Browse Articles

A simple, statistically robust test of discrimination

In observational studies of discrimination, the most common statistical approaches consider either the rate at which decisions are made (benchmark tests) or the success rate of those decisions (outcome tests). Both tests, however, have well-known statistical limitations, sometimes suggesting discrimination even when there is none. Despite the fallibility of the benchmark and outcome tests individually, here we prove a surprisingly strong statistical guarantee: Under a common nonparametric assumption, at least one of the two tests must be correct; consequently, when both tests agree, they are guaranteed to yield correct conclusions. We present empirical evidence that the underlying assumption holds approximately in several important domains, including lending, education, and criminal justice—and that our hybrid test is robust to the moderate violations of the assumption that we observe in practice. Applying this approach to 2.8 million police stops across California, we find evidence of widespread racial discrimination.

Coronavirus endoribonuclease antagonizes ZBP1-mediated necroptosis and delays multiple cell death pathways

Identifying conserved mechanisms used by viruses to delay host innate responses can reveal potential targets for antiviral therapeutics. Here, we investigated coronavirus nonstructural protein 15 (nsp15), which encodes a highly conserved endoribonuclease (EndoU). EndoU functions as an immune antagonist by limiting the accumulation of viral replication intermediates that would otherwise be sensed by the host. Despite being a promising antiviral target, it has been difficult to develop small-molecule inhibitors that target the EndoU active site. We generated nsp15 mutants of the coronaviruses severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and mouse hepatitis virus (MHV)-A59 and identified conserved residues within the amino-terminal domain that are required for EndoU activity. Loss of EndoU activity caused the activation of host sensors, which limited viral replication in interferon-responsive cells and attenuated disease in MHV-infected mice. Using transcriptional profiling, we found that MHV EndoU mutant viruses upregulate multiple host sensors, including Z-form nucleic acid-binding protein 1 (ZBP1). We found that nsp15 mutants induced early, robust ZBP1-mediated necroptosis. EndoU mutant viruses also induced ZBP1-independent apoptosis and pyroptosis pathways, causing early, robust cell death that limits virus replication and pathogenesis. Overall, we document the importance of the amino-terminal domain for EndoU function. We also highlight the importance of nsp15/EndoU activity for evading host sensors, delaying cell death, and promoting pathogenesis.

RNA-targeted proteomics identifies YBX1 as critical for efficient HCMV mRNA translation

Viruses have evolved unique strategies to circumvent host control of protein synthesis and enable viral protein synthesis in the face of the host response. Defining the factors that regulate viral messenger RNA (mRNA) translation is thus critical to understand how viruses replicate and cause disease. To identify factors that might regulate viral mRNA translation, we developed a technique for identifying proteins associated with a native RNA expressed from its endogenous promoter and genomic locus. This approach uses a guide RNA to target dCas13b fused to a biotin ligase domain to a specific RNA, where it covalently labels proteins in close proximity. Using this approach, we identified multiple proteins associated with transcripts encoding the human cytomegalovirus (HCMV) IE1 and IE2 proteins and found that several associated proteins positively or negatively regulate HCMV replication. We confirmed that one such protein, the cellular Y-box binding protein 1 (YBX1), binds to HCMV immediate early mRNAs and is required for efficient viral protein expression and virus replication. Ablating YBX1 expression reduced the association of HCMV immediate early mRNAs with polysomes, demonstrating a role for YBX1 as a positive regulator of viral RNA translation. These results provide a powerful tool for unraveling RNA–protein interactions that can be used in a wide range of biological processes and reveal a role for YBX1 as a critical regulator of HCMV immediate early gene expression.

Significant amplification of electromagnetic waves in disordered dispersive temporal multilayered structures with randomness in plasma frequency or dielectric permittivity

Cas9-mediated gene-editing frequency in microalgae is doubled by harnessing the interaction between importin α and phytopathogenic NLSs

Pathogen-derived nuclear localization signals (NLSs) enable vigorous nuclear invasion in the host by the virulence proteins harboring them. Herein, inspired by the robust nuclear import mechanism, we show that NLSs originating from the plant infection–associated Agrobacterium proteins VirD2 and VirE2 can be incorporated into the Cas9 system as efficient nuclear delivery enhancers, thereby improving the low gene-editing frequency in a model microalga, Chlamydomonas reinhardtii , caused by poor nuclear localization of the bulky nuclease. Prior to evaluation of the NLSs, IPA1 (Cre04.g215850) was first defined in the alga as the nuclear import-related importin alpha (Impα) that serves as a counterpart adaptor protein of the NLSs, based on extensive in silico analyses considering the protein’s sequence, tertiary folding behavior, and structural basis when interacting with a well-studied SV40TAg NLS. Through precursive affinity explorations, we reproducibly found that the NLSs mediated the binding between the Cas9 and Impα with nM affinities and visually confirmed that the fusion of the NLSs strictly localized the peptide-bearing cargoes in the microalgal nucleus without compensating for their cleavage ability. When employed in a real-world application, the VirD2 NLS increases the mutation frequency (~1.12 × 10 −5 ) over 2.4-fold compared to an archetypal SV40TAg NLS (~0.46 × 10 −5 ) when fused with Cas9. We demonstrate the cross-species versatility of the Impα-dependent strategy by successfully applying it to an industrial alga, Chlorella Sp. HS2. This work, focused on affinity augmentation, provides insights into increasing the frequency of gene editing, which can be advantageously used in programmable mutagenesis with broad applicability.

Some new evidence using fractional integration about trends, breaks and persistence in polar amplification

Photoreduction of mercuric bromides in polar ice

In the polar regions, which are vulnerable receptors of mercury pollution, atmospheric mercury depletion events (AMDEs) efficiently convert elemental mercury (Hg(0)) into oxidized mercury (Hg(II)) via bromine oxidation. Hg(II) subsequently deposits onto snow and sea ice. While field observations have shown that a large percentage of deposited mercury is re-emitted from the ice to the atmosphere by a photoinduced process, the fundamental photochemistry that drives the re-emission process remains unknown. Here, using multiconfigurational quantum chemistry, we find that the photoreduction of HgBr 2 , HgBr 3 − , and HgBr 4 2− in ice is more efficient than in the gas phase. This results from the influence of water molecules on the molecular geometry and electronic structure of mercuric bromides in ice, which enhances the absorption intensities at wavelengths relevant in the troposphere (λ > 290 nm), as compared to gas phase. Kinetic modeling shows that ~30 to 60% of deposited mercury in AMDEs can be reemitted due to the photoreduction of mercuric bromides in ice, in agreement with field observations. Our results reveal a photoreduction mechanism of sunlight-induced excited state chemistry of mercuric bromides on ice. These findings strongly suggest that this chemistry should be incorporated into atmospheric models to account for ice-atmosphere mercury cycling in the polar environments, currently not considered.

Quantification of extrusion-induced excavation volume in shield tunnelling through squeezing cohesive-frictional ground

Abstract When tunnelling through weak and highly deformable ground, relevant deformations occur ahead of the tunnel face and result in face displacements that are opposite to the advance direction (“extrusion”). In mechanised tunnelling, the cutterhead continuously removes the ground extruding at the tunnel face during advance. Therefore, the total excavation volume is higher than the volume that corresponds to the tunnel cross-section area. Previous investigations by the authors showed that the additional, extrusion-induced excavation volume may be considerable in the case of purely cohesive ground. This paper extends this work for the case of cohesive-frictional ground. Firstly, we quantify the extrusion-induced excavation volume for a wide parameter range by means of a numerical model that uses re-meshing to consider the continuous re-profiling taking place at the tunnel face during advance. The results of the performed parametric study are summarised in a single dimensionless design chart. Secondly, we derive a simple closed-form expression, which, despite the underlying simplifications, allows for an accurate and rapid quantification of the extrusion-induced excavation volume. The results show that face extrusion has an effect on excavation volume in the cohesive-frictional case, although less pronounced than when tunnelling through low-permeability clays with purely cohesive short-term strength. The study suggests that if the additional excavation volume due to face extrusion is not taken into account in the design of the mechanised advance, it may (a) pose logistical and disposal challenges and (b) lead to erroneous conclusions about the stability of the tunnel face, both of which affect the rate of tunnel advance.

TEX38 localizes ZDHHC19 to the plasma membrane and regulates sperm head morphogenesis in mice

Sperm morphogenesis is a tightly regulated differentiation process, disruption of which leads to sperm malfunction and male infertility. Here, we show that Tex38 knockout (KO) male mice are infertile. Tex38 KO spermatids exhibit excess retention of residual cytoplasm around the head, resulting in abnormal sperm morphology with backward head bending. TEX38 interacts and colocalizes with ZDHHC19, a testis-enriched acyltransferase catalyzing protein S-palmitoylation, at the plasma membrane of spermatids. ZDHHC19 and TEX38 are each downregulated in mouse testes lacking the other protein. TEX38 stabilizes and localizes ZDHHC19 to the plasma membrane of cultured cells and vice versa, consolidating their interdependence. Mice deficient in ZDHHC19 or harboring a C142S mutation that disables the palmitoyltransferase activity of ZDHHC19 display phenotypes resembling those of Tex38 KO mice. Strikingly, ZDHHC19 palmitoylates ARRDC5, an arrestin family protein regulating sperm differentiation. Overall, our findings indicate that TEX38 forms a stable complex with ZDHHC19 at the plasma membrane of spermatids, which governs downstream S-palmitoylation of proteins essential for morphological transformation of spermatids.

Respiratory compliance related to prognostic of lung transplant patients with veno‑venous extracorporeal membrane oxygenation support

Archaeology and traversing America’s pre-Columbian fault line

TNMpBC-NeoBCSS model: a breast cancer specific survival prediction model for triple-negative metaplastic breast carcinoma patients with neoadjuvant therapy

Copy number variation contributes to parallel local adaptation in an invasive plant

Adaptation is a critical determinant of the diversification, persistence, and geographic range limits of species. Yet the genetic basis of adaptation is often unknown and potentially underpinned by a wide range of mutational types—from single nucleotide changes to large-scale alterations of chromosome structure. Copy number variation (CNV) is thought to be an important source of adaptive genetic variation, as indicated by decades of candidate gene studies that point to CNVs underlying rapid adaptation to strong selective pressures. Nevertheless, population-genomic studies of CNVs face unique logistical challenges not encountered by other forms of genetic variation. Consequently, few studies have systematically investigated the contributions of CNVs to adaptation at a genome-wide scale. We present a genome-wide analysis of CNV contributing to the adaptation of an invasive weed, Ambrosia artemisiifolia . CNVs show clear signatures of parallel local adaptation between North American (native) and European (invaded) ranges, implying widespread reuse of CNVs during adaptation to shared heterogeneous patterns of selection. We used a local principal component analysis (PCA) to genotype CNV regions in whole-genome sequences of samples collected over the last two centuries. We identified 16 large CNV regions of up to 11.85 megabases in length, eight of which show signals of rapid evolutionary change, with pronounced frequency shifts between historic and modern populations. Our results provide compelling genome-wide evidence that CNV underlies rapid adaptation over contemporary timescales of natural populations.

Deletion of pcnB affects antibiotic susceptibility in resistant Escherichia coli by reducing copy number of ColE1-family plasmids

Prediction of carbon nanostructure mechanical properties and the role of defects using machine learning

Graphene-based nanostructures hold immense potential as strong and lightweight materials, however, their mechanical properties such as modulus and strength are difficult to fully exploit due to challenges in atomic-scale engineering. This study presents a database of over 2,000 pristine and defective nanoscale CNT bundles and other graphitic assemblies, inspired by microscopy, with associated stress–strain curves from reactive molecular dynamics (MD) simulations using the reactive INTERFACE force field (IFF-R). These 3D structures, containing up to 80,000 atoms, enable detailed analyses of structure-stiffness-failure relationships. By leveraging the database and physics- and chemistry-informed machine learning (ML), accurate predictions of elastic moduli and tensile strength are demonstrated at speeds 1,000 to 10,000 times faster than efficient MD simulations. Hierarchical Graph Neural Networks with Spatial Information (HS-GNNs) are introduced, which integrate chemistry knowledge. HS-GNNs as well as extreme gradient boosted trees (XGBoost) achieve forecasts of mechanical properties of arbitrary carbon nanostructures with only 3 to 6% mean relative error. The reliability equals experimental accuracy and is up to 20 times higher than other ML methods. Predictions maintain 8 to 18% accuracy for large CNT bundles, CNT junctions, and carbon fiber cross-sections outside the training distribution. The physics- and chemistry-informed HS-GNN works remarkably well for data outside the training range while XGBoost works well with limited training data inside the training range. The carbon nanostructure database is designed for integration with multimodal experimental and simulation data, scalable beyond 100 nm size, and extendable to chemically similar compounds and broader property ranges. The ML approaches have potential for applications in structural materials, nanoelectronics, and carbon-based catalysts.

Multiple item representations in visual working memory simultaneously guide attention

Resilient tree-planting strategies for carbon dioxide removal under compounding climate and economic uncertainties

To meet decarbonization targets, nations around the globe have made ambitious commitments to expand forested land. Operationalizing these commitments requires choosing a planting strategy: How many trees should be planted, of which species, and where? Given those choices must be made now but have long-term consequences, such decisions are plagued by uncertainty. For example, species that are well suited to present conditions may perform poorly under future climates, yet those future climates are themselves highly uncertain. Using the exemplar of the United Kingdom, a nation committed to achieving net zero emissions by midcentury, we quantify key uncertainties pertaining to coevolving climate and economic conditions and examine how modern methods of decision-making under uncertainty can advise on planting choices. Our analysis reveals that the best planting strategy assuming a “high-emissions” future is radically different to that for a future that remains on a “near-historic” path. Planting for the former while experiencing the latter results in substantial net costs to UK society. Assimilating uncertainty into decision-making identifies planting strategies that diversify risk and significantly reduce the probability of high-cost outcomes. Importantly, our research reveals that the scope for mitigating risk through choice of planting strategy is relatively limited. Despite this persistent risk, we find that tree planting remains a highly cost-effective carbon removal solution when compared to alternative technologies, even when those alternatives are assumed to be riskless.

On the effectiveness of electrical characterization of mature Staphylococcal Biofilm

In the activation of HPV-specific human B cells HPV-VLP vaccines mimic membrane-associated antigens

B cell responses to membrane-presented antigens appear to be strongly favored over soluble antigens in vivo suggesting that vaccines that mimic membrane-presented antigens may be highly efficacious. We recently demonstrated that human B cell responses to membrane-associated but not to soluble antigens in vitro depended on the expression and activity of the plasma membrane mechanosensitive ion channel, Piezo1. Here, we provide evidence that the efficacy of the current human papillomavirus virus-like particle (HPV VLP) vaccines may be due in part to their inherent ability to mimic Piezo1-dependent membrane presentation of antigens to B cells. We compared HPV-specific human B cell responses to HPV VLPs versus soluble HPV pentameric capsomeres and showed that although both induced calcium responses, only HPV VLP-induced responses were blocked by Piezo1 inhibitors. The kinetics of internalization of HPV-VLP and capsomeres into HPV-specific B cells were similar and neither required Piezo1 function as shown by small interfering RNA (siRNA)-mediated knockdown of Piezo. However, trafficking of HPV-VLPs into intracellular major histocompatibility complex (MHC) class II, lysosomal associated membrane protein 1 (LAMP1) + antigen-processing compartments was Piezo1-dependent, whereas trafficking of capsomeres was not. In addition, a time course of intracellular trafficking suggested that colocalization of HPV-VLP with MHC classII was more stable over time as compared to capsomeres. Taken together these findings suggest that the ability of HPV-VLP vaccines to mimic Piezo1-dependent membrane antigen presentation may be exploited in the design of highly effective human vaccines.

Production, isolation, optimization, and characterization of microbial PHA from Bacillus australimaris

Abstract Population explosion in recent years has driven the environment to overuse nondegradable substances. Microbial polyesters known as polyhydroxyalkanoates (PHAs) are generated and retained as cytoplasmic granules in microorganisms with restricted nutritional availability and can be used to manufacture bioplastics. The current study attempts to screen soil isolates for PHA production and optimize their media parameters. Among all the isolates, 17 were identified and confirmed by Sudan black staining, as they are screening for PHA production and are identified by their colony characteristics. The isolation of the most promising strain, GS-14, was achieved through the sodium hypochlorite method, and subsequent quantification involved establishing a standard curve of crotonic acid. Notably, isolate GS-14 presented the highest yield, which was determined by extrapolating its data onto the standard curve. Characterization of the PHA polymer was subsequently performed, and the results were used to discern its properties. FTIR confirmed characteristic PHA absorption bands, with a prominent C = O stretching peak at 1732 cm⁻¹. LC-MS detected a molecular mass of 641.6 g/mol, indicative of an oligomeric species, while the actual polymer molecular weight is estimated between 5,000 and 20,000 Da. DSC revealed an exothermic peak at 174 °C, allowing the calculation of crystallinity, a key determinant of mechanical properties. Furthermore, the PHA-producing organism was identified as Bacillus australimaris through the sequencing of 16 S ribosomal RNA. The media optimization was performed via Minitab software, with statistical analyses employed to interpret the resulting data comprehensively.