Cell division angle predicts the level of tissue mechanics that tune the amount of cerebellar folding.

Modeling has led to proposals that the amount of neural tissue folding is set by the level of differential expansion between tissue layers and that the wavelength is set by the thickness of the outer layer. Here, we used inbred mouse strains with distinct amounts of cerebellar folding to investigate these predictions. We identified a distinct critical period during which the folding amount diverges between the two strains. In this period, regional changes in the level of differential expansion between the external granule layer (EGL) and underlying core correlate with the folding amount in each strain. Additionally, the thickness of the EGL varies regionally during the critical period alongside corresponding changes in wavelength. The number of SHH-expressing Purkinje cells predicts the folding amount, but the proliferation rate in the EGL is the same between the strains. However, regional changes in the cell division angle within the EGL predicts both the tangential expansion and the thickness of the EGL. Cell division angle is likely a tunable mechanism whereby both the level of differential expansion along the perimeter and the thickness of the EGL are regionally tuned to set the amount and wavelength of folding.

Targeting lipid nanoparticles to the blood-brain barrier to ameliorate acute ischemic stroke.

Effective delivery of mRNA or small molecule drugs to the brain is a significant challenge in developing treatment for acute ischemic stroke (AIS). To address the problem, we have developed targeted nanomedicine to increase drug concentrations in endothelial cells of the blood-brain barrier (BBB) of the injured brain. Inflammation during ischemic stroke causes continuous neuronal death and an increase in the infarct volume. To enable targeted delivery to the inflamed BBB, we conjugated lipid nanocarriers (NCs) with antibodies that bind cell adhesion molecules expressed at the BBB. In the transient middle cerebral artery occlusion mouse model, NCs targeted to vascular cellular adhesion molecule-1 (VCAM) achieved the highest level of brain delivery, nearly two orders of magnitude higher than untargeted ones. VCAM-targeted lipid nanoparticles with luciferase-encoding mRNA and Cre-recombinase showed selective expression in the ischemic brain. Anti-inflammatory drugs administered intravenously after ischemic stroke reduced cerebral infarct volume by 62% (interleukin-10 mRNA) or 35% (dexamethasone) only when they were encapsulated in VCAM-targeted NCs. Thus, VCAM-targeted lipid NCs represent a new platform for strongly concentrating drugs within the compromised BBB of penumbra, thereby ameliorating AIS.

Chlorination of Pu and U Metal Using GaCl3.

The oxidative chlorination of the plutonium metal was achieved through a reaction with gallium(III) chloride (GaCl3). In DME (DME = 1,2-dimethoxyethane) as the solvent, substoichiometric (2.8 equiv) amounts of GaCl3 were added, which consumed roughly 60% of the plutonium metal over the course of 10 days. The salt species [PuCl2(dme)3][GaCl4] was isolated as pale-purple crystals, and both solid-state and solution UV-vis-NIR spectroscopies were consistent with the formation of a trivalent plutonium complex. The analogous reaction was performed with uranium metal, generating a dicationic trivalent uranium complex crystallized as the [UCl(dme)3][GaCl4]2 salt. The extraction of [UCl(dme)3][GaCl4]2 in DME at 70 °C followed by crystallization produced [{U(dme)3}2(µ-Cl3)][GaCl4]3, a product arising from the loss of GaCl3. This method of halogenation worked on a small scale for plutonium and uranium, providing a route to cationic Pu3+ and dicationic U3+ complexes using GaCl3 in DME.

Oxidative Dissolution of Lanthanide Metals Ce and Ho in Molten GaCl3.

Gallium trichloride (GaCl3) was used as a solvent for the oxidative dissolution of the lanthanide (Ln) metals cerium (Ce) and holmium (Ho). Reactions were performed at temperatures above 100 °C in sealed vessels to maintain the liquid phase for GaCl3 during the oxidizing reactions. The best results were obtained from reactions using 8 equiv of GaCl3 to metal where the inorganic complexes [Ga][Ln(GaCl4)4] [Ln = Ce (1), Ho (2)] could be isolated. Recrystallization of 1 and 2 employing fluorobenzene (C6H5F) produced [Ga(η6-C6H5F)2][Ln(GaCl4)4] [Ln = Ce (3), Ho (4)] where reversible η6 coordination of C6H5F to [Ga]+ was observed. All complexes were characterized through elemental analysis (F and Cl), IR and UV-vis-near-IR spectroscopies, and both solution and solid-state NMR techniques.

The Influence of Phosphorus Substituents on the Structures and Solution Speciation of Trivalent Uranium and Lanthanide Phosphinodiboranates.

Here, we report the mechanochemical synthesis and characterization of homoleptic uranium and lanthanide phosphinodiboranates with isopropyl and ethyl substituents attached to phosphorus. M(H3BPiPr2BH3)3 complexes with M = U, Nd, Sm, Tb, and Er were prepared by ball milling UI3(THF)4, SmBr3, or MI3 with three equivalents of K(H3BPiPr2BH3). M(H3BPEt2BH3)3 with M = U and Nd were prepared similarly using K(H3BPEt2BH3), and the complexes were purified by extraction and crystallization from Et2O or CH2Cl2. Single-crystal XRD studies revealed that all five M(H3BPiPr2BH3)3 crystallize as dimers, despite the significant differences in metal radii across the series. In contrast, Nd(H3BPEt2BH3)3 with smaller ethyl substituents crystallized as a coordination polymer. Crystals of U(H3BPEt2BH3)3 were not suitable for structural analysis, but crystals of U(H3BPMe2BH3)3 isolated in low yield by solution methods were isostructural with Nd(H3BPEt2BH3)3. 1H and 11B NMR studies in C6D6 revealed that all of the complexes form mixtures of monomer and oligomers when dissolved, and the extent of oligomerization was highly dependent on metal radius and phosphorus substituent size. A comprehensive analysis of all structurally characterized uranium and lanthanide phosphinodiboranate complexes reported to date, including those with larger Ph and tBu substituents, revealed that the degree of oligomerization in solution can be correlated to differences in B-P-B angles obtained from single-crystal XRD studies. Density functional theory calculations, which included structural optimizations in combination with conformational searches using tight binding methods, replicated the general experimental trends and revealed free energy differences that account for the different solution and solid-state structures. Collectively, these results reveal how steric changes to phosphorus substituents significantly removed from metal coordination sites can have a significant influence on solution speciation, deoligomerization energies, and the solid-state structure of homoleptic phosphinodiboranate complexes containing trivalent f-metals.

Clinical Outcomes of Oral Zinc Therapy in Hepatic Encephalopathy Treatment.

BACKGROUND: Additional therapies for hepatic encephalopathy (HE) treatment are warranted. There are data evaluating the use of zinc for HE; however, clinical outcomes, specifically in the United States, are unknown. OBJECTIVE: To compare 30-day and 1-year all-cause readmission rates in patients with cirrhosis complicated by HE on lactulose and rifaximin to those on lactulose, rifaximin, and zinc. METHODS: This retrospective study included patients admitted with documented cirrhosis and home medications of lactulose and rifaximin, with or without zinc. Patients were stratified into 2 groups: those receiving lactulose and rifaximin for HE (control) and those receiving lactulose, rifaximin, and zinc for HE (treatment). The primary outcomes were 30-day and 1-year all-cause readmission rates. RESULTS: One-hundred fifty-seven patients were included (102 in control group, 55 in treatment group). Regarding 30-day and 1-year all-cause readmission rates, there was no difference between the control and treatment groups. CONCLUSION AND RELEVANCE: This is the first study conducted in the United States evaluating zinc for HE treatment. Zinc did not impact 30-day or 1-year all-cause readmission rates. Further studies are warranted to evaluate the potential benefit of zinc for HE, possibly in correlation with Model for End-stage Liver Disease-Sodium (MELD-Na) scores.

Magnetism Studies of Bis(acyl)phosphide-Supported Eu3+ and Eu2+ Complexes.

A series of bis(acyl)phosphide-supported Eu complexes were synthesized (bis(acyl)phosphide = BAP). In this study, BAP ligands proved to be excellent ligands for the synthesis of both Eu3+ and Eu2+ molecular complexes. Sodium bis(mesitoyl)phosphide (Na(mesBAP)) and sodium bis(2,4,6-triisopropylbenzoyl)phosphide (Na(trippBAP)) were employed as ligand precursors for the synthesis of the Eu3+ complexes Eu(bis(mesitoyl)phosphide)3(thf)2 (Eu(mesBAP)3(thf)2) and Eu(bis(2,4,6-triisopropylbenzoyl)phosphide)3 (Eu(trippBAP)3), as well as the Eu2+ complex, Eu(bis(2,4,6-triisopropylbenzoyl)phosphide)2(dme)2 (Eu(trippBAP)2(dme)2) (thf = tetrahydrofuran, dme = 1,2-dimethoxyethane). All complexes were characterized using a combination of UV-vis-NIR-IR and NMR spectroscopies, and single-crystal X-ray diffraction (SC-XRD). The magnetic properties of these three monomeric Eu complexes were investigated by variable-temperature magnetic susceptibility. The magnetic data are typical for these ions, with Eu(trippBAP)2(dme)2 displaying Curie-type behavior. Both Eu(trippBAP)3 and Eu(mesBAP)3(thf)2 possess similar 7F0-7F1 spin-orbit energy gaps and a similar zero-field splitting of the 7F1 state.

Quantifying Variations in Metal-Ligand Cooperative Binding Strength with Cyclic Voltammetry and Redox-Active Ligands.

Metal-ligand cooperativity (MLC), a phenomenon that leverages reactive ligands to promote synergistic reactions with metals, has proven to be a powerful approach to achieving new and unprecedented chemical transformations with metal complexes. While many examples of MLC are known with a wide range of substrates, experimentally quantifying how ligand modifications affect MLC binding strength remains a challenge. Here we describe how cyclic voltammetry (CV) was used to quantify differences in MLC binding strength in a series of square-pyramidal Ru complexes. This method relies on using multifunctional ligands (those capable of both MLC and ligand-centered redox activity) as electrochemical reporters of MLC binding strength. The synthesis and characterization of Ru complexes with three different redox-active tetradentate ligands and two different ancillary phosphines (PPh3 and PCy3) are described. Titration CV studies conducted using BH3·THF with BH3 as a model MLC substrate allowed ΔGMLC to be quantified for each complex. Compared to our base triaryl ligand, increasing π conjugation in the backbone of the redox-active ligand enhanced MLC binding, whereas increasing π conjugation in the flanking groups decreased the MLC binding strength. Structures and spectroscopic data collected for the isolated MLC complexes are also described along with supporting DFT calculations that were used to illuminate electronic factors that likely account for the observed differences in the MLC binding strength. These results demonstrate how redox-active ligands and CV can be used to quantify subtle differences in the MLC binding strength across a series of structurally related complexes with different ligand modifications.

Homoleptic Uranium-Bis(acyl)phosphide Complexes.

The first uranium bis(acyl)phosphide (BAP) complexes were synthesized from the reaction between sodium bis(mesitoyl)phosphide (Na(mesBAP)) or sodium bis(2,4,6-triisopropylbenzoyl)phosphide (Na(trippBAP)) and UI3(1,4-dioxane)1.5. Thermally stable, homoleptic BAP complexes were characterized by single-crystal X-ray diffraction and electron paramagnetic resonance (EPR) spectroscopy, when appropriate, for the elucidation of the electronic structure and bonding of these complexes. EPR spectroscopy revealed that the BAP ligands on the uranium center retain a significant amount of electron density. The EPR spectrum of the trivalent U(trippBAP)3 has a rhombic signal near g = 2 (g1 = 2.03; g2 = 2.01; and g3 = 1.98) that is consistent with the EPR-observed unpaired electron being located in a molecular orbital that appears ligand-derived. However, upon warming the complex to room temperature, no resonance was observed, indicating the presence of uranium character.

Optimization of Biocompatibility for a Hydrophilic Biological Molecule Encapsulation System.

Despite considerable advances in recent years, challenges in delivery and storage of biological drugs persist and may delay or prohibit their clinical application. Though nanoparticle-based approaches for small molecule drug encapsulation are mature, encapsulation of proteins remains problematic due to destabilization of the protein. Reverse micelles composed of decylmonoacyl glycerol (10MAG) and lauryldimethylamino-N-oxide (LDAO) in low-viscosity alkanes have been shown to preserve the structure and stability of a wide range of biological macromolecules. Here, we present a first step on developing this system as a future platform for storage and delivery of biological drugs by replacing the non-biocompatible alkane solvent with solvents currently used in small molecule delivery systems. Using a novel screening approach, we performed a comprehensive evaluation of the 10MAG/LDAO system using two preparation methods across seven biocompatible solvents with analysis of toxicity and encapsulation efficiency for each solvent. By using an inexpensive hydrophilic small molecule to test a wide range of conditions, we identify optimal solvent properties for further development. We validate the predictions from this screen with preliminary protein encapsulation tests. The insight provided lays the foundation for further development of this system toward long-term room-temperature storage of biologics or toward water-in-oil-in-water biologic delivery systems.

Quantifying the Influence of Covalent Metal-Ligand Bonding on Differing Reactivity of Trivalent Uranium and Lanthanide Complexes.

Qualitative differences in the reactivity of trivalent lanthanide and actinide complexes have long been attributed to differences in covalent metal-ligand bonding, but there are few examples where thermodynamic aspects of this relationship have been quantified, especially with U3+ and in the absence of competing variables. Here we report a series of dimeric phosphinodiboranate complexes with trivalent f-metals that show how shorter-than-expected U-B distances indicative of increased covalency give rise to measurable differences in solution deoligomerization reactivity when compared to isostructural complexes with similarly sized lanthanides. These results, which are in excellent agreement with supporting DFT and QTAIM calculations, afford rare experimental evidence concerning the measured effect of variations in metal-ligand covalency on the reactivity of trivalent uranium and lanthanide complexes.

Convenient Syntheses of Trivalent Uranium Halide Starting Materials without Uranium Metal.

Low-valent uranium coordination chemistry continues to rely heavily on access to trivalent starting materials, but these reagents are typically prepared from uranium turnings, which are becoming increasingly difficult to acquire. Here we report convenient syntheses of UI3(THF)4 (THF = tetrahydrofuran) and UBr3(THF)4 from UCl4, a more accessible uranium starting material that can be prepared from commercially available uranium oxides. UCl3(THF)2 (1), UBr3(THF)4 (2), and UI3(THF)4 (3) were prepared by single-pot reductions from UCl4 using KH and KC8 and converted to 2 or 3 by halide exchange with the corresponding Me3SiX (where X = Br or I). Reduction of UI4(Et2O)2 (4; Et2O = diethyl ether) and UI4(1,4-dioxane)2 (5) was also shown to cleanly yield 3. Complex 1 was also synthesized separately by the addition of anhydrous HCl to U(BH4)3(THF)2, which was prepared by thermal reduction of U(BH4)4. All three trivalent uranium halide complexes were isolated in high crystalline yields (typically 85-99%) and their formulations were confirmed by single-crystal X-ray diffraction, elemental analysis, and 1H NMR and IR spectroscopy. Elemental analysis conducted on triplicate samples of 1-3 exposed to vacuum for different time intervals revealed significant THF loss for all three complexes in as little as 15 min. Overall, these results offer expedient entry into low-valent uranium chemistry for researchers lacking access to uranium turnings.

No impact of acute hyperglycaemia on arterial stiffness in the early and late follicular phases of the menstrual cycle in young females.

NEW FINDINGS: • What is the central question of this study? This is the first study to examine the impact of acute hyperglycaemia on arterial stiffness across the early and late follicular phases of the menstrual cycle. • What is the main finding and its importance? Central and peripheral arterial stiffness were not impacted by acute hyperglycaemia. This indicates that premenopausal women might experience protection against deleterious effects of acute hyperglycaemia, regardless of menstrual cycle phase. This research furthers our understanding of the interaction between nutrient intake, hormonal fluctuation and vascular function in premenopausal women. ABSTRACT: Acute hyperglycaemia may result in transient increases in arterial stiffness. However, research in healthy premenopausal women is lacking, and the impact of menstrual phase [early follicular (EF; low oestrogen) and late follicular (LF; high oestrogen)] on vulnerability to acute hyperglycaemia-induced changes in arterial stiffness is unknown. We hypothesized that an acute hyperglycaemia-induced increase in arterial stiffness in the EF phase would be attenuated in the LF phase. Seventeen healthy, naturally menstruating women [21 ± 1 years of age (mean ± SD)] participated in three experimental visits. During two visits, in the EF and LF phase, arterial stiffness was assessed via central and peripheral (arm and leg) pulse wave velocity (PWV) before and 15, 45, 75 and 105 min after consuming an oral glucose challenge (75 g glucose in 300 ml of solution). Blood samples were taken to assess glucose, insulin, oestrogen and progesterone concentrations. During a third visit in the EF phase, participants ingested 300 ml of water as a time control for PWV. Despite significant increases in blood glucose and insulin (P < 0.001), both central and peripheral arm PWV remained unchanged across time and phase, indicating that neither acute hyperglycaemia nor menstrual phase had an impact on central or peripheral arm arterial stiffness. There was a small effect of phase for peripheral leg PWV, where PWV was lower in the LF phase (P = 0.04, Cohen's d = 0.39); however, and in contrast to recent results in young men, peripheral leg PWV was unaffected by hyperglycaemia. These results suggest that premenopausal women might experience protection from acute hyperglycaemia-induced increases in arterial stiffness.

Direct write printing of a self-encapsulating liquid metal-silicone composite.

Silicone composites featuring inclusions of liquid metal particles are soft and stretchable materials with useful electric, dielectric, mechanical, and thermal properties. Until recently, these materials have primarily been cast as films. This work examines the possibility of using uncured liquid metal-elastomer (LME) composites as inks for direct writing. The liquid metal inclusions act as rheological modifiers for the silicone, forming a gel-structure that can be extruded from a nozzle and hold its shape after printing. Additionally, by tuning the particle size, larger particles in the printed structures can settle to form metal-rich regions at the bottom of the structures, encased by metal-depleted (insulating) regions. Using mechanical force, the liquid metal-rich interior can be rendered conductive by sintering without affecting the insulating exterior. Thus, it is possible to print this soft and stretchable material while creating conductors with self-insulating shells.

Oxide-mediated mechanisms of gallium foam generation and stabilization during shear mixing in air.

Foaming of gallium-based liquid metals improves their processability and-seemingly in contrast to processing of other metal foams-can be achieved through shear-mixing in air without addition of solid microparticles. Resolving this discrepancy, systematic processing-structure-property characterization demonstrates that many crumpled oxide particles are generated prior to air bubble accumulation.

Chelating Borohydrides for Lanthanides and Actinides: Structures, Mechanochemistry, and Case Studies with Phosphinodiboranates.

In this Forum Article, we review the development of chelating borohydride ligands called aminodiboranates (H3BNR2BH3-) and phosphinodiboranates (H3BPR2BH3-) for the synthesis of trivalent f-element complexes. The advantages and history of using mechanochemistry to prepare molecular borohydride complexes are described along with new results demonstrating the mechanochemical synthesis of M2(H3BPtBu2BH3)6, where M = U, Nd, Tb, Er, and Lu (1-5). Multinuclear NMR, IR, and single-crystal X-ray diffraction data are reported for 1-5 alongside complementary density functional theory calculations to reveal differences in their structure and reactivity with and without tetrahydrofuran. The results demonstrate how mechanochemistry can be used to access f-element complexes with chelating borohydrides in improved and reproducible yields, which is an important step toward investigating the properties of lanthanide and actinide phosphinodiboranate complexes with different phosphorus substituents. The relevance of these results is contextualized by a discussion of structural factors known to influence the volatility of f-element borohydrides and applications that require the development of volatile f-element complexes.

Higher intakes of flavonoids are associated with lower salivary IL-1ß and maintenance of periodontal health 3-4 years after scaling and root planing.

AIMS: Higher intakes of fruits and vegetables, and vitamin C are associated with improved periodontal healing post-scaling and root planing (SRP). This study determined if this association was sustained at 3-4 years post-SRP, and if flavonoid intake is associated with periodontal health. Whether reduced probing depth (PD) is sustained and whether PD is correlated with salivary IL-1ß, IL-6 and CRP at 3-4 years post-SRP were also studied. MATERIALS AND METHODS: Clinical periodontal outcomes, dietary intakes and salivary markers of inflammation were measured in patients (n = 43, 23 females, 37-93 years) who had undergone SRP 3-4 years earlier and had been part of a periodontal maintenance programme. RESULTS: Flavonoid intake was inversely associated with PD (p = .042) and salivary IL-1ß concentration (p = .015) after adjustment for multiple confounders. When changes in PD were considered, the association of flavonoid intake with reduced PD became borderline significant (p = .051) but persisted for IL-1ß (p = .018). PD at 3-4 years and 2-4 months post-SRP was similar. There was a positive correlation between PD and salivary IL-1ß (p = .005) but not with salivary CRP and IL-6. CONCLUSION: Higher flavonoid intake is associated with lower IL-1ß. Also, regular supportive periodontal therapy maintained the improved PD at 3-4 years post-SRP regardless of smoking status.

Self-reported access to health care, communicable diseases, violence and perception of legal status among online transgender identifying sex workers in the UK.

OBJECTIVES: Transgender-identifying sex workers (TGISWs) are among the most vulnerable groups but are rarely the focus of health research. Here we evaluated perceived barriers to healthcare access, risky sexual behaviours and exposure to violence in the United Kingdom (UK), based on a survey of all workers on BirchPlace, the main transgender sex commerce website in the UK. STUDY DESIGN: The study design used in the study is an opt-in text-message 12-item questionnaire. METHODS: Telephone contacts were harvested from BirchPlace's website (n = 592 unique and active numbers). The questionnaire was distributed with Qualtrics software, resulting in 53 responses. RESULTS: Our survey revealed significant reported barriers to healthcare access, exposure to risky sexual behaviours and to physical violence. Many transgender sex workers reportedly did not receive a sexual screening, and 28% engaged in condomless penetrative sex within the preceding six months, and 68% engaged in condomless oral sex. 17% responded that they felt unable to access health care they believed medically necessary. Half of the participants suggested their quality of life would be improved by law reform. CONCLUSIONS: TGISWs report experiencing a high level of risky sexual behaviour, physical violence and inadequate healthcare access. Despite a National Health System, additional outreach may be needed to ensure access to services by this population.

Exploring pre-surgery and post-surgery substance use disorder and alcohol use disorder in bariatric surgery: a qualitative scoping review.

INTRODUCTION: Bariatric surgery (BS) produces superior weight loss compared to non-surgical interventions. However, studies suggest bariatric patients who have undergone gastric-bypass surgery have an increased risk of developing new onset substance use disorder (SUD) or suffer negative outcomes after surgery. As such, many bariatric programs consider alcohol/ illicit drug misuse a contraindication to BS. The purpose of this systematic review was to investigate weight loss outcomes, post-surgery substance use patterns and other morbidity/mortality in BS patients with a history of substance use/SUD. METHODS: Studies were identified by searching Ovid Medline(R), Embase, and PsychInfo. We included all study types investigating humans of any age/sex who had undergone any BS procedure with data regarding substance use before and/or after surgery. Outcome measures included metabolic outcomes and psychiatric outcomes after bariatric surgery in patients reporting substance use prior to bariatric surgery and substance use patterns after bariatric surgery. RESULTS: Fifty-eight studies were included in the review. Studies reporting weight loss after BS did not demonstrate an association between substance use and negative weight loss outcomes. Several studies reported a significant portion of participants having new onset or increased substance use after BS. Factors associated with new onset or increased substance use/SUD after BS included the type of surgery, a history of SUD, a family history of SUD, coping skills/life stressors, age, male sex and alcohol sensitization after surgery. CONCLUSION: Substance use history does not appear to influence weight loss after BS, however it may contribute to increased substance use after BS. Clinicians should ensure valid screening tools when assessing BS candidates for substance use history and ensure long term follow-up care post-operatively.

Correction: Exploring pre-surgery and post-surgery substance use disorder and alcohol use disorder in bariatric surgery: a qualitative scoping review.

In the original Article, Leo Akioyamen's surname was misspelled as "Aikiyomen." This has been updated in the XML, PDF and HTML versions of this Article.