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"Sanchez, D."
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Longitudinal liver sampling in patients with chronic hepatitis B starting antiviral therapy reveals hepatotoxic CD8+ T cells
Accumulation of activated immune cells results in nonspecific hepatocyte killing in chronic hepatitis B (CHB), leading to fibrosis and cirrhosis. This study aims to understand the underlying mechanisms in humans and to define whether these are driven by widespread activation or a subpopulation of immune cells. We enrolled CHB patients with active liver damage to receive antiviral therapy and performed longitudinal liver sampling using fine-needle aspiration to investigate mechanisms of CHB pathogenesis in the human liver. Single-cell sequencing of total liver cells revealed a distinct liver-resident, polyclonal CD8+ T cell population that was enriched at baseline and displayed a highly activated immune signature during liver damage. Cytokine combinations, identified by in silico prediction of ligand-receptor interaction, induced the activated phenotype in healthy liver CD8+ T cells, resulting in nonspecific Fas ligand-mediated killing of target cells. These results define a CD8+ T cell population in the human liver that can drive pathogenesis and a key pathway involved in their function in CHB patients.
Journal Article
In situ investigation of phase transformations in Ti-6Al-4V under additive manufacturing conditions combining laser melting and high-speed micro-X-ray diffraction
We present combined
in situ
X-ray diffraction and high-speed imaging to monitor the phase evolution upon cyclic rapid laser heating and cooling mimicking the direct energy deposition of Ti-6Al-4V in real time. Additive manufacturing of the industrially relevant alloy Ti-6Al-4V is known to create a multitude of phases and microstructures depending on processing technology and parameters. Current setups are limited by an averaged measurement through the solid and liquid parts. In this work the combination of a micro-focused intense X-ray beam, a fast detector and unidirectional cooling provide the spatial and temporal resolution to separate contributions from solid and liquid phases in limited volumes. Upon rapid heating and cooling, the β ↔ α′ phase transformation is observed repeatedly. At room temperature, single phase α′ is observed. Secondary β-formation upon formation of α′ is attributed to V partitioning to the β-phase leading to temporary stabilization. Lattice strains in the α′-phase are found to be sensitive to the α′ → β phase transformation. Based on lattice strain of the β-phase, the martensite start temperature is estimated at 923 K in these experiments. Off-axis high speed imaging confirms a technically relevant solidification front velocity and cooling rate of 10.3 mm/s and 4500 K/s, respectively.
Journal Article
Regulation of black-hole accretion by a disk wind during a violent outburst of V404 Cygni
A sustained, neutral wind from the outer accretion disk is observed in the transient black hole V404 Cygni during a violent outburst; this unusual wind, which expands at one per cent of the speed of light and triggers a nebular phase once accretion drops sharply and the ejecta become optically thin, probably regulates the outburst evolution of the black hole.
Accretion regulated by a disk wind in V404 Cygni black hole
Teo Muñoz-Darias
et al
. report observations of a sustained outer accretion disk wind in the stellar-mass black hole in the V404 Cygni binary system that is unlike any seen previously. The outflowing wind is neutral, has a large covering factor and expands at 1% of the speed of light. The luminous, but brief, accretion phases shown by transients with large accretion disks imply that this type of outflow could be a previously unknown factor regulating mass accretion onto black holes.
Accretion of matter onto black holes is universally associated with strong radiative feedback
1
and powerful outflows
2
. In particular, black-hole transients
3
have outflows whose properties
4
are strongly coupled to those of the accretion flow. This includes X-ray winds of ionized material, expelled from the accretion disk encircling the black hole, and collimated radio jets
5
,
6
. Very recently, a distinct optical variability pattern has been reported in the transient stellar-mass black hole V404 Cygni, and interpreted as disrupted mass flow into the inner regions of its large accretion disk
7
. Here we report observations of a sustained outer accretion disk wind in V404 Cyg, which is unlike any seen hitherto. We find that the outflowing wind is neutral, has a large covering factor, expands at one per cent of the speed of light and triggers a nebular phase once accretion drops sharply and the ejecta become optically thin. The large expelled mass (>10
−8
solar masses) indicates that the outburst was prematurely ended when a sizeable fraction of the outer disk was depleted by the wind, detaching the inner regions from the rest of the disk. The luminous, but brief, accretion phases shown by transients with large accretion disks
2
imply that this outflow is probably a fundamental ingredient in regulating mass accretion onto black holes.
Journal Article
A three-dimensional view of structural changes caused by deactivation of fluid catalytic cracking catalysts
Since its commercial introduction three-quarters of a century ago, fluid catalytic cracking has been one of the most important conversion processes in the petroleum industry. In this process, porous composites composed of zeolite and clay crack the heavy fractions in crude oil into transportation fuel and petrochemical feedstocks. Yet, over time the catalytic activity of these composite particles decreases. Here, we report on ptychographic tomography, diffraction, and fluorescence tomography, as well as electron microscopy measurements, which elucidate the structural changes that lead to catalyst deactivation. In combination, these measurements reveal zeolite amorphization and distinct structural changes on the particle exterior as the driving forces behind catalyst deactivation. Amorphization of zeolites, in particular, close to the particle exterior, results in a reduction of catalytic capacity. A concretion of the outermost particle layer into a dense amorphous silica–alumina shell further reduces the mass transport to the active sites within the composite.
Catalyst deactivation in fluid catalytic cracking processes is unavoidably associated with structural changes. Here, the authors visualize the deactivation of zeolite catalysts by ptychography and other imaging techniques, showing pronounced amorphization of the outer layer of the catalyst particles.
Journal Article
The photochemical ring-opening of 1,3-cyclohexadiene imaged by ultrafast electron diffraction
The ultrafast photoinduced ring-opening of 1,3-cyclohexadiene constitutes a textbook example of electrocyclic reactions in organic chemistry and a model for photobiological reactions in vitamin D synthesis. Although the relaxation from the photoexcited electronic state during the ring-opening has been investigated in numerous studies, the accompanying changes in atomic distance have not been resolved. Here we present a direct and unambiguous observation of the ring-opening reaction path on the femtosecond timescale and subångström length scale using megaelectronvolt ultrafast electron diffraction. We followed the carbon–carbon bond dissociation and the structural opening of the 1,3-cyclohexadiene ring by the direct measurement of time-dependent changes in the distribution of interatomic distances. We observed a substantial acceleration of the ring-opening motion after internal conversion to the ground state due to a steepening of the electronic potential gradient towards the product minima. The ring-opening motion transforms into rotation of the terminal ethylene groups in the photoproduct 1,3,5-hexatriene on the subpicosecond timescale.
The photochemical electrocyclic ring-opening of 1,3-cyclohexadiene is a textbook organic chemistry reaction. Now, using ultrafast electron diffraction its reaction pathway has been resolved on the level of atomic distances and on its natural femtosecond timescale. Furthermore, coherent isomerization dynamics of the photoproduct 1,3,5-hexatriene were observed.
Journal Article
Decreased hospital admissions through emergency departments during the COVID-19 pandemic
Emergency Department (ED) visits decreased significantly in the United States during the COVID-19 pandemic. A troubling proportion of this decrease was among patients who typically would have been admitted to the hospital, suggesting substantial deferment of care. We sought to describe and characterize the impact of COVID-19 on hospital admissions through EDs, with a specific focus on diagnosis group, age, gender, and insurance coverage.
We conducted a retrospective, observational study of aggregated third-party, anonymized ED patient data. This data included 501,369 patient visits from twelve EDs in Massachusetts from 1/1/2019–9/9/2019, and 1/1/2020–9/8/2020. We analyzed the total arrivals and hospital admissions and calculated confidence intervals for the change in admissions for each characteristic. We then developed a Poisson regression model to estimate the relative contribution of each characteristic to the decrease in admissions after the statewide lockdown, corresponding to weeks 11 through 36 (3/11/2020–9/8/2020).
We observed a 32% decrease in admissions during weeks 11 to 36 in 2020, with significant decreases in admissions for chronic respiratory conditions and non-orthopedic needs. Decreases were particularly acute among women and children, as well as patients with Medicare or without insurance. The most common diagnosis during this time was SARS-CoV-2.
Our findings demonstrate decreased hospital admissions through EDs during the pandemic and suggest that several patient populations may have deferred necessary care. Further research is needed to determine the clinical and operational consequences of this delay.
Journal Article
Magnetic resonance spectroscopy of an atomically thin material using a single-spin qubit
Two-dimensional (2D) materials offer a promising platform for exploring condensed matter phenomena and developing technological applications. However, the reduction of material dimensions to the atomic scale poses a challenge for traditional measurement and interfacing techniques that typically couple to macroscopic observables. We demonstrate a method for probing the properties of 2D materials via nanometer-scale nuclear quadrupole resonance (NQR) spectroscopy using individual atomlike impurities in diamond. Coherent manipulation of shallow nitrogen-vacancy (NV) color centers enables the probing of nanoscale ensembles down to approximately 30 nuclear spins in atomically thin hexagonal boron nitride (h-BN). The characterization of low-dimensional nanoscale materials could enable the development of new quantum hybrid systems, combining atomlike systems coherently coupled with individual atoms in 2D materials.
Journal Article
Rehybridization dynamics into the pericyclic minimum of an electrocyclic reaction imaged in real-time
Electrocyclic reactions are characterized by the concerted formation and cleavage of both σ and π bonds through a cyclic structure. This structure is known as a pericyclic transition state for thermal reactions and a pericyclic minimum in the excited state for photochemical reactions. However, the structure of the pericyclic geometry has yet to be observed experimentally. We use a combination of ultrafast electron diffraction and excited state wavepacket simulations to image structural dynamics through the pericyclic minimum of a photochemical electrocyclic ring-opening reaction in the molecule α-terpinene. The structural motion into the pericyclic minimum is dominated by rehybridization of two carbon atoms, which is required for the transformation from two to three conjugated π bonds. The σ bond dissociation largely happens after internal conversion from the pericyclic minimum to the electronic ground state. These findings may be transferrable to electrocyclic reactions in general.
Electrocyclic reactions proceed through critical geometries, which are known as pericyclic transition states in thermal reactions and pericyclic minima in photochemical reactions. Here, the authors image the structure of a pericyclic minimum in real time using a combination of ultrafast electron diffraction and ab initio dynamics simulations.
Journal Article
Epigenetic Modifiers as Potential Therapeutic Targets in Diabetic Kidney Disease
Diabetic kidney disease is one of the fastest growing causes of death worldwide. Epigenetic regulators control gene expression and are potential therapeutic targets. There is functional interventional evidence for a role of DNA methylation and the histone post-translational modifications—histone methylation, acetylation and crotonylation—in the pathogenesis of kidney disease, including diabetic kidney disease. Readers of epigenetic marks, such as bromodomain and extra terminal (BET) proteins, are also therapeutic targets. Thus, the BD2 selective BET inhibitor apabetalone was the first epigenetic regulator to undergo phase-3 clinical trials in diabetic kidney disease with an endpoint of kidney function. The direct therapeutic modulation of epigenetic features is possible through pharmacological modulators of the specific enzymes involved and through the therapeutic use of the required substrates. Of further interest is the characterization of potential indirect effects of nephroprotective drugs on epigenetic regulation. Thus, SGLT2 inhibitors increase the circulating and tissue levels of β-hydroxybutyrate, a molecule that generates a specific histone modification, β-hydroxybutyrylation, which has been associated with the beneficial health effects of fasting. To what extent this impact on epigenetic regulation may underlie or contribute to the so-far unclear molecular mechanisms of cardio- and nephroprotection offered by SGLT2 inhibitors merits further in-depth studies.
Journal Article