High-performance 4-nm-resolution X-ray tomography using burst ptychography.

Advances in science, medicine and engineering rely on breakthroughs in imaging, particularly for obtaining multiscale, three-dimensional information from functional systems such as integrated circuits or mammalian brains. Achieving this goal often requires combining electron- and photon-based approaches. Whereas electron microscopy provides nanometre resolution through serial, destructive imaging of surface layers1, ptychographic X-ray computed tomography2 offers non-destructive imaging and has recently achieved resolutions down to seven nanometres for a small volume3. Here we implement burst ptychography, which overcomes experimental instabilities and enables much higher performance, with 4-nanometre resolution at a 170-times faster acquisition rate, namely, 14,000 resolution elements per second. Another key innovation is tomographic back-propagation reconstruction4, allowing us to image samples up to ten times larger than the conventional depth of field. By combining the two innovations, we successfully imaged a state-of-the-art (seven-nanometre node) commercial integrated circuit, featuring nanostructures made of low- and high-density materials such as silicon and metals, which offer good radiation stability and contrast at the selected X-ray wavelength. These capabilities enabled a detailed study of the chip's design and manufacturing, down to the level of individual transistors. We anticipate that the combination of nanometre resolution and higher X-ray flux at next-generation X-ray sources will have a revolutionary impact in fields ranging from electronics to electrochemistry and neuroscience.

Perivascular B cells link intestinal angiogenesis to immunity and to the gut-brain axis during neuroinflammation.

Disruption of gut barrier function and intestinal immune cell homeostasis are increasingly considered critical players in pathogenesis of extra-intestinal inflammatory diseases, including multiple sclerosis (MS) and its prototypical animal model, the experimental autoimmune encephalomyelitis (EAE). Breakdown of epithelial barriers increases intestinal permeability and systemic dissemination of microbiota-derived molecules. However, whether the gut-vascular barrier (GVB) is altered during EAE has not been reported. Here, we demonstrate that endothelial cell proliferation and vessel permeability increase before EAE clinical onset, leading to vascular remodeling and expansion of intestinal villi capillary bed during disease symptomatic phase in an antigen-independent manner. Concomitant to onset of angiogenesis observed prior to neurological symptoms, we identify an increase of intestinal perivascular immune cells characterized by the surface marker lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1). LYVE-1+ is expressed more frequently on B cells that show high levels of CD73 and have proangiogenic properties. B cell depletion was sufficient to mitigate enteric blood endothelial cell proliferation following immunization for EAE. In conclusion, we propose that altered intestinal vasculature driven by a specialized LYVE-1+ B cell subset promotes angiogenesis and that loss of GVB function is implicated in EAE development and autoimmunity.

Modifiable risk factors for neurocognitive and psychosocial problems after Hodgkin lymphoma.

Long-term survivors of childhood Hodgkin lymphoma (HL) experience a high burden of chronic health morbidities. Correlates of neurocognitive and psychosocial morbidity have not been well established. A total of 1760 survivors of HL (mean ± SD age, 37.5 ± 6.0 years; time since diagnosis, 23.6 ± 4.7 years; 52.1% female) and 3180 siblings (mean age, 33.2 ± 8.5 years; 54.5% female) completed cross-sectional surveys assessing neurocognitive function, emotional distress, quality of life, social attainment, smoking, and physical activity. Treatment exposures were abstracted from medical records. Chronic health conditions were graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.3 (1 = mild, 2 = moderate, 3 = severe/disabling, and 4 = life-threatening). Multivariable analyses, adjusted for age, sex, and race, estimated relative risk (RR) of impairment in survivors vs siblings and, among survivors, risk of impairment associated with demographic, clinical, treatment, and grade 2 or higher chronic health conditions. Compared with siblings, survivors had significantly higher risk (all, P < .05) of neurocognitive impairment (eg, memory, 8.1% vs 5.7%), anxiety (7.0% vs 5.4%), depression (9.1% vs 7%), unemployment (9.6% vs 4.4%), and impaired physical/mental quality of life (eg, physical function, 11.2% vs 3.0%). Smoking was associated with a higher risk of impairment in task efficiency (RR, 1.56; 95% confidence interval [CI], 1.02-2.39), emotional regulation (RR, 1.84; 95% CI, 1.35-2.49), anxiety (RR, 2.43; 95% CI, 1.51-3.93), and depression (RR, 2.73; 95% CI, 1.85-4.04). Meeting the exercise guidelines of the Centers for Disease Control and Prevention was associated with a lower risk of impairment in task efficiency (RR, 0.70; 95% CI, 0.52-0.95), organization (RR, 0.60; 95% CI, 0.45-0.80), depression (RR, 0.66; 95% CI, 0.48-0.92), and multiple quality of life domains. Cardiovascular and neurologic conditions were associated with impairment in nearly all domains. Survivors of HL are at elevated risk for neurocognitive and psychosocial impairment, and risk is associated with modifiable factors that provide targets for interventions to improve long-term functional outcomes.

Systematic analysis of differential rhythmic liver gene expression mediated by the circadian clock and feeding rhythms.

The circadian clock and feeding rhythms are both important regulators of rhythmic gene expression in the liver. To further dissect the respective contributions of feeding and the clock, we analyzed differential rhythmicity of liver tissue samples across several conditions. We developed a statistical method tailored to compare rhythmic liver messenger RNA (mRNA) expression in mouse knockout models of multiple clock genes, as well as PARbZip output transcription factors (Hlf/Dbp/Tef). Mice were exposed to ad libitum or night-restricted feeding under regular light-dark cycles. During ad libitum feeding, genetic ablation of the core clock attenuated rhythmic-feeding patterns, which could be restored by the night-restricted feeding regimen. High-amplitude mRNA expression rhythms in wild-type livers were driven by the circadian clock, but rhythmic feeding also contributed to rhythmic gene expression, albeit with significantly lower amplitudes. We observed that Bmal1 and Cry1/2 knockouts differed in their residual rhythmic gene expression. Differences in mean expression levels between wild types and knockouts correlated with rhythmic gene expression in wild type. Surprisingly, in PARbZip knockout mice, the mean expression levels of PARbZip targets were more strongly impacted than their rhythms, potentially due to the rhythmic activity of the D-box-repressor NFIL3. Genes that lost rhythmicity in PARbZip knockouts were identified to be indirect targets. Our findings provide insights into the diurnal transcriptome in mouse liver as we identified the differential contributions of several core clock regulators. In addition, we gained more insights on the specific effects of the feeding-fasting cycle.

Surgical recovery from the COVID-19 pandemic in English adult neurosurgical centres.

OBJECTIVES: The COVID-19 pandemic required a change in resource priority from Neurosurgical care in order to treat medically unwell patients suffering from the complications of COVID-19 infections. We demonstrate the impact of COVID-19 on total bed days in 24 Neurosurgical centres in England offering adult Neurosurgery as well as the total spells (single inpatient episodes) for operative Neurosurgical patients between 2020 and 2022 when compared with 2019. METHODS: We used Capse Healthcare Knowledge System software iCompare in order to show the change in total spells for patients undergoing a primary or secondary Neurosurgical procedure as defined using the National Neurosurgical Audit Programme (NNAP) OPCS-4 coding framework between 2019 and 2022. RESULTS: The overall mortality rate of COVID-19 patients was 12.3% and the percentage of total bed days taken up by COVID-19 patients in hospitals at large was on average 7.7%. The total number of spells for all procedures over the 24 centres in 2022 was 39,019 compared with 45,742 in 2019. There was a cumulative deficit of 24,904 spells. The loss of spells was not equally distributed across regions and hospital Trusts. The average number of referral to treatment pathways completed within 18 weeks has declined from 76% to 57% over the study period and the referral to treatment clearance time has risen from 17 to 24 weeks. CONCLUSIONS: The mean elective cranial output in 2022 compared with 2019 is at 88% with spinal output lagging at 69%. If the rate of change year on year were to remain at current levels then we would reach pre-pandemic levels of output by 2026.

Seizures' impact on cognition and quality of life in childhood cancer survivors.

BACKGROUND: The objective of this study was to determine the impact of seizure-related factors on neurocognitive, health-related quality of life (HRQOL), and social outcomes in survivors of childhood cancer. METHODS: Survivors of childhood cancer treated at St. Jude Children's Hospital (n = 2022; 48.3% female; median age, 31.5 years; median time since diagnosis, 23.6 years) completed neurocognitive testing and questionnaires. The presence, severity, resolution, and treatment history of seizures were abstracted from medical records. Adjusting for the age at diagnosis, sex, and prior cancer therapy, multivariable models examined the impact of seizures on neurocognitive and HRQOL outcomes. Mediation analyses were conducted for social outcomes. RESULTS: Seizures were identified in 232 survivors (11.5%; 29.9% of survivors with central nervous system [CNS] tumors and 9.0% of those without CNS tumors). In CNS tumor survivors, seizures were associated with poorer executive function and processing speed (P < .02); in non-CNS tumor survivors, seizures were associated with worse function in every domain (P < .05). Among non-CNS survivors, seizure severity was associated with worse processing speed (P = .023), and resolution was associated with better executive function (P = .028) and attention (P = .044). In CNS survivors, seizure resolution was associated with improved attention (P = .047) and memory (P < .02). Mediation analysis revealed that the impact of seizures on social outcomes was mediated by neurocognitive function. CONCLUSIONS: Seizures in cancer survivors adversely affect long-term functional and psychosocial outcomes independently of cancer therapy. The resolution of seizure occurrence is associated with better outcomes. Seizure severity is associated with poorer outcomes and should be a focus of clinical management and patient education.

Environmental control for X-ray nanotomography.

The acquisition speed and spatial resolution of X-ray nanotomography have continuously improved over the last decades. Coherent diffraction-based techniques breach the 10 nm resolution barrier frequently and thus pose stringent demands on sample positioning accuracy and stability. At the same time there is an increasing desire to accommodate in situ or operando measurements. Here, an environmental control system for X-ray nanotomography is introduced to regulate the temperature of a sample from room temperature up to 850°C in a controlled atmospheric composition. The system allows for a 360° sample rotation, permitting tomographic studies in situ or operando free of missing wedge constraints. The system is implemented and available at the flOMNI microscope at the Swiss Light Source. In addition to the environmental control system itself, the related modifications of flOMNI are described. Tomographic measurements of a nanoporous gold sample at 50°C and 600°C at a resolution of sub-20 nm demonstrate the performance of the device.

High-speed free-run ptychography at the Australian Synchrotron.

Over the last decade ptychography has progressed rapidly from a specialist ultramicroscopy technique into a mature method accessible to non-expert users. However, to improve scientific value ptychography data must reconstruct reliably, with high image quality and at no cost to other correlative methods. Presented here is the implementation of high-speed ptychography used at the Australian Synchrotron on the XFM beamline, which includes a free-run data collection mode where dead time is eliminated and the scan time is optimized. It is shown that free-run data collection is viable for fast and high-quality ptychography by demonstrating extremely high data rate acquisition covering areas up to 352 000 µm2 at up to 140 µm2 s-1, with 13× spatial resolution enhancement compared with the beam size. With these improvements, ptychography at velocities up to 250 µm s-1 is approaching speeds compatible with fast-scanning X-ray fluorescence microscopy. The combination of these methods provides morphological context for elemental and chemical information, enabling unique scientific outcomes.

The circadian oscillator analysed at the single-transcript level.

The circadian clock is an endogenous and self-sustained oscillator that anticipates daily environmental cycles. While rhythmic gene expression of circadian genes is well-described in populations of cells, the single-cell mRNA dynamics of multiple core clock genes remain largely unknown. Here we use single-molecule fluorescence in situ hybridisation (smFISH) at multiple time points to measure pairs of core clock transcripts, Rev-erbα (Nr1d1), Cry1 and Bmal1, in mouse fibroblasts. The mean mRNA level oscillates over 24 h for all three genes, but mRNA numbers show considerable spread between cells. We develop a probabilistic model for multivariate mRNA counts using mixtures of negative binomials, which accounts for transcriptional bursting, circadian time and cell-to-cell heterogeneity, notably in cell size. Decomposing the mRNA variability into distinct noise sources shows that clock time contributes a small fraction of the total variability in mRNA number between cells. Thus, our results highlight the intrinsic biological challenges in estimating circadian phase from single-cell mRNA counts and suggest that circadian phase in single cells is encoded post-transcriptionally.

Efficient coupling between single mode fibers and glass chip waveguides via graded refractive index fiber tips.

Coupling characteristics between a single mode fiber (SMF) and a waveguide embedded in a glass chip via a graded index fiber (GIF) tip are investigated at a wavelength of 976 nm. The GIF tips comprise a coreless fiber section and a GIF section. A depressed cladding waveguide in a ZBLAN glass chip with a core diameter of 35 µm is coupled with GIF tips that have a range of coreless fiber and GIF lengths. An experimental coupling efficiency as high as 88% is obtained while a numerical simulation predicts 92.9% for the same GIF tip configuration. Since it is measured in the presence of Fresnel reflection, it can be further improved by anti-reflection coating. Additionally, it is demonstrated that a gap can be introduced between the chip waveguide and the GIF tip while maintaining the high coupling efficiency, thus allowing a thin planar optical component to be inserted. The results presented here will enable miniaturization and simplification of photonic chips with integrated waveguides by replacing bulk coupling lenses with integrated optical fibers.

In situ Bragg coherent X-ray diffraction imaging of corrosion in a Co-Fe alloy microcrystal.

Corrosion is a major concern for many industries, as corrosive environments can induce structural and morphological changes that lead to material dissolution and accelerate material failure. The progression of corrosion depends on nanoscale morphology, stress, and defects present. Experimentally monitoring this complex interplay is challenging. Here we implement in situ Bragg coherent X-ray diffraction imaging (BCDI) to probe the dissolution of a Co-Fe alloy microcrystal exposed to hydrochloric acid (HCl). By measuring five Bragg reflections from a single isolated microcrystal at ambient conditions, we compare the full three-dimensional (3D) strain state before corrosion and the strain along the [111] direction throughout the corrosion process. We find that the strained surface layer of the crystal dissolves to leave a progressively less strained surface. Interestingly, the average strain closer to the centre of the crystal increases during the corrosion process. We determine the localised corrosion rate from BCDI data, revealing the preferential dissolution of facets more exposed to the acid stream, highlighting an experimental geometry effect. These results bring new perspectives to understanding the interplay between crystal strain, morphology, and corrosion; a prerequisite for the design of more corrosion-resistant materials.

Interleukin-6 as a prognostic biomarker of clinical outcomes after traumatic brain injury: a systematic review.

Traumatic brain injury (TBI) is a major cause of mortality and morbidity worldwide. There are currently no early biomarkers for prognosis in routine clinical use. Interleukin-6 (IL-6) is a potential biomarker in the context of the established role of neuroinflammation in TBI recovery. Therefore, a systematic review of the literature was performed to assess and summarise the evidence for IL-6 secretion representing a useful biomarker for clinical outcomes. A multi-database literature search between January 1946 and July 2021 was performed. Studies were included if they reported adult TBI patients with IL-6 concentration in serum, cerebrospinal fluid (CSF) and/or brain parenchyma analysed with respect to functional outcome and/or mortality. A synthesis without meta-analysis is reported. Fifteen studies were included, reporting 699 patients. Most patients were male (71.7%), and the pooled mean age was 40.8 years; 78.1% sustained severe TBI. Eleven studies reported IL-6 levels in serum, six in CSF and one in the parenchyma. Five studies on serum demonstrated higher IL-6 concentrations were associated with poorer outcomes, and five showed no signification association. In CSF studies, one found higher IL-6 levels were associated with poorer outcomes, one found them to predict better outcomes and three found no association. Greater parenchymal IL-6 was associated with better outcomes. Despite some inconsistency in findings, it appears that exaggerated IL-6 secretion predicts poor outcomes after TBI. Future efforts require standardisation of IL-6 measurement practices as well as assessment of the importance of IL-6 concentration dynamics with respect to clinical outcomes, ideally within large prospective studies. Prospero registration number: CRD42021271200.

Optimum Energy Management for Air Conditioners in IoT-Enabled Smart Home.

This paper addresses the optimal pre-cooling problem for air conditioners (AC) used in Internet of Things (IoT)-enabled smart homes while ensuring that user-defined thermal comfort can be achieved. The proposed strategy utilises renewable energy generation periods and moves some of the air conditioning loads to these periods to reduce the electricity demand. In particular, we propose a multi-stage approach which maximises the utilisation of renewable energy at the first stage to satisfy air conditioning loads, and then schedules residual energy consumption of these loads to low price periods at the second stage. The proposed approach is investigated for the temperature and renewable generation data of NSW, Australia, over the period 2012-2013. It is shown that the approach developed can significantly reduce the energy consumption and cost associated with AC operation for nearly all days in summer when cooling is required. Specifically, the proposed approach was found to achieve a 24% cost saving in comparison to the no pre-cooling case for the highest average temperature day in January, 2013. The analysis also demonstrated that the proposed scheme performed better when the thermal insulation levels in the smart home are higher. However, the optimal pre-cooling scheme can still achieve reduced energy costs under lower thermal insulation conditions compared to the no pre-cooling case.

Annealing of focused ion beam damage in gold microcrystals: an in situ Bragg coherent X-ray diffraction imaging study.

Focused ion beam (FIB) techniques are commonly used to machine, analyse and image materials at the micro- and nanoscale. However, FIB modifies the integrity of the sample by creating defects that cause lattice distortions. Methods have been developed to reduce FIB-induced strain; however, these protocols need to be evaluated for their effectiveness. Here, non-destructive Bragg coherent X-ray diffraction imaging is used to study the in situ annealing of FIB-milled gold microcrystals. Two non-collinear reflections are simultaneously measured for two different crystals during a single annealing cycle, demonstrating the ability to reliably track the location of multiple Bragg peaks during thermal annealing. The thermal lattice expansion of each crystal is used to calculate the local temperature. This is compared with thermocouple readings, which are shown to be substantially affected by thermal resistance. To evaluate the annealing process, each reflection is analysed by considering facet area evolution, cross-correlation maps of the displacement field and binarized morphology, and average strain plots. The crystal's strain and morphology evolve with increasing temperature, which is likely to be caused by the diffusion of gallium in gold below ∼280°C and the self-diffusion of gold above ∼280°C. The majority of FIB-induced strains are removed by 380-410°C, depending on which reflection is being considered. These observations highlight the importance of measuring multiple reflections to unambiguously interpret material behaviour.

Design guidelines for collimating or focusing graded-index fiber tips.

Graded-index optical fiber probes suitable for focusing or collimating the output of an optical fiber at a wavelength of 1.3 µm have become an enabling technology in optical coherence tomography imaging applications for in vivo bioimaging. Such fiber tips however remain uncommon in other photonics applications. This paper provides the first numerical study of graded-index fiber tips covering a broad range of wavelengths spanning from the UV to short-infrared. The wavelength dependency and the influence of probe geometry on performance characteristics such as far-field divergence angle, spot size and working distance are analyzed. The paper yields easily accessible design guidelines for the fabrication of collimating or focusing fiber tips. Fiber collimators have considerable potential for use in free-space systems and could benefit a range of devices such as variable attenuators, dynamic wavelength equalisers and large 3D optical cross-connect switches, whereas focusing fiber tips have applications in high-resolution imaging.

Group 11 Borataalkene Complexes: Models for Alkene Activation.

A series of linear late transition metal (M=Cu, Ag, Au and Zn) complexes featuring a side-on [B=C]- containing ligand have been isolated and characterised. The [B=C]- moiety is isoelectronic with the C=C system of an alkene. Comparison across the series shows that in the solid-state, deviation between the η2 and η1 coordination mode occurs. A related zinc complex containing two [B=C]- ligands was prepared as a further point of comparison for the η1 coordination mode. The bonding in these new complexes has been interrogated by computational techniques (QTAIM, NBO, ETS-NOCV) and rationalised in terms of the Dewar-Chatt-Duncanson model. The combined structural and computational data provide unique insight into catalytically relevant linear d10 complexes of Cu, Ag and Au. Slippage is proposed to play a key role in catalytic reactions of alkenes through disruption and polarisation of the π-system. Through the preparation and analysis of a consistent series of group 11 complexes, we show that variation of the metal can impact the coordination mode and hence substrate activation.

Physical fitness and neurocognitive outcomes in adult survivors of childhood acute lymphoblastic leukemia: A report from the St. Jude Lifetime cohort.

BACKGROUND: Survivors of childhood acute lymphoblastic leukemia (ALL) are at increased risk for both treatment-related exercise intolerance and neurocognitive deficits. This analysis aimed to identify the association between exercise intolerance and neurocognitive impairments in ALL survivors. METHODS: Cardiopulmonary exercise testing, results from a 2-hour standardized neuropsychological assessment, and self-report questionnaires were obtained for 341 adult survivors of childhood ALL and 288 controls. Multivariable modeling was used to test associations between oxygen uptake at 85% estimated heart rate (rpkVO2 ) and neuropsychological test and self-reported questionnaire domains, adjusted for sex, age at diagnosis, cranial radiation, anthracycline, and methotrexate exposure and tobacco smoking status. RESULTS: Compared with controls, survivors had worse rpkVO2 and performance on verbal intelligence, focused attention, verbal fluency, working memory, dominant/nondominant motor speed, visual-motor speed, memory span, and reading and math measures (all P < .001). In adjusted models, exercise intolerance was associated with decreases in performance of verbal ability, focused attention, verbal fluency, working memory, dominant motor speed, nondominant motor speed, visual-motor speed, memory span, reading academics, and math academics in survivors. CONCLUSION: This study demonstrates an association between exercise intolerance and neurocognitive outcomes. Research is needed to determine whether interventions that improve exercise tolerance impact neurocognitive function in ALL survivors.

Observation of Transient and Asymptotic Driven Structural States of Tungsten Exposed to Radiation.

Combining spatially resolved x-ray Laue diffraction with atomic-scale simulations, we observe how ion-irradiated tungsten undergoes a series of nonlinear structural transformations with increasing radiation exposure. Nanoscale defect-induced deformations accumulating above 0.02 displacements per atom (dpa) lead to highly fluctuating strains at ∼0.1 dpa, collapsing into a driven quasisteady structural state above ∼1 dpa. The driven asymptotic state is characterized by finely dispersed vacancy defects coexisting with an extended dislocation network and exhibits positive volumetric swelling, due to the creation of new crystallographic planes through self-interstitial coalescence, but negative lattice strain.

Defluoroalkylation of sp3 C-F Bonds of Industrially Relevant Hydrofluoroolefins.

A simple, one-pot procedure is reported for the selective defluoroalkylation of trifluoromethyl alkene derivatives with aldehydes and ketones. The reaction sequence allows construction of a new C-C bond in a highly selective manner from a single sp3 C-F bond of a CF3 group in the presence of sp2 C-F bonds. The scope incorporates industrially relevant fluorocarbons including HFO-1234yf and HFO-1234ze. No catalyst, additives or transition metals are required, rather the methodology relies on a recently developed boron reagent. Remarkably, the boron site of this reagent plays a dual role in the reaction sequence, being nucleophilic at boron in the C-F cleavage step (SN 2') but electrophilic at boron en route to the carbon-carbon bond-forming step (SE 2'). The duplicitous behaviour is underpinned by a hydrogen atom migration from boron to the carbon atom of a carbene ligand.

Neuroanatomical abnormalities related to dexamethasone exposure in survivors of childhood acute lymphoblastic leukemia.

Survivors of childhood acute lymphoblastic leukemia (ALL) treated with chemotherapy only are at risk for neurocognitive impairment. Regions of interest were identified a priori based on glucocorticoid receptor distribution, and sex-stratified multivariable linear regression models were used to test associations between brain MRI morphology and total number of intrathecal injections, and serum concentration of dexamethasone and methotrexate. Compared with controls, ALL survivors have persistently smaller volumes in the bilateral cerebellum (P < 0.005), hippocampal subregions (P < 0.03), temporal lobe regions (P < 0.03), frontal lobe regions (P < 0.04), and parietal lobe regions (precuneus; P < 0.002). Long-term problems with learning may be related to residual posttreatment brain differences.