Two-dimensional heavy fermions in the van der Waals metal CeSiI.

Heavy-fermion metals are prototype systems for observing emergent quantum phases driven by electronic interactions1-6. A long-standing aspiration is the dimensional reduction of these materials to exert control over their quantum phases7-11, which remains a significant challenge because traditional intermetallic heavy-fermion compounds have three-dimensional atomic and electronic structures. Here we report comprehensive thermodynamic and spectroscopic evidence of an antiferromagnetically ordered heavy-fermion ground state in CeSiI, an intermetallic comprising two-dimensional (2D) metallic sheets held together by weak interlayer van der Waals (vdW) interactions. Owing to its vdW nature, CeSiI has a quasi-2D electronic structure, and we can control its physical dimension through exfoliation. The emergence of coherent hybridization of f and conduction electrons at low temperature is supported by the temperature evolution of angle-resolved photoemission and scanning tunnelling spectra near the Fermi level and by heat capacity measurements. Electrical transport measurements on few-layer flakes reveal heavy-fermion behaviour and magnetic order down to the ultra-thin regime. Our work establishes CeSiI and related materials as a unique platform for studying dimensionally confined heavy fermions in bulk crystals and employing 2D device fabrication techniques and vdW heterostructures12 to manipulate the interplay between Kondo screening, magnetic order and proximity effects.

Conformational control of Cas9 by CRISPR hybrid RNA-DNA guides mitigates off-target activity in T cells.

The off-target activity of the CRISPR-associated nuclease Cas9 is a potential concern for therapeutic genome editing applications. Although high-fidelity Cas9 variants have been engineered, they exhibit varying efficiencies and have residual off-target effects, limiting their applicability. Here, we show that CRISPR hybrid RNA-DNA (chRDNA) guides provide an effective approach to increase Cas9 specificity while preserving on-target editing activity. Across multiple genomic targets in primary human T cells, we show that 2'-deoxynucleotide (dnt) positioning affects guide activity and specificity in a target-dependent manner and that this can be used to engineer chRDNA guides with substantially reduced off-target effects. Crystal structures of DNA-bound Cas9-chRDNA complexes reveal distorted guide-target duplex geometry and allosteric modulation of Cas9 conformation. These structural effects increase specificity by perturbing DNA hybridization and modulating Cas9 activation kinetics to disfavor binding and cleavage of off-target substrates. Overall, these results pave the way for utilizing customized chRDNAs in clinical applications.

A structural basis for the assembly and functions of a viral polymer that inactivates multiple tumor suppressors.

Evolution of minimal DNA tumor virus' genomes has selected for small viral oncoproteins that hijack critical cellular protein interaction networks. The structural basis for the multiple and dominant functions of adenovirus oncoproteins has remained elusive. E4-ORF3 forms a nuclear polymer and simultaneously inactivates p53, PML, TRIM24, and MRE11/RAD50/NBS1 (MRN) tumor suppressors. We identify oligomerization mutants and solve the crystal structure of E4-ORF3. E4-ORF3 forms a dimer with a central ß core, and its structure is unrelated to known polymers or oncogenes. E4-ORF3 dimer units coassemble through reciprocal and nonreciprocal exchanges of their C-terminal tails. This results in linear and branched oligomer chains that further assemble in variable arrangements to form a polymer network that partitions the nuclear volume. E4-ORF3 assembly creates avidity-driven interactions with PML and an emergent MRN binding interface. This reveals an elegant structural solution whereby a small protein forms a multivalent matrix that traps disparate tumor suppressors.

The role of environmental sensitivity in the mental health of Syrian refugee children: a multi-level analysis.

Individuals with high environmental sensitivity have nervous systems that are disproportionately receptive to both the protective and imperilling aspects of the environment, suggesting their mental health is strongly context-dependent. However, there have been few consolidated attempts to examine putative markers of sensitivity, across different levels of analysis, within a single cohort of individuals with high-priority mental health needs. Here, we examine psychological (self-report), physiological (hair hormones) and genetic (polygenic scores) markers of sensitivity in a large cohort of 1591 Syrian refugee children across two waves of data. Child-caregiver dyads were recruited from informal tented settlements in Lebanon, and completed a battery of psychological instruments at baseline and follow-up (12 months apart). Univariate and multivariate Bayesian linear mixed models were used to examine a) the interrelationships between markers of sensitivity and b) the ability of sensitivity markers to predict anxiety, depression, post-traumatic stress disorder, and externalising behaviour. Self-reported sensitivity (using the Highly Sensitive Child Scale) significantly predicted a higher burden of all forms of mental illness across both waves, however, there were no significant cross-lagged pathways. Physiological and genetic markers were not stably predictive of self-reported sensitivity, and failed to similarly predict mental health outcomes. The measurement of environmental sensitivity may have significant implications for identifying and treating mental illness, especially amongst vulnerable populations, but clinical utility is currently limited to self-report assessment.

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.

DNA Repair Profiling Reveals Nonrandom Outcomes at Cas9-Mediated Breaks.

The repair outcomes at site-specific DNA double-strand breaks (DSBs) generated by the RNA-guided DNA endonuclease Cas9 determine how gene function is altered. Despite the widespread adoption of CRISPR-Cas9 technology to induce DSBs for genome engineering, the resulting repair products have not been examined in depth. Here, the DNA repair profiles of 223 sites in the human genome demonstrate that the pattern of DNA repair following Cas9 cutting at each site is nonrandom and consistent across experimental replicates, cell lines, and reagent delivery methods. Furthermore, the repair outcomes are determined by the protospacer sequence rather than genomic context, indicating that DNA repair profiling in cell lines can be used to anticipate repair outcomes in primary cells. Chemical inhibition of DNA-PK enabled dissection of the DNA repair profiles into contributions from c-NHEJ and MMEJ. Finally, this work elucidates a strategy for using "error-prone" DNA-repair machinery to generate precise edits.

A video processing and machine learning based method for evaluating safety-critical operator engagement in a motorway control room.

In safety-critical automatic systems, safety can be compromised if operators lack engagement. Effective detection of undesirable engagement states can inform the design of interventions for enhancing engagement. However, the existing engagement measurement methods suffer from several limitations which damage their effectiveness in the work environment. A novel engagement evaluation methodology, which adopts Artificial Intelligence (AI) technologies, has been proposed. It was developed using motorway control room operators as subjects. Openpose and Open Source Computer Vision Library (OpenCV) were used to estimate the body postures of operators, then a Support Vector Machine (SVM) was utilised to build the engagement evaluation model based on discrete states of operator engagement. The average accuracy of the evaluation results reached 0.89 and the weighted average precision, recall, and F1-score were all above 0.84. This study emphasises the importance of specific data labelling when measuring typical engagement states, forming the basis for potential control room improvements.Practitioner summary: This study demonstrates an automatic, real-time, objective, and relatively unobtrusive method for measuring dynamic operator engagement states. Computer vision technologies were used to estimate body posture, then machine learning (ML) was utilised to build the engagement evaluation model. The overall evaluation shows the effectiveness of this framework.Abbreviations: AI: Artificial Intelligence; OpenCV: Open Source Computer Vision Library; SVM: Support Vector Machine; UWES: Utrecht Work Engagement Scale; ISA Engagement Scale: Intellectual, Social, Affective Engagement Scale; DSSQ: Dundee Stress State Questionnaire; SSSQ: Short Stress State Questionnaire; EEG: electroencephalography; ECG: Electrocardiography; VMOE: Video-based Measurement for Operator Engagement; CMU: Carnegie Mellon University; CNN: Convolutional Neural Network; 2D: two dimensional; ML: Machine learning.

Nonthermal Bonding Origin of a Novel Photoexcited Lattice Instability in SnSe.

Lattice dynamics measurements are often crucial tools for understanding how materials transform between different structures. We report time-resolved x-ray scattering-based measurements of the nonequilibrium lattice dynamics in SnSe, a monochalcogenide reported to host a novel photoinduced lattice instability. By fitting interatomic force models to the fluence dependent excited-state dispersion, we determine the nonthermal origin of the lattice instability to be dominated by changes of interatomic interactions along a bilayer-connecting bond, rather than of an intralayer bonding network that is of primary importance to the lattice instability in thermal equilibrium.

Electronic and Thermal Properties of the Cation Substitution-Derived Quaternary Chalcogenide CuInSnSe4.

Quaternary chalcogenides continue to be of interest for a variety of technological applications, with physical properties stemming from their structural complexity and stoichiometric variation. In certain structure types, partial vacancies on specific lattice positions present an opportunity to investigate electrical and thermal properties in light of these lattice defects. In this work, we investigated the structural, thermal, and electronic properties of CuInSnSe4, a material that belongs to a relatively unexplored class of quaternary chalcogenides with a defect adamantine crystal structure. First-principles calculations together with experimental measurements revealed a chalcopyrite-like structure with inherent vacancies and characteristic s-p and p-d orbital hybridizations in the electronic structure of the material. Cation disorder and lattice anharmonicity result in very low thermal conductivity with values significantly lower than those for related compositions. This work reveals the fundamental physical properties of a previously uninvestigated quaternary chalcogenide and may aid investigations of similar as well as other quaternary chalcogenide compositions.

Risk and resilience in Syrian refugee children: A multisystem analysis.

Refugee children are often exposed to substantial trauma, placing them at increased risk for mental illness. However, this risk can be mitigated by a capacity for resilience, conferred from multiple ecological systems (e.g., family, community), including at an individual biological level. We examined the ability of hair cortisol concentrations and polygenic scores for mental health to predict risk and resilience in a sample of Syrian refugee children (n = 1359). Children were categorized as either at-risk or resilient depending on clinical thresholds for posttraumatic stress disorder, depression, and externalizing behavior problems. Logistic regression was used to examine main and interacting effects while controlling for covariates. Elevated hair cortisol concentrations were significantly associated with reduced resilience (odds ratio (OR)=0.58, 95%CI [0.40, 0.83]) while controlling for levels of war exposure. Polygenic scores for depression, self-harm, and neuroticism were not found to have any significant main effects. However, a significant interaction emerged between hair cortisol and polygenic scores for depression (OR=0.04, 95%CI [0.003 0.47]), suggesting that children predisposed to depression were more at risk for mental health problems when hair cortisol concentrations were high. Our results suggest that biomarkers (separately and in combination) might support early identification of refugee children at risk for mental health problems.

Anharmonic lattice dynamics and superionic transition in AgCrSe2.

Intrinsically low lattice thermal conductivity ([Formula: see text]) in superionic conductors is of great interest for energy conversion applications in thermoelectrics. Yet, the complex atomic dynamics leading to superionicity and ultralow thermal conductivity remain poorly understood. Here, we report a comprehensive study of the lattice dynamics and superionic diffusion in [Formula: see text] from energy- and momentum-resolved neutron and X-ray scattering techniques, combined with first-principles calculations. Our results settle unresolved questions about the lattice dynamics and thermal conduction mechanism in [Formula: see text] We find that the heat-carrying long-wavelength transverse acoustic (TA) phonons coexist with the ultrafast diffusion of Ag ions in the superionic phase, while the short-wavelength nondispersive TA phonons break down. Strong scattering of phonon quasiparticles by anharmonicity and Ag disorder are the origin of intrinsically low [Formula: see text] The breakdown of short-wavelength TA phonons is directly related to the Ag diffusion, with the vibrational spectral weight associated to Ag oscillations evolving into stochastic decaying fluctuations. Furthermore, the origin of fast ionic diffusion is shown to arise from extended flat basins in the energy landscape and collective hopping behavior facilitated by strong repulsion between Ag ions. These results provide fundamental insights into the complex atomic dynamics of superionic conductors.

The past as present in health promotion: the case for a 'public health humanities'.

Health promotion is conceived as a unifying concept for improving the health of populations. This means addressing the socio-cultural, economic and commercial causes of ill-health, which are necessarily informed by past policies and socio-cultural contexts. However, historical scholarship has rarely figured in health promotion practice or scholarship. This gap resides in the determinants of health, and notably in the analyses of tobacco control and skin cancer prevention, two long-running campaigns that have shaped modern health promotion in Australia. Both highlight a need for understanding the profound impact of history on the present and the value of learning from past successes and failures. Doing so requires integrating historical analyses into existing health promotion scholarship. To achieve this aim, we present a new 'public health humanities' methodology. This novel interdisciplinary framework is conceived as a spectrum in which historical studies integrate with existing health promotion disciplines to solve complex health problems. We draw on the many calls for more interdisciplinarity in health promotion and derive this methodology from proposals in the medical humanities and cognate fields that have wrestled with combining history and present-focused disciplines. Using tobacco control and skin cancer prevention as case studies, we demonstrate how public health humanities uses interdisciplinary teams and shared research questions to generate valuable new knowledge unavailable with traditional methods. Furthermore, we show how it creates evaluation criteria to consider the powerful impact of issues like colonialism on current inequities that hinder health promotion strategies, and from which lessons may be derived for the future.

Measuring the Change in Soft Palate Length and Shape Following Maxillary Advancement: A Cohort Study in Patients with Orofacial Clefts.

OBJECTIVE: To evaluate a method of measuring the change in palatal length and shape following maxillary advancement using synchronous lateral videofluoroscopy and voice recording in order to understand how movement of the maxilla may affect VPI risk in patients with cleft lip and/or palate (CL/P). DESIGN: Retrospective cohort study of children with cleft lip and/or palate. SETTING: Single center, tertiary children's hospital. PARTICIPANTS: Patients with cleft lip and/or palate who underwent maxillary advancement between 2016-21 inclusive. INTERVENTIONS: Maxillary advancement surgery, including those who underwent concurrent mandibular procedures. MAIN OUTCOME MEASURES: The length of the soft palate and the genu angle were measured throughout palatal dynamic range. Pre- and post-operative measurements were compared using a one sided T-test, with subgroup analysis for patients with clinical VPI. RESULTS: Ten patients were examined. The mean distance of maxillary advancement was 10.5 mm. The average increase in pre-genu soft palate length was 2.8 mm in the resting position and 2.9 mm in the closed position. The genu angle decreased in the closed position by 16.3 degrees. CONCLUSIONS: The soft palate showed limited ability to lengthen following maxillary advancement and this may explain the risk of VPI. There was partial compensation by the muscle sling of the palate as demonstrated by a more acute post-operative genu angle and this suggests one reason for the variability of VPI reported. Future research is required to investigate how length and shape changes measured using this method can predict VPI risk.

YouTube as a Source of Patient Education for Transcranial Craniosynostosis Procedures.

INTRODUCTION: The internet has improved access to knowledge, with a reported 72% of internet users accessing health information online. YouTube is the most popular video-sharing website and is a frequently accessed source for health information. There are concerns, however, that patients and carers may be unable to identify and filter for trustworthy sources of information on these platforms. This study aimed to assess the quality of videos that are likely to be accessed when families search YouTube for transcranial procedures for the management of craniosynostosis. METHODOLOGY: This was a cross-sectional, observational study that evaluated YouTube videos when searching for "fronto-orbital advancement" or "cranial vault remodeling." The first 25 videos for each term were included. Videos were assessed for quality using the previously validated JAMA and DISCERN scoring tools. RESULTS: There was low interobserver variability for the scoring tools used. There was no statistically significant correlation between the video quality and any video characteristics assessed. Videos published by organizations had higher mean quality scores for both the JAMA and DISCERN tools when compared to surgeon, patient, or medical device company-produced videos. CONCLUSION: This study showed that searching YouTube for fronto-orbital advancement and cranial vault remodeling yields videos of low quality and therefore patients and carers should be discouraged from "YouTube-ing" these procedures. Platforms such as YouTube may provide an opportunity for craniofacial units to create and disseminate high-quality educational videos to complement routine perioperative education.

Magnetic Interactions of the Centrosymmetric Skyrmion Material Gd_{2}PdSi_{3}.

The experimental realization of magnetic skyrmion crystals in centrosymmetric materials has been driven by theoretical understanding of how a delicate balance of anisotropy and frustration can stabilize topological spin structures in applied magnetic fields. Recently, the centrosymmetric material Gd_{2}PdSi_{3} was shown to host a field-induced skyrmion crystal, but the skyrmion stabilization mechanism remains unclear. Here, we employ neutron-scattering measurements on an isotopically enriched polycrystalline Gd_{2}PdSi_{3} sample to quantify the interactions that drive skyrmion formation. Our analysis reveals spatially extended interactions in triangular planes, and large ferromagnetic interplanar magnetic interactions that are modulated by the Pd/Si superstructure. The skyrmion crystal emerges from a zero-field helical magnetic order with magnetic moments perpendicular to the magnetic propagation vector, indicating that the magnetic dipolar interaction plays a significant role. Our experimental results establish an interaction space that can promote skyrmion formation, facilitating identification and design of centrosymmetric skyrmion materials.

Controllable Emergent Spatial Spin Modulation in Sr_{2}IrO_{4} by In Situ Shear Strain.

Symmetric anisotropic interaction can be ferromagnetic and antiferromagnetic at the same time but for different crystallographic axes. We show that the competition of anisotropic interactions of orthogonal irreducible representations can be a general route to obtain new exotic magnetic states. We demonstrate it here by observing the emergence of a continuously tunable 12-layer spatial spin modulation when distorting the square-lattice planes in the quasi-two-dimensional antiferromagnetic Sr_{2}IrO_{4} under in situ shear strain. This translation-symmetry-breaking phase is a result of an unusual strain-activated anisotropic interaction which is at the fourth order and competing with the inherent quadratic anisotropic interaction. Such a mechanism of competing anisotropy is distinct from that among the ferromagnetic, antiferromagnetic, and/or the Dzyaloshinskii-Moriya interactions, and it could be widely applicable and highly controllable in low-dimensional magnets.

Line-Graph Approach to Spiral Spin Liquids.

Competition among exchange interactions is able to induce novel spin correlations on a bipartite lattice without geometrical frustration. A prototype example is the spiral spin liquid, which is a correlated paramagnetic state characterized by subdimensional degenerate propagation vectors. Here, using spectral graph theory, we show that spiral spin liquids on a bipartite lattice can be approximated by a further-neighbor model on the corresponding line-graph lattice that is nonbipartite, thus broadening the space of candidate materials that may support the spiral spin liquid phases. As illustrations, we examine neutron scattering experiments performed on two spinel compounds, ZnCr_{2}Se_{4} and CuInCr_{4}Se_{8}, to demonstrate the feasibility of this new approach and expose its possible limitations in experimental realizations.

Mobile Sources Are Still an Important Source of Secondary Organic Aerosol and Fine Particulate Matter in the Los Angeles Region.

Secondary organic aerosol (SOA) is a significant component of atmospheric fine particulate matter. Mobile sources have historically been a major source of SOA precursors in urban environments, but decades of regulations have reduced their emissions. Less regulated sources, such as volatile chemical products (VCPs), are of growing importance. We analyzed ambient and emissions data to assess the contribution of mobile sources to SOA formation in Los Angeles during the period of 2009-2019. During this period, air quality in the Los Angeles region has improved, but organic aerosol (OA) concentrations did not decrease as much as primary pollutants. This appears to be largely due to SOA, whose mass fraction in OA increased over this period. In 2010, about half of the freshly formed SOA measured in Pasadena, CA appears to be formed from hydrocarbon (non-oxygenated) precursors. Chemical mass balance analysis indicates that these hydrocarbon SOA precursors (including intermediate volatility organic compounds) can largely be explained by emissions from mobile sources in 2010. Our analysis indicates that continued reduction in emissions from mobile sources should lead to additional significant decreases in atmospheric SOA and PM2.5 mass in the Los Angeles region.

Guide RNA functional modules direct Cas9 activity and orthogonality.

The RNA-guided Cas9 endonuclease specifically targets and cleaves DNA in a sequence-dependent manner and has been widely used for programmable genome editing. Cas9 activity is dependent on interactions with guide RNAs, and evolutionarily divergent Cas9 nucleases have been shown to work orthogonally. However, the molecular basis of selective Cas9:guide-RNA interactions is poorly understood. Here, we identify and characterize six conserved modules within native crRNA:tracrRNA duplexes and single guide RNAs (sgRNAs) that direct Cas9 endonuclease activity. We show the bulge and nexus are necessary for DNA cleavage and demonstrate that the nexus and hairpins are instrumental in defining orthogonality between systems. In contrast, the crRNA:tracrRNA complementary region can be modified or partially removed. Collectively, our results establish guide RNA features that drive DNA targeting by Cas9 and open new design and engineering avenues for CRISPR technologies.

Nucleic acid cleavage with a hyperthermophilic Cas9 from an uncultured Ignavibacterium.

Clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (Cas9) systems have been effectively harnessed to engineer the genomes of organisms from across the tree of life. Nearly all currently characterized Cas9 proteins are derived from mesophilic bacteria, and canonical Cas9 systems are challenged by applications requiring enhanced stability or elevated temperatures. We discovered IgnaviCas9, a Cas9 protein from a hyperthermophilic Ignavibacterium identified through mini-metagenomic sequencing of samples from a hot spring. IgnaviCas9 is active at temperatures up to 100 °C in vitro, which enables DNA cleavage beyond the 44 °C limit of Streptococcus pyogenes Cas9 (SpyCas9) and the 70 °C limit of both Geobacillus stearothermophilus Cas9 (GeoCas9) and Geobacillus thermodenitrificans T12 Cas9 (ThermoCas9). As a potential application of this enzyme, we demonstrate that IgnaviCas9 can be used in bacterial RNA-seq library preparation to remove unwanted cDNA from 16s ribosomal rRNA without increasing the number of steps, thus underscoring the benefits provided by its exceptional thermostability in improving molecular biology and genomic workflows. IgnaviCas9 is an exciting addition to the CRISPR-Cas9 toolbox and expands its temperature range.