Mb region between two co-dominant polymorphic markers at 14.5-15.5 Mb on chromosome A10. The flowering time locus was delineated to be between 14.60 and 15.5 Mb based on genotypic data at the crossover site, and candidate genes within this region are associated with flowering time in canola and/or Arabidopsis. The co-dominant markers identified on chromosome A10 should be useful for marker assisted selection in breeding programs but will need to be validated to other breeding populations or germplasm accessions of canola.

Does the radical GPRI strongly depend on the population scheme? A comparative study to predict radical attack on unsaturated molecules with the radical general-purpose reactivity indicator.

The reactivity of 22 unsaturated molecules undergoing attack by a methyl radical (⋅CH3) have been elucidated using the condensed radical general-purpose reactivity indicator (condensed radical GPRI) appropriate for relatively nucleophilic or electrophilic molecules. Using the appropriate radical GPRI equation for electrophilic attack or nucleophilic radical attack, seven different population schemes were used to assign the most reactive atoms in each of the 22 molecules. The results show that the condensed radical GPRI is sensitive to the population scheme chosen, but less sensitive than the radical Fukui function. Therefore, the reliability of these methods depends on the population scheme. Our investigation indicates that the condensed radical GPRI is most accurate in predicting the dominant products of the methyl radical addition reactions on a variety of unsaturated molecules when the Hirshfeld, Merz-Singh-Kollman, or Voronoi deformation density population schemes are used. Furthermore, for all populations schemes in the majority of instances where the radical Fukui function failed the radical GPRI was able to identify the most reactive atom under certain reactivity conditions.

Mouse models of Slc35a2 brain mosaicism reveal mechanisms of mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy.

OBJECTIVE: Brain somatic variants in SLC35A2 were recently identified as a genetic marker for mild malformations of cortical development with oligodendroglial hyperplasia in epilepsy (MOGHE). The role of SLC35A2 in cortical development and the contributions of abnormal neurons and oligodendrocytes to seizure activity in MOGHE remain largely unexplored. METHODS: Here, we generated a novel Slc35a2 floxed allele, which we used to develop two Slc35a2 conditional knockout mouse lines targeting (1) the Emx1 dorsal telencephalic lineage (excitatory neurons and glia) and (2) the Olig2 lineage (oligodendrocytes). We examined brain structure, behavior, and seizure activity. RESULTS: Knockout of Slc35a2 from the Emx1 lineage, which targets both cortical neurons and oligodendrocytes, resulted in early lethality and caused abnormal cortical development, increased oligodendroglial cell density, early onset seizures, and developmental delays akin to what is observed in patients with MOGHE. By tracing neuronal development with 5-Ethynyl-2'-deoxyuridine (EdU) birthdating experiments, we found that Slc35a2 deficiency disrupts corticogenesis by delaying radial migration of neurons from the subventricular zone. To discern the contributions of oligodendrocytes to these phenotypes, we knocked out Slc35a2 from the Olig2 lineage. This recapitulated the increased oligodendroglial cell density and resulted in abnormal electroencephalographic activity, but without a clear seizure phenotype, suggesting Slc35a2 deficiency in neurons is required for epileptogenesis. SIGNIFICANCE: This study presents two novel Slc35a2 conditional knockout mouse models and characterizes the effects on brain development, behavior, and epileptogenesis. Together, these results demonstrate a direct causal role for SLC35A2 in MOGHE-like phenotypes, including a critical role in neuronal migration during brain development, and identify neurons as key contributors to SLC35A2-related epileptogenesis.

Large Decreases in Tailpipe Criteria Pollutant Emissions from the U.S. Light-Duty Vehicle Fleet Expected in 2020-2040.

The U.S. EPA MOVES3 model was used to assess the impact of the large-scale introduction of electric vehicles on emissions of criteria pollutants (CO, hydrocarbons [HC], NOx, and particulate matter [PM]) and CO2 from the U.S. light-duty vehicle fleet. Large reductions in emissions of these criteria pollutants occurred in 2000-2020. These trends are expected to continue through 2040 driven by turnover of the conventional fleet with old vehicles being replaced by battery electric vehicles (BEVs) and by new internal combustion engine vehicles (ICEVs) with modern emission control systems. Without the introduction of BEVs, the absolute emissions of CO, NOx, HC, and PM2.5 from the U.S. light-duty vehicle fleet are expected to decrease by approximately 61, 88, 55, and 20% from 2020 to 2040. Introduction of BEVs with market share increasing linearly to 100% in 2040 provides additional benefits, which, combined with ICEV fleet turnover, would lead to decreases of absolute emissions of CO, NOx, HC, and PM2.5 of approximately 77, 94, 71, and 37% from 2020 to 2040. Reductions in CO2 emissions follow a similar pattern. Large decreases in criteria pollutant and CO2 emissions from light duty vehicles lie ahead.

Materials Challenges in the Electric Vehicle Transition.

The ongoing transition toward electric vehicles (EVs) is changing materials used for vehicle production, of which the consequences for the environmental performance of EVs are not well understood and managed. We demonstrate that electrification coupled with lightweighting of automobiles will lead to significant changes in the industry's demand not only for battery materials but also for other materials used throughout the entire vehicle. Given the automotive industry's substantial consumption of raw materials, changes in its material demands are expected to trigger volatilities in material prices, consequently impacting the material composition and attractiveness of EVs. In addition, the materials recovered during end-of-life recycling of EVs as the vehicle fleet turns over will impact recycled material supplies both positively and negatively, impacting material availabilities and the economic incentive to engage in recycling. These supply chain impacts will influence material usage and the associated environmental performance of not only the automotive sector but also other metal-heavy industries such as construction. In light of these challenges, we propose the need for new research to understand the dynamic materials impacts of the EV transition that encompasses its implications on EV adoption and fleet life cycle environmental performance. Effectively coordinating the coevolution of material supply chains is crucial for making the sustainable transition to EVs a reality.

Computed Tomography-Guided Prostate Sampling and Fiducial Marker Insertion in Patients With Absent Rectums.

OBJECTIVES: We aimed to present our experience and the outcomes of a novel technique, computed tomography (CT)-guided prostate biopsy and fiducial marker insertion in patients with absent rectums. METHODS: Patients who underwent CT-guided prostate biopsy at a single institution from November 2010 to November 2022 were retrospectively reviewed. Patients were included if they had a clinical suspicion of prostate cancer and had absent rectums from previous surgical resection. Contrast-enhanced CT scan was used to perform transgluteal prostate biopsy. Patient demographics, multiparametric magnetic resonance imaging, and biopsy details were recorded. RESULTS: Thirteen biopsy procedures and 1 CT-guided fiducial marker insertion were performed on 12 unique patients. The reasons for the absence of rectums included surgical resection for rectal cancer (n = 10) and surgical resection for inflammatory bowel disease (n = 2). Clinically significant cancer was found in 7 of 13 biopsy results (52.8%), clinically insignificant cancer in 3 of 13 (23.1%), and benign cancer in 3 of 13 (23.1%). No complications were recorded. CONCLUSIONS: Our data support CT-guided prostate biopsy as an accurate and effective technique for investigating prostate cancer that requires tissue sampling in patients with absent rectums.

Method for the production of a compact source of atomic line spectra in the vacuum ultraviolet.

Atomic emission spectra provide a means to identify and to gain insight into the electronic structure of emitting or absorbing matter. Detailed procedures are provided for the construction of low-pressure electrodeless discharge lamps that yield targeted emission in the vacuum ultraviolet for the spectroscopic study of water vapor and halogen species aboard an array of airborne observation platforms in the upper atmosphere, as well as in laboratory environments. While specific to the production of Lyman-alpha, atomic chlorine, and atomic bromine emissions in this study, the configuration of the lamps and their interchangeability with respect to operation lend these procedures to constructing sources engaging a wide selection of atomic and molecular spectra with straightforward modifications. The features and limitations of each type of lamp are discussed, as well as methods to improve spectral purity and factors affecting operational lifetime.

Evaluation of a virtual ward model of care and readmission characteristics during the COVID-19 pandemic within an Australian tertiary hospital.

BACKGROUND: Virtual ward (VW) models of care established during the coronavirus disease 2019 (COVID-19) pandemic provided safe and equitable provision of ambulatory care for low-risk patients; however, little is known about patients who require escalation of care to hospitals from VWs. AIM: To assess our VW model of care and describe the characteristics of patients admitted to the hospital from the VW. METHODS: Observational study of all patients admitted to a tertiary hospital COVID-19 VW between 1 December 2021 and 30 June 2022. Utilisation and epidemiological characteristics were assessed for all patients while additional demographics, assessments, treatments and outcomes were assessed for patients admitted to the hospital from the VW. RESULTS: Of 9494 patient admissions, 269 (2.83%) patients identified as Aboriginal and Torres Strait Islander and 1774 (18.69%) were unvaccinated. The median length of stay was 5.10 days and the mean Index of Relative Socio-economic Advantage and Disadvantage decile was 5.73. One hundred sixty (1.69%) patients were admitted to the hospital from the VW, of which 25 were adults admitted to medical wards. Of this cohort, prominent comorbidities were obesity, hypertension, asthma and frailty, while the main symptoms on admission to the VW were cough, fatigue, nausea and sore throat. High Pandemic Respiratory Infection Emergency System Triage (PRIEST), Veterans Health Administration COVID-19 (VACO), COVID Home Safely Now (CHOSEN) and 4C mortality scores existed for those readmitted. CONCLUSIONS: This VW model of care was both safe and effective when applied to a broad socioeconomic population during the COVID-19 pandemic. While readmission to the hospital was low, this study identified key characteristics of such presentations, which may assist future triaging, escalation and resource allocation within VWs during the COVID-19 pandemic and beyond.

Promoting psychobiography: models and perspectives from multiple countries.

This article promotes and advocates for the integration of psychobiography into academic training in psychology. While psychobiography has been foundational to the discipline of psychology since Freud's study of Leonardo da Vinci, its procedures and methods have been sorely neglected in academic psychology. Following a brief introduction to psychobiography, the authors provide a historical review of the specialty area, review the current scope of psychobiographical training in psychology, and summarize the benefits of psychobiography to both the training of students and the broader psychology field. Next, models and examples of psychobiography integration across three continents and five countries are provided. The article concludes with specific recommendations for advancing psychobiography in academic psychology.

An information-theoretic approach to basis-set fitting of electron densities and other non-negative functions.

The numerical ill-conditioning associated with approximating an electron density with a convex sum of Gaussian or Slater-type functions is overcome by using the (extended) Kullback-Leibler divergence to measure the deviation between the target and approximate density. The optimized densities are non-negative and normalized, and they are accurate enough to be used in applications related to molecular similarity, the topology of the electron density, and numerical molecular integration. This robust, efficient, and general approach can be used to fit any non-negative normalized functions (e.g., the kinetic energy density and molecular electron density) to a convex sum of non-negative basis functions. We present a fixed-point iteration method for optimizing the Kullback-Leibler divergence and compare it to conventional gradient-based optimization methods. These algorithms are released through the free and open-source BFit package, which also includes a L2-norm squared optimization routine applicable to any square-integrable scalar function.

Sustaining productivity gains in the face of climate change: A research agenda for US wheat.

Wheat is a globally important crop and one of the "big three" US field crops. But unlike the other two (maize and soybean), in the United States its development is commercially unattractive, and so its breeding takes place primarily in public universities. Troublingly, the incentive structures within these universities may be hindering genetic improvement just as climate change is complicating breeding efforts. "Business as usual" in the US public wheat-breeding infrastructure may not sustain productivity increases. To address this concern, we held a multidisciplinary conference in which researchers from 12 US (public) universities and one European university shared the current state of knowledge in their disciplines, aired concerns, and proposed initiatives that could facilitate maintaining genetic improvement of wheat in the face of climate change. We discovered that climate-change-oriented breeding efforts are currently considered too risky and/or costly for most university wheat breeders to undertake, leading to a relative lack of breeding efforts that focus on abiotic stressors such as drought and heat. We hypothesize that this risk/cost burden can be reduced through the development of appropriate germplasm, relevant screening mechanisms, consistent germplasm characterization, and innovative models predicting the performance of germplasm under projected future climate conditions. However, doing so will require coordinated, longer-term, inter-regional efforts to generate phenotype data, and the modification of incentive structures to consistently reward such efforts.

Synthesis and Bioluminescence of 'V'-Shaped Firefly Luciferin Analogues Based on A Novel Benzobisthiazole Core.

The design of π-extended conjugation 'V'-shaped red shifted bioluminescent D-luciferin analogues based on a novel benzobisthiazole core is described. The divergent synthetic route allowed access to a range of amine donor substituents through an SN Ar reaction. In spectroscopic studies, the 'V'-shaped luciferins exhibited narrower optical band gaps, more red-shifted absorption and emission spectra than D-luciferin. Their bioluminescence characteristics were recorded against four different luciferases (PpyLuc, FlucRed, CBR2 and PLR3). With native luciferase PpyLuc, the 'V'-shaped luciferins demonstrated more red-shifted emissions than D-luciferin (λbl =561 nm) by 60 to 80 nm. In addition, the benzobisthiazole luciferins showed a wide range of bioluminescence spectra from the visible light region (λbl =500 nm) to the nIR window (>650 nm). The computational results validate the design concept which can be used as a guide for further novel D-luciferin analogues based upon other 'V'-shaped heterocyclic cores.

Bioluminescence, photophysical, computational and molecular docking studies of fully conformationally restricted enamine infraluciferin.

A new rationally designed fully rotationally restricted luciferin has been synthesised. This synthetic luciferin, based upon the structure of infraluciferin, has two intramolecular H-bonds to reduce degrees of freedom, an amine group to enhance ICT process, and an alkenyl group to increase π-conjugation. In the spectroscopic measurements and computational calculations, enamine luciferin showed more red-shifted absorption and fluorescence emission than LH2 and iLH2. With PpyWT luciferase enamine luciferin gave bioluminescence at 564 nm which is similar to LH2 at 561 nm. Further investigation by docking studies revealed that the emission wavelength of enamine luciferin might be attributed to the unwanted twisted structure caused by Asp531 within the enzyme. With mutant luciferase FlucRed, the major emission peak was shifted to 606 nm, a distinct shoulder above 700 nm, and 21% of its spectrum located in the nIR range.

High-Resolution Melting-Based Marker Development for Wheat Leaf Rust Resistance Gene Lr34.

Deploying adult plant resistance (APR) against rust diseases is an important breeding objective of most wheat-breeding programs. The gene Lr34 is an effective and widely deployed broad-spectrum APR gene in wheat against leaf rust fungus Puccinia triticina. Various molecular markers have been developed for Lr34, but they either require post-PCR handling processes or are not economical. Herein, we developed a high-resolution melting (HRM)-based diagnostic assay for Lr34 based on a 3-bp 'TTC' deletion in exon 11 of the resistant allele. The susceptible cultivar Thatcher (Tc) and the near-isogenic Thatcher line (RL6058) with Lr34 yielded distinct melting profiles and were differentiated with high reproducibility. For further validation, all three copies of Lr34 were cloned in plasmid vectors, and HRM analysis using individual and combination (equimolar mixture of three copies) homoeologs yielded distinct melting profiles. An additional layer of genotyping was provided by a LunaProbe assay. The allele-specific probes successfully distinguished the homoeologs but not Tc and RL6058. Furthermore, the practical deployment of the HRM assay was tested by running the marker on a set of breeding lines. When compared with a kompetitive allele-specific PCR (KASP) Lr34 assay, the HRM assay had similar genotyping results and was able to accurately differentiate the resistant and susceptible breeding lines. However, our HRM assay was unable to detect the heterozygote. To our knowledge, this is the first report of an HRM assay for genotyping a wheat rust resistance gene.