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While high circulating tumor DNA (ctDNA) levels are associated with poor survival for multiple cancers, variant-specific differences in the association of ctDNA levels and survival have not been examined. Here we investigate KRAS ctDNA (ctKRAS) variant-specific associations with overall and progression-free survival (OS/PFS) in first-line metastatic pancreatic ductal adenocarcinoma (mPDAC) for patients receiving chemoimmunotherapy (PRINCE, NCT03214250), and an independent cohort receiving standard of care (SOC) chemotherapy. For PRINCE, higher baseline plasma levels are associated with worse OS for ctKRAS G12D (log-rank p = 0.0010) but not G12V (p = 0.7101), even with adjustment for clinical covariates. Early, on-therapy clearance of G12D (p = 0.0002), but not G12V (p = 0.4058), strongly associates with OS for PRINCE. Similar results are obtained for the SOC cohort, and for PFS in both cohorts. These results suggest ctKRAS G12D but not G12V as a promising prognostic biomarker for mPDAC and that G12D clearance could also serve as an early biomarker of response.

Coccidioidomycosis, listed as a priority mycosis by the WHO, is endemic in the United States but often overlooked in Central and South America. Employing a multi-institutional approach, we investigate how disease characteristics, pathogen genetic variation, and environmental factors impact coccidioidomycosis epidemiology and outcomes in South America. We identified 292 cases (1978-2021) and 42 outbreaks in Piauí and Maranhão states, Brazil, the largest series outside the US/Mexico epidemic zone. The male-to-female ratio was 57.4:1 and the most common activity was armadillo hunting (91.1%) 4 to 30 days before symptom onset. Most patients (92.8%) exhibited typical acute pulmonary disease, with cough (93%), fever (90%), and chest pain (77%) as predominant symptoms. The case fatality rate was 8%. Our negative binomial regression model indicates that reduced precipitation levels in the current (p = 0.015) and preceding year (p = 0.001) predict heightened incidence. Unlike other hotspots, acidic soil characterizes this region. Brazilian strains differ genomically from other C. posadasii lineages. Northeastern Brazil presents a distinctive coccidioidomycosis profile, with armadillo hunters facing elevated risks. Low annual rainfall emerges as a key factor in increasing cases. A unique C. posadasii lineage in Brazil suggests potential differences in environmental, virulence, and/or pathogenesis traits compared to other Coccidioides genotypes.

Single-atom catalysts (SACs) offer efficient metal utilization and distinct reactivity compared to supported metal nanoparticles. Structure-function relationships for SACs often assume that active sites have uniform coordination environments at particular binding sites on support surfaces. Here, we investigate the distribution of coordination environments of Pt SAs dispersed on shape-controlled anatase TiO2 supports specifically exposing (001) and (101) surfaces. Pt SAs on (101) are found on the surface, consistent with existing structural models, whereas those on (001) are beneath the surface after calcination. Pt SAs under (001) surfaces exhibit lower reactivity for CO oxidation than those on (101) surfaces due to their limited accessibility to gas phase species. Pt SAs deposited on commercial-TiO2 are found both at the surface and in the bulk, posing challenges to structure-function relationship development. This study highlights heterogeneity in SA coordination environments on oxide supports, emphasizing a previously overlooked consideration in the design of SACs.

Abstract Wastewater is a geospatially- and temporally-linked microbial fingerprint of a given population, making it a potentially valuable tool for tracking public health across locales and time. Here, we integrate targeted and bulk RNA sequencing (N = 2238 samples) to track the viral, bacterial, and functional content over geospatially distinct areas within Miami Dade County, USA, from 2020-2022. We used targeted amplicon sequencing to track diverse SARS-CoV-2 variants across space and time, and we found a tight correspondence with positive PCR tests from University students and Miami-Dade hospital patients. Additionally, in bulk metatranscriptomic data, we demonstrate that the bacterial content of different wastewater sampling locations serving small population sizes can be used to detect putative, host-derived microorganisms that themselves have known associations with human health and diet. We also detect multiple enteric pathogens (e.g., Norovirus) and characterize viral diversity across sites. Moreover, we observed an enrichment of antimicrobial resistance genes (ARGs) in hospital wastewater; antibiotic-specific ARGs correlated to total prescriptions of those same antibiotics (e.g Ampicillin, Gentamicin). Overall, this effort lays the groundwork for systematic characterization of wastewater that can potentially influence public health decision-making.

The glycosylation of IgG plays a critical role during human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, activating immune cells and inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during human acute viral infection. The analysis of IgM N-glycosylation from healthy controls and hospitalized coronavirus disease 2019 (COVID-19) patients reveals increased high-mannose and sialylation that correlates with COVID-19 severity. These trends are confirmed within SARS-CoV-2-specific immunoglobulin N-glycan profiles. Moreover, the degree of total IgM mannosylation and sialylation correlate significantly with markers of disease severity. We link the changes of IgM N-glycosylation with the expression of Golgi glycosyltransferases. Lastly, we observe antigen-specific IgM antibody-dependent complement deposition is elevated in severe COVID-19 patients and modulated by exoglycosidase digestion. Taken together, this work links the IgM N-glycosylation with COVID-19 severity and highlights the need to understand IgM glycosylation and downstream immune function during human disease.

Post-acute sequelae of SARS-CoV-2 (PASC) is a significant public health concern. We describe Patient Reported Outcomes (PROs) on 590 participants prospectively assessed from hospital admission for COVID-19 through one year after discharge. Modeling identified 4 PRO clusters based on reported deficits (minimal, physical, mental/cognitive, and multidomain), supporting heterogenous clinical presentations in PASC, with sub-phenotypes associated with female sex and distinctive comorbidities. During the acute phase of disease, a higher respiratory SARS-CoV-2 viral burden and lower Receptor Binding Domain and Spike antibody titers were associated with both the physical predominant and the multidomain deficit clusters. A lower frequency of circulating B lymphocytes by mass cytometry (CyTOF) was observed in the multidomain deficit cluster. Circulating fibroblast growth factor 21 (FGF21) was significantly elevated in the mental/cognitive predominant and the multidomain clusters. Future efforts to link PASC to acute anti-viral host responses may help to better target treatment and prevention of PASC.

Acne is a dermatologic disease with a strong pathologic association with human commensal Cutibacterium acnes. Conspicuously, certain C. acnes phylotypes are associated with acne, whereas others are associated with healthy skin. Here we investigate if the evolution of a C. acnes enzyme contributes to health or acne. Two hyaluronidase variants exclusively expressed by C. acnes strains, HylA and HylB, demonstrate remarkable clinical correlation with acne or health. We show that HylA is strongly pro-inflammatory, and HylB is modestly anti-inflammatory in a murine (female) acne model. Structural and phylogenic studies suggest that the enzymes evolved from a common hyaluronidase that acquired distinct enzymatic activity. Health-associated HylB degrades hyaluronic acid (HA) exclusively to HA disaccharides leading to reduced inflammation, whereas HylA generates large-sized HA fragments that drive robust TLR2-dependent pathology. Replacing an amino acid, Serine to Glycine near the HylA catalytic site enhances the enzymatic activity of HylA and produces an HA degradation pattern intermediate to HylA and HylB. Selective targeting of HylA using peptide vaccine or inhibitors alleviates acne pathology. We suggest that the functional divergence of HylA and HylB is a major driving force behind C. acnes health- and acne- phenotype and propose targeting of HylA as an approach for acne therapy.

Abstract Safe storage and utilisation of hydrogen is an ongoing area of research, showing potential to enable hydrogen becoming an effective fuel, substituting current carbon-based sources. Hydrogen storage is associated with a high energy cost due to its low density and boiling point, which drives a high price. Clathrates (gas hydrates) are water-based (ice-like) structures incorporating small non-polar compounds such as H2 in cages formed by hydrogen bonded water molecules. Since only water is required to construct the cages, clathrates have been identified as a potential solution for safe storage of hydrogen. In bulk, pure hydrogen clathrate (H2O-H2) only forms in harsh conditions, but confined in nanospaces the properties of water are altered and hydrogen storage at mild pressure and temperature could become possible. Here, specifically a hydrophobic mesoporous silica is proposed as a host material, providing a suitable nano-confinement for ice-like clathrate hydrate. The hybrid silica material shows an important decrease of the pressure required for clathrate formation (approx. 20%) compared to the pure H2O-H2 system. In-situ inelastic neutron scattering (INS) and neutron diffraction (ND) provided unique insights into the interaction of hydrogen with the complex surface of the hybrid material and demonstrated the stability of nano-confined hydrogen clathrate hydrate.

Abstract Zika virus (ZIKV), an emerging mosquito-borne flavivirus, is associated with congenital neurological complications. Here, we investigate potential pathological correlates of virus gene expression in representative ZIKV strains through RNA sequencing and ribosome profiling. In addition to the single long polyprotein found in all flaviviruses, we identify the translation of unrecognised upstream open reading frames (uORFs) in the genomic 5′ region. In Asian/American strains, ribosomes translate uORF1 and uORF2, whereas in African strains, the two uORFs are fused into one (African uORF). We use reverse genetics to examine the impact on ZIKV fitness of different uORFs mutant viruses. We find that expression of the African uORF and the Asian/American uORF1 modulates virus growth and tropism in human cortical neurons and cerebral organoids, suggesting a potential role in neurotropism. Although the uORFs are expressed in mosquito cells, we do not see a measurable effect on transmission by the mosquito vector in vivo. The discovery of ZIKV uORFs sheds new light on the infection of the human brain cells by this virus and raises the question of their existence in other neurotropic flaviviruses.

Abstract In lung disease, persistence of KRT8-expressing aberrant basaloid cells in the alveolar epithelium is associated with impaired tissue regeneration and pathological tissue remodeling. We analyzed single cell RNA sequencing datasets of human interstitial lung disease and found the profibrotic Interleukin-11 (IL11) cytokine to be highly and specifically expressed in aberrant KRT8+ basaloid cells. IL11 is similarly expressed by KRT8+ alveolar epithelial cells lining fibrotic lesions in a mouse model of interstitial lung disease. Stimulation of alveolar epithelial cells with IL11 causes epithelial-to-mesenchymal transition and promotes a KRT8-high state, which stalls the beneficial differentiation of alveolar type 2 (AT2)-to-AT1 cells. Inhibition of IL11-signaling in AT2 cells in vivo prevents the accumulation of KRT8+ cells, enhances AT1 cell differentiation and blocks fibrogenesis, which is replicated by anti-IL11 therapy. These data show that IL11 inhibits reparative AT2-to-AT1 differentiation in the damaged lung to limit endogenous alveolar regeneration, resulting in fibrotic lung disease.

Abstract Specialized function gradient computing hardware could greatly improve the performance of state-of-the-art optimization algorithms. Prior work on such hardware, performed in the context of Ising Machines and related concepts, is limited to quadratic polynomials and not scalable to commonly used higher-order functions. Here, we propose an approach for massively parallel gradient calculations of high-degree polynomials, which is conducive to efficient mixed-signal in-memory computing circuit implementations and whose area scales proportionally with the product of the number of variables and terms in the function and, most importantly, independent of its degree. Two flavors of such an approach are proposed. The first is limited to binary-variable polynomials typical in combinatorial optimization problems, while the second type is broader at the cost of a more complex periphery. To validate the former approach, we experimentally demonstrated solving a small-scale third-order Boolean satisfiability problem based on integrated metal-oxide memristor crossbar circuits, with competitive heuristics algorithm. Simulation results for larger-scale, more practical problems show orders of magnitude improvements in area, speed and energy efficiency compared to the state-of-the-art. We discuss how our work could enable even higher-performance systems after co-designing algorithms to exploit massively parallel gradient computation.

Abstract Mammalian DNA replication relies on various DNA helicase and nuclease activities to ensure accurate genetic duplication, but how different helicase and nuclease activities are properly directed remains unclear. Here, we identify the ubiquitin-specific protease, USP50, as a chromatin-associated protein required to promote ongoing replication, fork restart, telomere maintenance, cellular survival following hydroxyurea or pyridostatin treatment, and suppression of DNA breaks near GC-rich sequences. We find that USP50 supports proper WRN-FEN1 localisation at or near stalled replication forks. Nascent DNA in cells lacking USP50 shows increased association of the DNA2 nuclease and RECQL4 and RECQL5 helicases and replication defects in cells lacking USP50, or FEN1 are driven by these proteins. Consequently, suppression of DNA2 or RECQL4/5 improves USP50-depleted cell resistance to agents inducing replicative stress and restores telomere stability. These data define an unexpected regulatory protein that promotes the balance of helicase and nuclease use at ongoing and stalled replication forks.

Abstract Euclidean space is the fabric of the world we live in. Whether and how geometric experience shapes our spatial-temporal representations of the world remained unknown. We deprived male rats of experience with crucial features of Euclidean geometry by rearing them inside spheres, and compared activity of large hippocampal neuronal ensembles during navigation and sleep with that of cuboid cage-reared controls. Sphere-rearing from birth permitted emergence of accurate neuronal ensemble spatial codes and preconfigured and plastic time-compressed neuronal sequences. However, sphere-rearing led to diminished individual place cell tuning, more similar neuronal mapping of different track ends/corners, and impaired pattern separation and plasticity of multiple linear tracks, coupled with reduced preconfigured sleep network repertoires. Subsequent experience with multiple linear environments over four days largely reversed these effects. Thus, early-life experience with Euclidean geometry enriches the hippocampal repertoire of preconfigured neuronal patterns selected toward unique representation and discrimination of multiple linear environments.

Abstract CD38 has emerged as a potential therapeutic target for patients with systemic lupus erythematosus (SLE) but it is not known whether CD38 alters CD4+ T cell function. Using primary human T cells and CD38-sufficient and CD38-deficient Jurkat T cells, we demonstrate that CD38 shifts the T cell lipid profile of gangliosides from GM3 to GM2 by upregulating B4GALNT1 in a Sirtuin 1-dependent manner. Enhanced expression of GM2 causes ER stress by enhancing Ca2+ flux through the PLCγ1-IP3 pathway. Interestingly, correction of the calcium overload by an IP3 receptor inhibitor, but not by a store-operated calcium entry (SOCE) inhibitor, improves IL-2 production by CD4+ T cells in SLE. This study demonstrates that CD38 affects calcium homeostasis in CD4+ T cells by controlling cell membrane lipid composition that results in suppressed IL-2 production. CD38 inhibition with biologics or small drugs should be expected to benefit patients with SLE.

Abstract Lignin, a major plant cell wall component, has an important role in plant-defense mechanisms against pathogens and is a promising renewable carbon source to produce bio-based chemicals. However, our understanding of microbial metabolism is incomplete regarding certain lignin-related compounds like p-coumaryl and sinapyl alcohols. Here, we reveal peripheral pathways for the catabolism of the three main lignin precursors (p-coumaryl, coniferyl, and sinapyl alcohols) in the plant pathogen Xanthomonas citri. Our study demonstrates all the necessary enzymatic steps for funneling these monolignols into the tricarboxylic acid cycle, concurrently uncovering aryl aldehyde reductases that likely protect the pathogen from aldehydes toxicity. It also shows that lignin-related aromatic compounds activate transcriptional responses related to chemotaxis and flagellar-dependent motility, which might play an important role during plant infection. Together our findings provide foundational knowledge to support biotechnological advances for both plant diseases treatments and conversion of lignin-derived compounds into bio-based chemicals.

Abstract N. gonorrhoeae, which causes the sexually transmissible infection gonorrhoea, remains a significant public health threat globally, with challenges posed by increasing transmission and antimicrobial resistance (AMR). The COVID-19 pandemic introduced exceptional circumstances into communicable disease control, impacting the transmission of gonorrhoea and other infectious diseases. Through phylogenomic and phylodynamic analysis of 5881 N. gonorrhoeae genomes from Australia, we investigated N. gonorrhoeae transmission over five years, including a time period during the COVID-19 pandemic. Using a novel cgMLST-based genetic threshold, we demonstrate persistence of large N. gonorrhoeae genomic clusters over several years, with some persistent clusters associated with heterosexual transmission. We observed a decline in both N. gonorrhoeae transmission and genomic diversity during the COVID-19 pandemic, suggestive of an evolutionary bottleneck. The longitudinal, occult transmission of N. gonorrhoeae over many years further highlights the urgent need for improved diagnostic, treatment, and prevention strategies for gonorrhoea.

Abstract Research into the role of thalamocortical circuits in anesthesia-induced unconsciousness is difficult due to anatomical and functional complexity. Prior neuroimaging studies have examined either the thalamus as a whole or focused on specific subregions, overlooking the distinct neuronal subtypes like core and matrix cells. We conducted a study of heathy volunteers and functional magnetic resonance imaging during conscious baseline, deep sedation, and recovery. We advanced the functional gradient mapping technique to delineate the functional geometry of thalamocortical circuits, within a framework of the unimodal-transmodal functional axis of the cortex. Here we show a significant shift in this geometry during deep sedation, marked by a transmodal-deficient geometry. This alteration is closely linked to the spatial variations in the matrix cell composition within the thalamus. This research bridges cellular and systems-level understanding, highlighting the crucial role of thalamic core–matrix functional architecture in understanding the neural mechanisms of states of consciousness.

Abstract Autoimmune diseases such as systemic lupus erythematosus (SLE) display a strong female bias. Although sex hormones have been associated with protecting males from autoimmunity, the molecular mechanisms are incompletely understood. Here we report that androgen receptor (AR) expressed in T cells regulates genes involved in T cell activation directly, or indirectly via controlling other transcription factors. T cell-specific deletion of AR in mice leads to T cell activation and enhanced autoimmunity in male mice. Mechanistically, Ptpn22, a phosphatase and negative regulator of T cell receptor signaling, is downregulated in AR-deficient T cells. Moreover, a conserved androgen-response element is found in the regulatory region of Ptpn22 gene, and the mutation of this transcription element in non-obese diabetic mice increases the incidence of spontaneous and inducible diabetes in male mice. Lastly, Ptpn22 deficiency increases the disease severity of male mice in a mouse model of SLE. Our results thus implicate AR-regulated genes such as PTPN22 as potential therapeutic targets for autoimmune diseases.

Abstract Binding-activated optical sensors are powerful tools for imaging, diagnostics, and biomolecular sensing. However, biosensor discovery is slow and requires tedious steps in rational design, screening, and characterization. Here we report on a platform that streamlines biosensor discovery and unlocks directed nanosensor evolution through genetically encodable fluorogenic amino acids (FgAAs). Building on the classical knowledge-based semisynthetic approach, we engineer ~15 kDa nanosensors that recognize specific proteins, peptides, and small molecules with up to 100-fold fluorescence increases and subsecond kinetics, allowing real-time and wash-free target sensing and live-cell bioimaging. An optimized genetic code expansion chemistry with FgAAs further enables rapid (~3 h) ribosomal nanosensor discovery via the cell-free translation of hundreds of candidates in parallel and directed nanosensor evolution with improved variant-specific sensitivities (up to ~250-fold) for SARS-CoV-2 antigens. Altogether, this platform could accelerate the discovery of fluorogenic nanosensors and pave the way to modify proteins with other non-standard functionalities for diverse applications.

Abstract Primordial carbon delivered to the early earth by asteroids and meteorites provided a diverse source of extraterrestrial organics from pre-existing simple organic compounds, complex solar-irradiated macromolecules, and macromolecules from extended hydrothermal processing. Surface regolith collected by the Hayabusa2 spacecraft from the carbon-rich asteroid 162173 Ryugu present a unique opportunity to untangle the sources and processing history of carbonaceous matter. Here we show carbonaceous grains in Ryugu can be classified into three main populations defined by spectral shape: Highly aromatic (HA), Alkyl-Aromatic (AA), and IOM-like (IL). These carbon populations may be related to primordial chemistry, since C and N isotopic compositions vary between the three groups. Diffuse carbon is occasionally dominated by molecular carbonate preferentially associated with coarse-grained phyllosilicate minerals. Compared to related carbonaceous meteorites, the greater diversity of organic functional chemistry in Ryugu indicate the pristine condition of these asteroid samples.

Abstract Implantable devices interfacing with peripheral nerves exhibit limited longevity and resolution. Poor nerve-electrode interface quality, invasive surgical placement and development of foreign body reaction combine to limit research and clinical application of these devices. Here, we develop cuff implants with a conformable design that achieve high-quality and stable interfacing with nerves in chronic implantation scenarios. When implanted in sensorimotor nerves of the arm in awake rats for 21 days, the devices record nerve action potentials with fascicle-specific resolution and extract from these the conduction velocity and direction of propagation. The cuffs exhibit high biocompatibility, producing lower levels of fibrotic scarring than clinically equivalent PDMS silicone cuffs. In addition to recording nerve activity, the devices are able to modulate nerve activity at sub-nerve resolution to produce a wide range of paw movements. When used in a partial nerve ligation rodent model, the cuffs identify and characterise changes in nerve C fibre activity associated with the development of neuropathic pain in freely-moving animals. The developed implantable devices represent a platform enabling new forms of fine nerve signal sensing and modulation, with applications in physiology research and closed-loop therapeutics.

Abstract Sub-equatorial Africa is today inhabited predominantly by Bantu-speaking groups of Western African descent who brought agriculture to the Luangwa valley in eastern Zambia ~2000 years ago. Before their arrival the area was inhabited by hunter-gatherers, who in many cases were subsequently replaced, displaced or assimilated. In Zambia, we know little about the genetic affinities of these hunter-gatherers. We examine ancestry of two isolated communities in Zambia, known as BaTwa and possible descendants of recent hunter-gatherers. We genotype over two million genome-wide SNPs from two BaTwa populations (total of 80 individuals) and from three comparative farming populations to: (i) determine if the BaTwa carry genetic links to past hunter-gatherer-groups, and (ii) characterise the genetic affinities of past Zambian hunter-gatherer-groups. The BaTwa populations do harbour a hunter-gatherer-like genetic ancestry and Western African ancestry. The hunter-gatherer component is a unique local signature, intermediate between current-day Khoe-San ancestry from southern Africa and central African rainforest hunter-gatherer ancestry.

Abstract Durable factor VIII expression that normalizes hemostasis is an unrealized goal of hemophilia A adeno-associated virus-mediated gene therapy. Trials with initially normal factor VIII activity observed unexplained year-over-year declines in expression while others reported low-level, stable expression inadequate to restore normal hemostasis. Here we demonstrate that male mice recapitulate expression-level-dependent loss of factor VIII levels due to declines in vector copy number. We show that an enhanced function factor VIII variant (factor VIII-R336Q/R562Q), resistant to activated protein C-mediated inactivation, normalizes hemostasis at below-normal expression without evidence of prothrombotic risk in male hemophilia A mice. These data support that factor VIII-R336Q/R562Q may restore normal factor VIII function at low levels of expression to permit durability using low vector doses to minimize dose-dependent adeno-associated virus toxicities. This work informs the mechanism of factor VIII durability after gene transfer and supports that factor VIII-R336Q/R562Q may safely overcome current hemophilia A gene therapy limitations.

Abstract Plants flower in response to environmental signals. These signals change the shape and developmental identity of the shoot apical meristem (SAM), causing it to form flowers and inflorescences. We show that the increases in SAM width and height during floral transition correlate with changes in size of the central zone (CZ), defined by CLAVATA3 expression, and involve a transient increase in the height of the organizing center (OC), defined by WUSCHEL expression. The APETALA2 (AP2) transcription factor is required for the rapid increases in SAM height and width, by maintaining the width of the OC and increasing the height and width of the CZ. AP2 expression is repressed in the SAM at the end of floral transition, and extending the duration of its expression increases SAM width. Transcriptional repression by SUPPRESSOR OF OVEREXPRESSION OF CONSTANS1 (SOC1) represents one of the mechanisms reducing AP2 expression during floral transition. Moreover, AP2 represses SOC1 transcription, and we find that reciprocal repression of SOC1 and AP2 contributes to synchronizing precise changes in meristem shape with floral transition.

Abstract Laboratory evolution studies have demonstrated that parallel evolutionary trajectories can lead to genetically distinct enzymes with high activity towards a non-preferred substrate. However, it is unknown whether such enzymes have convergent conformational dynamics and mechanistic features. To address this question, we use as a model the wild-type Homo sapiens kynureninase (HsKYNase), which is of great interest for cancer immunotherapy. Earlier, we isolated HsKYNase_66 through an unusual evolutionary trajectory, having a 410-fold increase in the k cat/KM for kynurenine (KYN) and reverse substrate selectivity relative to HsKYNase. Here, by following a different evolutionary trajectory we generate a genetically distinct variant, HsKYNase_93D9, that exhibits KYN catalytic activity comparable to that of HsKYNase_66, but instead it is a “generalist” that accepts 3’-hydroxykynurenine (OH-KYN) with the same proficiency. Pre-steady-state kinetic analysis reveals that while the evolution of HsKYNase_66 is accompanied by a change in the rate-determining step of the reactions, HsKYNase_93D9 retains the same catalytic mechanism as HsKYNase. HDX-MS shows that the conformational dynamics of the two enzymes are markedly different and distinct from ortholog prokaryotic enzymes with high KYN activity. Our work provides a mechanistic framework for understanding the relationship between evolutionary mechanisms and phenotypic traits of evolved generalist and specialist enzyme species.

Abstract The role of developmental cell death in the formation of brain circuits is not well understood. Cajal-Retzius cells constitute a major transient neuronal population in the mammalian neocortex, which largely disappears at the time of postnatal somatosensory maturation. In this study, we used mouse genetics, anatomical, functional, and behavioral approaches to explore the impact of the early postnatal death of Cajal-Retzius cells in the maturation of the cortical circuit. We find that before their death, Cajal-Retzius cells mainly receive inputs from layer 1 neurons, which can only develop their mature connectivity onto layer 2/3 pyramidal cells after Cajal-Retzius cells disappear. This developmental connectivity progression from layer 1 GABAergic to layer 2/3 pyramidal cells regulates sensory-driven inhibition within, and more so, across cortical columns. Here we show that Cajal-Retzius cell death prevention leads to layer 2/3 hyper-excitability, delayed learning and reduced performance in a multi-whisker-dependent texture discrimination task.

Noble metals supported on reducible oxides, like CoOx and TiOx, exhibit superior activity in many chemical reactions, but the origin of the increased activity is not well understood. To answer this question we studied thin films of CoOx supported on an Au(111) single crystal surface as a model for the CO oxidation reaction. We show that three reaction regimes exist in response to chemical and topographic restructuring of the CoOx catalyst as a function of reactant gas phase CO/O2 stoichiometry and temperature. Under oxygen-lean conditions and moderate temperatures (≤150 °C), partially oxidized films (CoOx1) forms containing Co3+ species that are effective in a wide temperature range. Resonant photoemission spectroscopy (ResPES) revealed the unique role of Co3+ sites in catalyzing the CO oxidation. Density function theory (DFT) calculations provided deeper insights into the pathway and free energy barriers for the reactions on these oxide phases. These findings in this work highlight the versatility of catalysts and their evolution to form different active phases, both topological and chemically, in response to reaction conditions exposing a new paradigm in the catalyst structure during operation.