A reversible epigenetic memory of inflammatory injury controls lineage plasticity and tumor initiation in the mouse pancreas.

Inflammation is essential to the disruption of tissue homeostasis and can destabilize the identity of lineage-committed epithelial cells. Here, we employ lineage-traced mouse models, single-cell transcriptomic and chromatin analyses, and CUT&TAG to identify an epigenetic memory of inflammatory injury in the pancreatic acinar cell compartment. Despite resolution of pancreatitis, our data show that acinar cells fail to return to their molecular baseline, with retention of elevated chromatin accessibility and H3K4me1 at metaplasia genes, such that memory represents an incomplete cell fate decision. In vivo, we find this epigenetic memory controls lineage plasticity, with diminished metaplasia in response to a second insult but increased tumorigenesis with an oncogenic Kras mutation. The lowered threshold for oncogenic transformation, in turn, can be restored by blockade of MAPK signaling. Together, we define the chromatin dynamics, molecular encoding, and recall of a prolonged epigenetic memory of inflammatory injury that impacts future responses but remains reversible.

Pharma - manufacturing: the unappreciated and overlooked indispensable skill.

The process of vaccine production, manufacturing, is time-intensive, complex, expensive, and highly technical, requiring close coordination and collaboration among multiple companies with different inputs, from active pharmaceutical ingredients to glass, and specializations, and with the supply chains spread across many countries. Covid-19 pandemic highlighted that neglecting and ignoring the need for a global effort in vaccine manufacturing and delivery can have alarming, and devastating, repercussions, especially when the world needs a robust healthcare ecosystem to make sure that all of us are safe. So, the natural question is: what does the world need to be well-prepared for the next virus; what does it take to have the manufacturing of vaccines become less concentrated in a few countries and centers and diversified to more countries so that distribution can be more universal, so that all of us are safe? First will need to be the political recognition, and the acceptance, that no country can do or supply everything alone in the pharmaceutical sector - no country can be an island -and that binding international agreements will need to be adopted to make access to medicine more equitable and secure around the world. Furthermore, and critically so, significant long-term sustained investment in human resources must be adopted to fill major gaps in expertise, starting with a robust educational system whose graduates have the knowledge, ability, and capacity to work in this technical industry. Only then, with a professional-educated labor force, can resilient pharma-manufacturing clusters be successfully built throughout the world, which can, and will, give life to the new health code: "No one is safe, until everyone is safe."

Composite Spin Hall Conductivity from Non-Collinear Antiferromagnetic Order.

Non-collinear antiferromagnets (AFMs) are an exciting new platform for studying intrinsic spin Hall effects (SHEs), phenomena that arise from the materials' band structure, Berry phase curvature, and linear response to an external electric field. In contrast to conventional SHE materials, symmetry analysis of non-collinear antiferromagnets does not forbid non-zero longitudinal and out-of-plane spin currents with x ̂ , z ̂ $\hat{x},\hat{z}$ polarization and predicts an anisotropy with current orientation to the magnetic lattice. Here, multi-component out-of-plane spin Hall conductivities σ xz x , $\sigma _{{\rm{xz}}}^{\rm{x}},$ σ xz y , σ xz z $\sigma _{{\rm{xz}}}^{\rm{y}},\ \sigma _{{\rm{xz}}}^{\rm{z}}$ are reported in L12 -ordered antiferromagnetic PtMn3 thin films that are uniquely generated in the non-collinear state. The maximum spin torque efficiencies (ξ  = JS  /Je  ≈ 0.3) are significantly larger than in Pt (ξ  ≈  0.1). Additionally, the spin Hall conductivities in the non-collinear state exhibit the predicted orientation-dependent anisotropy, opening the possibility for new devices with selectable spin polarization. This work demonstrates symmetry control through the magnetic lattice as a pathway to tailored functionality in magnetoelectronic systems.

Limits to the strain engineering of layered square-planar nickelate thin films.

The layered square-planar nickelates, Ndn+1NinO2n+2, are an appealing system to tune the electronic properties of square-planar nickelates via dimensionality; indeed, superconductivity was recently observed in Nd6Ni5O12 thin films. Here, we investigate the role of epitaxial strain in the competing requirements for the synthesis of the n = 3 Ruddlesden-Popper compound, Nd4Ni3O10, and subsequent reduction to the square-planar phase, Nd4Ni3O8. We synthesize our highest quality Nd4Ni3O10 films under compressive strain on LaAlO3 (001), while Nd4Ni3O10 on NdGaO3 (110) exhibits tensile strain-induced rock salt faults but retains bulk-like transport properties. A high density of extended defects forms in Nd4Ni3O10 on SrTiO3 (001). Films reduced on LaAlO3 become insulating and form compressive strain-induced c-axis canting defects, while Nd4Ni3O8 films on NdGaO3 are metallic. This work provides a pathway to the synthesis of Ndn+1NinO2n+2 thin films and sets limits on the ability to strain engineer these compounds via epitaxy.

Superconductivity in a quintuple-layer square-planar nickelate.

Since the discovery of high-temperature superconductivity in copper oxide materials1, there have been sustained efforts to both understand the origins of this phase and discover new cuprate-like superconducting materials2. One prime materials platform has been the rare-earth nickelates and, indeed, superconductivity was recently discovered in the doped compound Nd0.8Sr0.2NiO2 (ref. 3). Undoped NdNiO2 belongs to a series of layered square-planar nickelates with chemical formula Ndn+1NinO2n+2 and is known as the 'infinite-layer' (n = ∞) nickelate. Here we report the synthesis of the quintuple-layer (n = 5) member of this series, Nd6Ni5O12, in which optimal cuprate-like electron filling (d8.8) is achieved without chemical doping. We observe a superconducting transition beginning at ~13 K. Electronic structure calculations, in tandem with magnetoresistive and spectroscopic measurements, suggest that Nd6Ni5O12 interpolates between cuprate-like and infinite-layer nickelate-like behaviour. In engineering a distinct superconducting nickelate, we identify the square-planar nickelates as a new family of superconductors that can be tuned via both doping and dimensionality.

Short Photoswitchable Ceramides Enable Optical Control of Apoptosis.

We report short ceramide analogs that can be activated with light and further functionalized using azide-alkyne click chemistry. These molecules, termed scaCers, exhibit increased cell permeability compared to their long-chain analogs as demonstrated using mass spectrometry and imaging. Notably, scaCers enable optical control of apoptosis, which is not observed with long-chain variants. Additionally, they function as photoswitchable substrates for sphingomyelin synthase 2 (SMS2), exhibiting inverted light-dependence compared to their extended analogs.

Evaluation of Abicipar Pegol (an Anti-VEGF DARPin Therapeutic) in Patients With Neovascular Age-Related Macular Degeneration: Studies in Japan and the United States.

BACKGROUND AND OBJECTIVE: To evaluate comparability of abicipar pegol (abicipar) effects in patients with treatment-naïve neovascular age-related macular degeneration (nAMD) in Japan and the United States. PATIENTS AND METHODS: Phase 2, multicenter, randomized, double-masked, 20-week studies (BAMBOO, Japan; CYPRESS, United States). Patients (n = 25 each study) received three monthly intravitreal injections of abicipar 1 mg or 2 mg or five monthly intravitreal injections of ranibizumab 0.5 mg. RESULTS: Mean best-corrected visual acuity change from baseline at week 16 (primary endpoint) for abicipar 1 mg, abicipar 2 mg, and ranibizumab was +7.8 letters, +8.9 letters, and +17.4 letters (BAMBOO); +4.4 letters, +10.1 letters, and +15.2 letters (CYPRESS). Mean central retinal thickness change from baseline was -187.3 µm, -196.5 µm, and -230.4 µm (BAMBOO); -106.5 µm, -112.8 µm, and -124.4 µm (CYPRESS). Uveitis or vitritis was reported in three abicipar-treated patients. CONCLUSION: Abicipar demonstrated extended duration of effect and safety that were comparable between Japanese and non-Japanese patients with nAMD. Abicipar effectively treated Japanese patients with polypoidal choroidal vasculopathy. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e10-e22.].

OnabotulinumtoxinA for the Treatment of Poststroke Distal Lower Limb Spasticity: A Randomized Trial.

BACKGROUND: Poststroke distal lower limb spasticity impairs mobility, limiting activities of daily living and requiring additional caregiver time. OBJECTIVE: To evaluate the efficacy, safety, and sustained benefit of onabotulinumtoxinA in adults with poststroke lower limb spasticity (PSLLS). DESIGN: A multicenter, randomized, double-blind, phase 3, placebo-controlled trial (NCT01575054). SETTING: Sixty study centers across North America, Europe, Russia, the United Kingdom, and South Korea. PATIENTS: Adult patients (18-65 years of age) with PSLLS (Modified Ashworth Scale [MAS] ≥3) of the ankle plantar flexors and the most recent stroke ≥3 months before study enrollment. INTERVENTIONS: During the open-label phase, patients received ≤3 onabotulinumtoxinA treatments (≤400 U) or placebo at approximately 12-week intervals. Treatments were into the ankle plantar flexors (onabotulinumtoxinA 300 U into ankle plantar flexors; ≤100 U, optional lower limb muscles). MAIN OUTCOME MEASUREMENTS: The double-blind primary endpoint was MAS change from baseline (average score at weeks 4 and 6). Secondary measures included physician-assessed Clinical Global Impression of Change (CGI), MAS change from baseline in optional muscles, Goal Attainment Scale (GAS), and pain scale. RESULTS: Of 468 patients enrolled, 450 (96%) completed the double-blind phase and 413 (88%) completed the study. Small improvements in MAS observed with onabotulinumtoxinA during the double-blind phase (onabotulinumtoxinA, -0.8; placebo, -0.6, P = .01) were further enhanced with additional treatments through week 6 of the third open-label treatment cycle (onabotulinumtoxinA/onabotulinumtoxinA, -1.2; placebo/onabotulinumtoxinA, -1.4). Small improvements in CGI observed during the double-blind phase (onabotulinumtoxinA, 0.9; placebo, 0.7, P = .01) were also further enhanced through week 6 of the third open-label treatment cycle (onabotulinumtoxinA/onabotulinumtoxinA, 1.6; placebo/onabotulinumtoxinA, 1.6). Physician- and patient-assessed GAS scores improved with each subsequent treatment. No new safety signals emerged. CONCLUSIONS: OnabotulinumtoxinA significantly improved ankle MAS, CGI, and GAS scores compared with placebo; improvements were consistent and increased with repeated treatments of onabotulinumtoxinA over 1 year in patients with PSLLS. LEVEL OF EVIDENCE: I.

Suppression of Magnetoresistance in Thin WTe2 Flakes by Surface Oxidation.

Recent renewed interest in layered transition metal dichalcogenides stems from the exotic electronic phases predicted and observed in the single- and few-layer limit. Realizing these electronic phases requires preserving the desired transport properties down to a monolayer, which is challenging. Surface oxides are known to impart Fermi level pinning or degrade the mobility on a number of different systems, including transition metal dichalcogenides and black phosphorus. Semimetallic WTe2 exhibits large magnetoresistance due to electron-hole compensation; thus, Fermi level pinning in thin WTe2 flakes could break the electron-hole balance and suppress the large magnetoresistance. We show that WTe2 develops an ∼2 nm thick amorphous surface oxide, which shifts the Fermi level by ∼300 meV at the WTe2 surface. We also observe a dramatic suppression of the magnetoresistance for thin flakes. However, due to the semimetallic nature of WTe2, the effects of Fermi level pinning are well screened and are not the dominant cause for the suppression of magnetoresistance, supported by fitting a two-band model to the transport data, which showed the electron and hole carrier densities are balanced down to ∼13 nm. However, the fitting shows a significant decrease of the mobilities of both electrons and holes. We attribute this to the disorder introduced by the amorphous surface oxide layer. Thus, the decrease of mobility is the dominant factor in the suppression of magnetoresistance for thin WTe2 flakes. Our study highlights the critical need to investigate often unanticipated and sometimes unavoidable extrinsic surface effects on the transport properties of layered dichalcogenides and other 2D materials.

Secondhand hookah smoke: an occupational hazard for hookah bar employees.

BACKGROUND: Despite the increasing popularity of hookah bars, there is a lack of research assessing the health effects of hookah smoke among employees. This study investigated indoor air quality in hookah bars and the health effects of secondhand hookah smoke on hookah bar workers. METHODS: Air samples were collected during the work shift of 10 workers in hookah bars in New York City (NYC). Air measurements of fine particulate matter (PM2.5), fine black carbon (BC2.5), carbon monoxide (CO), and nicotine were collected during each work shift. Blood pressure and heart rate, markers of active smoking and secondhand smoke exposure (exhaled CO and saliva cotinine levels), and selected inflammatory cytokines in blood (ineterleukin (IL)-1b, IL-6, IL-8, interferon γ (IFN-γ), tumour necrosis factor (TNF-α)) were assessed in workers immediately prior to and immediately after their work shift. RESULTS: The PM2.5 (gravimetric) and BC2.5 concentrations in indoor air varied greatly among the work shifts with mean levels of 363.8 µg/m3 and 2.2 µg/m3, respectively. The mean CO level was 12.9 ppm with a peak value of 22.5 ppm CO observed in one hookah bar. While heart rate was elevated by 6 bpm after occupational exposure, this change was not statistically significant. Levels of inflammatory cytokines in blood were all increased at postshift compared to preshift testing with IFN-Υ increasing from 0.85 (0.13) to 1.6 (0.25) (mean (standard error of the mean; SEM)) pg/mL (p<0.01). Exhaled CO levels were significantly elevated after the work shift with 2 of 10 workers having values >90 ppm exhaled CO. CONCLUSIONS: These results demonstrate that hookah bars have elevated concentrations of indoor air pollutants that appear to cause adverse health effects in employees. These data indicate the need for further research and a marked need for better air quality monitoring and policies in such establishments to improve the indoor air quality for workers and patrons.