Noncentrosymmetric γ-Cs2I4O11 Obtained from IO4 Polyhedral Rearrangements in the Centrosymmetric ß-Phase.

We report the synthesis and optical properties of noncentrosymmetric (NCS) γ-Cs2I4O11 that was obtained through IO4 polyhedral rearrangements from centrosymmetric (CS) ß-Cs2I4O11. Trifluoroacetic acid (TFA) acts as a structure-directing agent and plays a key role in the synthesis. It is suggested that the function of TFA is to promote rearrangement reactions found in the organic synthesis of stereoisomers. γ-Cs2I4O11 crystallizes in the NCS monoclinic space group P21 (No. 4) and exhibits a strong second-harmonic-generation (SHG) response of 5.0 × KDP (KH2PO4) under 1064 nm laser radiation. Additional SHG experiments indicate that the material is type I phase matchable. First-principles calculations show that SHG intensity mainly comes from its d34, d21, and d23 SHG tensor components. The synthetic strategy of discovering γ-Cs2I4O11 provides a new way for designing novel NCS SHG materials.

First use of gene therapy to treat growth hormone resistant dwarfism in a mouse model.

The only treatment tested for growth hormone receptor (GHR) defective Laron Syndrome (LS) is injections of recombinant insulin-like-growth factor 1 (rhIGF1). The response is suboptimal and associated with progressive obesity. In this study, we treated 4-5-week-old Laron dwarf mice (GHR-/-) with an adeno-associated virus expressing murine GHR (AAV-GHR) injection at a dose of 4 × 1010 vector genome per mouse. Serum growth hormone (GH) levels decreased, and GH-responsive IGF1, IGF binding protein 3 (IGFBP3) and acid labile subunit (ALS) increased. There was a significant but limited increase in body weight and length, similar to the response to rhIGF1 treatment in LS patients. All the major organs increased in weight except the brain. Our study is the first to use gene therapy to treat GH-receptor deficiency. We propose that gene therapy with AAV-GHR may eventually be useful for the treatment of human LS.

Heteroanionic Control of Exemplary Second-Harmonic Generation and Phase Matchability in 1D LiAsS2-xSex.

The isostructural heteroanionic compounds ß-LiAsS2-xSex (x = 0, 0.25, 1, 1.75, 2) show a positive correlation between selenium content and second-harmonic response and greatly outperform the industry standard AgGaSe2. These materials crystallize in the noncentrosymmetric space group Cc as one-dimensional 1/∞ [AsQ2]- (Q = S, Se, S/Se) chains consisting of corner-sharing AsQ3 trigonal pyramids with charge-balancing Li+ atoms interspersed between the chains. LiAsS2-xSex melts congruently for 0 ≤ x ≤ 1.75, but when the Se content exceeds x = 1.75, crystallization is complicated by a phase transition. This behavior is attributed to the ß- to α-phase transition present in LiAsSe2, which is observed in the Se-rich compositions. The band gap decreases with increasing Se content, starting at 1.63 eV (LiAsS2) and reaching 1.06 eV (ß-LiAsSe2). Second-harmonic generation measurements as a function of wavelength on powder samples of ß-LiAsS2-xSex show that these materials exhibit significantly higher nonlinearity than AgGaSe2 (d36 = 33 pm/V), reaching a maximum of 61.2 pm/V for LiAsS2. In comparison, single-crystal measurements for LiAsSSe yielded a deff = 410 pm/V. LiAsSSe, LiAsS0.25Se1.75, and ß-LiAsSe2 show phase-matching behavior for incident wavelengths exceeding 3 µm. The laser-induced damage thresholds from two-photon absorption processes are on the same order of magnitude as AgGaSe2, with S-rich materials slightly outperforming AgGaSe2 and Se-rich materials slightly underperforming AgGaSe2.

Synthesis of the Candidate Topological Compound Ni3Pb2.

Spin-orbit coupling enables the realization of topologically nontrivial ground states. As spin-orbit coupling increases with increasing atomic number, compounds featuring heavy elements, such as lead, offer a pathway toward creating new topologically nontrivial materials. By employing a high-pressure flux synthesis method, we synthesized single crystals of Ni3Pb2, the first structurally characterized bulk binary phase in the Ni-Pb system. Combining experimental and theoretical techniques, we examined structure and bonding in Ni3Pb2, revealing the impact of chemical substitutions on electronic structure features of importance for controlling topological behavior. From these results, we determined that Ni3Pb2 completes a series of structurally related transition-metal-heavy main group intermetallic materials that exhibit diverse electronic structures, opening a platform for synthetically tunable topologically nontrivial materials.

Growth Hormone Stops Excessive Inflammation After Partial Hepatectomy, Allowing Liver Regeneration and Survival Through Induction of H2-Bl/HLA-G.

BACKGROUND AND AIMS: Growth hormone (GH) is important for liver regeneration after partial hepatectomy (PHx). We investigated this process in C57BL/6 mice that express different forms of the GH receptor (GHR) with deletions in key signaling domains. APPROACH AND RESULTS: PHx was performed on C57BL/6 mice lacking GHR (Ghr-/- ), disabled for all GH-dependent Janus kinase 2 signaling (Box1-/- ), or lacking only GH-dependent signal transducer and activator of transcription 5 (STAT5) signaling (Ghr391-/- ), and wild-type littermates. C57BL/6 Ghr-/- mice showed striking mortality within 48 hours after PHx, whereas Box1-/- or Ghr391-/- mice survived with normal liver regeneration. Ghr-/- mortality was associated with increased apoptosis and elevated natural killer/natural killer T cell and macrophage cell markers. We identified H2-Bl, a key immunotolerance protein, which is up-regulated by PHx through a GH-mediated, Janus kinase 2-independent, SRC family kinase-dependent pathway. GH treatment was confirmed to up-regulate expression of the human homolog of H2-Bl (human leukocyte antigen G [HLA-G]) in primary human hepatocytes and in the serum of GH-deficient patients. We find that injury-associated innate immune attack by natural killer/natural killer T cell and macrophage cells are instrumental in the failure of liver regeneration, and this can be overcome in Ghr-/- mice by adenoviral delivery of H2-Bl or by infusion of HLA-G protein. Further, H2-Bl knockdown in wild-type C57BL/6 mice showed elevated markers of inflammation after PHx, whereas Ghr-/- backcrossed on a strain with high endogenous H2-Bl expression showed a high rate of survival following PHx. CONCLUSIONS: GH induction of H2-Bl expression is crucial for reducing innate immune-mediated apoptosis and promoting survival after PHx in C57BL/6 mice. Treatment with HLA-G may lead to improved clinical outcomes following liver surgery or transplantation.

Structure Tuning, Strong Second Harmonic Generation Response, and High Optical Stability of the Polar Semiconductors Na1-xKxAsQ2.

The mixed cation compounds Na1-xKxAsSe2 (x = 0.8, 0.65, 0.5) and Na0.1K0.9AsS2 crystallize in the polar noncentrosymmetric space group Cc. The AAsQ2 (A = alkali metals, Q = S, Se) family features one-dimensional (1D) 1/∞[AQ2-] chains comprising corner-sharing pyramidal AQ3 units in which the packing of these chains is dependent on the alkali metals. The parallel 1/∞[AQ2-] chains interact via short As···Se contacts, which increase in length when the fraction of K atoms is increased. The increase in the As···Se interchain distance increases the band gap from 1.75 eV in γ-NaAsSe2 to 2.01 eV in Na0.35K0.65AsSe2, 2.07 eV in Na0.2K0.8AsSe2, and 2.18 eV in Na0.1K0.9AsS2. The Na1-xKxAsSe2 (x = 0.8, 0.65) compounds melt congruently at approximately 316 °C. Wavelength-dependent second harmonic generation (SHG) measurements on powder samples of Na1-xKxAsSe2 (x = 0.8, 0.65, 0.5) and Na0.1K0.9AsS2 suggest that Na0.2K0.8AsSe2 and Na0.1K0.9AsS2 have the highest SHG response and exhibit significantly higher laser-induced damage thresholds (LIDTs). Theoretical SHG calculations on Na0.5K0.5AsSe2 confirm its SHG response with the highest value of d33 = 22.5 pm/V (χ333(2) = 45.0 pm/V). The effective nonlinearity for a randomly oriented powder is calculated to be deff = 18.9 pm/V (χeff(2) = 37.8 pm/V), which is consistent with the experimentally obtained value of deff = 16.5 pm/V (χeff(2) = 33.0 pm/V). Three-photon absorption is the dominant mechanism for the optical breakdown of the compounds under intense excitation at 1580 nm, with Na0.2K0.8AsSe2 exhibiting the highest stability.

Dabigatran Reversal Before Intravenous Tenecteplase in Acute Ischemic Stroke.

Background and Purpose- Reversal of dabigatran before intravenous thrombolysis in patients with acute ischemic stroke has been well described using alteplase but experience with intravenous tenecteplase is limited. Tenecteplase seems at least noninferior to alteplase in patients with intracranial large vessel occlusion. We report on the experience of dabigatran reversal before tenecteplase thrombolysis for acute ischemic stroke. Methods- We included consecutive patients with ischemic stroke receiving dabigatran prestroke treated with intravenous tenecteplase after receiving idarucizumab. Patients were from 2 centers in New Zealand and Australia. We reported the clinical, laboratory, and radiological characteristics and their functional outcome. Results- We identified 13 patients receiving intravenous tenecteplase after dabigatran reversal. Nine (69%) were male, median age was 79 (interquartile range, 69-85) and median baseline National Institutes of Health Stroke Scale score was 6 (interquartile range, 4-21). Atrial fibrillation was the indication for dabigatran therapy in all patients. All patients had a prolonged thrombin clotting time (median, 80 seconds [interquartile range, 57-113]). Seven patients with large vessel occlusion were referred for endovascular thrombectomy, 2 of these patients (29%) had early recanalization with tenecteplase abrogating thrombectomy. No patients had parenchymal hemorrhage or symptomatic hemorrhagic transformation. Favorable functional outcome (modified Rankin Scale score, 0-2) occurred in 8 (62%) patients. Two deaths occurred from large territory infarction. Conclusions- Our experience suggests intravenous thrombolysis with tenecteplase following dabigatran reversal using idarucizumab may be safe in selected patients with acute ischemic stroke. Further studies are required to more precisely estimate the efficacy and risk of clinically significant hemorrhage.

Loss of growth hormone-mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity.

Growth hormone (GH) has an important function as an insulin antagonist with elevated insulin sensitivity evident in humans and mice lacking a functional GH receptor (GHR). We sought the molecular basis for this sensitivity by utilizing a panel of mice possessing specific deletions of GHR signaling pathways. Metabolic clamps and glucose homeostasis tests were undertaken in these obese adult C57BL/6 male mice, which indicated impaired hepatic gluconeogenesis. Insulin sensitivity and glucose disappearance rate were enhanced in muscle and adipose of mice lacking the ability to activate the signal transducer and activator of transcription (STAT)5 via the GHR (Ghr-391-/-) as for GHR-null (GHR-/-) mice. These changes were associated with a striking inhibition of hepatic glucose output associated with altered glycogen metabolism and elevated hepatic glycogen content during unfed state. The enhanced hepatic insulin sensitivity was associated with increased insulin receptor ß and insulin receptor substrate 1 activation along with activated downstream protein kinase B signaling cascades. Although phosphoenolpyruvate carboxykinase (Pck)-1 expression was unchanged, its inhibitory acetylation was elevated because of decreased sirtuin-2 expression, thereby promoting loss of PCK1. Loss of STAT5 signaling to defined chromatin immunoprecipitation targets would further increase lipogenesis, supporting hepatosteatosis while lowering glucose output. Finally, up-regulation of IL-15 expression in muscle, with increased secretion of adiponectin and fibroblast growth factor 1 from adipose tissue, is expected to promote insulin sensitivity.-Chhabra, Y., Nelson, C. N., Plescher, M., Barclay, J. L., Smith, A. G., Andrikopoulos, S., Mangiafico, S., Waxman, D. J., Brooks, A. J., Waters, M. J. Loss of growth hormone-mediated signal transducer and activator of transcription 5 (STAT5) signaling in mice results in insulin sensitivity with obesity.

JAK2 activation by growth hormone and other cytokines.

Growth hormone (GH) and structurally related cytokines regulate a great number of physiological and pathological processes. They do this by coupling their single transmembrane domain (TMD) receptors to cytoplasmic tyrosine kinases, either as homodimers or heterodimers. Recent studies have revealed that many of these receptors exist as constitutive dimers rather than being dimerized as a consequence of ligand binding, which has necessitated a new paradigm for describing their activation process. In the present study, we describe a model for activation of the tyrosine kinase Janus kinase 2 (JAK2) by the GH receptor homodimer based on biochemical data and molecular dynamics simulations. Binding of the bivalent ligand reorientates and rotates the receptor subunits, resulting in a transition from a form with parallel TMDs to one where the TMDs separate at the point of entry into the cytoplasm. This movement slides the pseudokinase inhibitory domain of one JAK kinase away from the kinase domain of the other JAK within the receptor dimer-JAK complex, allowing the two kinase domains to interact and trans-activate. This results in phosphorylation and activation of STATs and other signalling pathways linked to this receptor which then regulate postnatal growth, metabolism and stem cell activation. We believe that this model will apply to most if not all members of the class I cytokine receptor family, and will be useful in the design of small antagonists and agonists of therapeutic value.

Intrinsically disordered cytoplasmic domains of two cytokine receptors mediate conserved interactions with membranes.

Class 1 cytokine receptors regulate essential biological processes through complex intracellular signalling networks. However, the structural platform for understanding their functions is currently incomplete as structure-function studies of the intracellular domains (ICDs) are critically lacking. The present study provides the first comprehensive structural characterization of any cytokine receptor ICD and demonstrates that the human prolactin (PRL) receptor (PRLR) and growth hormone receptor (GHR) ICDs are intrinsically disordered throughout their entire lengths. We show that they interact specifically with hallmark lipids of the inner plasma membrane leaflet through conserved motifs resembling immuno receptor tyrosine-based activation motifs (ITAMs). However, contrary to the observations made for ITAMs, lipid association of the PRLR and GHR ICDs was shown to be unaccompanied by changes in transient secondary structure and independent of tyrosine phosphorylation. The results of the present study provide a new structural platform for studying class 1 cytokine receptors and may implicate the membrane as an active component regulating intracellular signalling.

Smg1 haploinsufficiency predisposes to tumor formation and inflammation.

SMG1 is a member of the phosphoinositide kinase-like kinase family of proteins that includes ATM, ATR, and DNA-PK, proteins with known roles in DNA damage and cellular stress responses. SMG1 has a well-characterized role in nonsense-mediated decay as well as suggested roles in the DNA damage response, resistance to oxidative stress, regulation of hypoxic responses, and apoptosis. To understand the roles of SMG1 further, we generated a Genetrap Smg1 mouse model. Smg1 homozygous KO mice were early embryonic lethal, but Smg1 heterozygous mice showed a predisposition to a range of cancers, particularly lung and hematopoietic malignancies, as well as development of chronic inflammation. These mice did not display deficiencies in known roles of SMG1, including nonsense-mediated decay. However, they showed elevated basal tissue and serum cytokine levels, indicating low-level inflammation before the development of tumors. Smg1 heterozygous mice also showed evidence of oxidative damage in tissues. These data suggest that the inflammation observed in Smg1 haploinsufficiency contributes to susceptibility to cancer and that Smg1-deficient animals represent a model of inflammation-enhanced cancer development.

Headless bone screw fixation for combined volar lunate facet distal radius fracture and capitate fracture: case report.

We report a case of concomitant fractures of the volar lunate facet of the distal radius and capitate body. Surgical fixation was achieved with open reduction internal fixation using headless compression screws for both fractures. Because of the nature of complications seen after both operative and nonsurgical management, these fractures warrant particular attention.

The multiple roles of GH in neural ageing and injury.

Advanced age is typically associated with a decrease in cognitive function including impairment in the formation and retention of new memories. The hippocampus is critical for learning and memory, especially spatial learning, and is particularly affected by ageing. With advanced age, multiple neural components can be detrimentally affected including a reduction in the number of neural stem and precursor cells, a decrease in the formation of adult born neurons (neurogenesis), and deficits in neural circuitry, all of which ultimately contribute to impaired cognitive function. Importantly, physical exercise has been shown to ameliorate many of these impairments and is able to improve learning and memory. Relevantly, growth hormone (GH) is an important protein hormone that decreases with ageing and increases following physical exercise. Originally described due to its role in longitudinal growth, GH has now been identified to play several additional key roles, especially in relation to the brain. Indeed, the regular decrease in GH levels following puberty is one of the most well documented components of neuroendocrine ageing. Growth hormone deficiency (GHD) has been described to have adverse effects on brain function, which can be ameliorated via GH replacement therapy. Physical exercise has been shown to increase circulating GH levels. Furthermore, we recently demonstrated the increase in exercise-mediated GH is critical for improved cognitive function in the aged mouse. Here we examine the multiple roles that GH plays, particularly in the aged brain and following trauma, irradiation and stroke, and how increasing GH levels can ameliorate deficits in cognition.

Safety and feasibility of the Wahoo Hybrid Access System, a dual-mode guide catheter, in a range of neuroendovascular procedures.

BACKGROUND: There is a clinical need for a guide catheter with combined stability and navigability, which can be used in a biaxial system for neuroendovascular procedures in place of triaxial systems. OBJECTIVE: To assess the safety and feasibility of the Q'Apel Medical Wahoo Hybrid Access System, a dual-mode 0.072″ internal diameter guide catheter, in a range of neuroendovascular procedures. METHODS: We performed a retrospective analysis of consecutive cases from a high-volume tertiary center in which the Wahoo Hybrid Access System was used as the guide catheter. Characteristics of the patients, vascular lesions, procedure, and procedural complications were assessed. RESULTS: A total of 102 patients were included for analysis. Vascular lesions were in the anterior circulation in 90 of 102 (88%), and posterior circulation in 12 of 102 (12%). Eighty-four cases were ruptured or unruptured aneurysm embolization procedures, the majority being balloon-assisted coiling (42%) and flow diversion (42%). All cases, including flow diversion, were performed as a biaxial system. There were no instances of prolapse of the catheter beyond the arterial segment in which it was initially placed. The procedure was able to be performed to completion in 101 of 102 (99%) cases. Thromboembolic complications occurred in 5 of 102 (5%); causality in two cases was unrelated to the guide catheter, and three were indeterminate. CONCLUSIONS: The Wahoo guide catheter is safe and feasible when used in a variety of neuroendovascular procedures. It can accommodate a range of devices, can be safely navigated into distal vasculature, and provides support for a range of procedures, including those which traditionally require triaxial support.

Safety and efficacy of eptifibatide in acute ischemic stroke requiring extracranial carotid artery stenting.

BACKGROUND: The antiplatelet management in acute ischemic stroke requiring carotid artery stenting is heterogenous, with no clear guidelines to direct management. OBJECTIVE: To evaluate the safety and efficacy of an intravenous eptifibatide protocol in the management of acute ischemic stroke requiring emergent carotid artery stenting. METHODS: We performed a retrospective analysis of consecutive patients who underwent carotid artery stenting for acute ischemic stroke at a high-volume tertiary neuroscience center, who were managed with an intravenous eptifibatide protocol. The protocol consists of an intravenous loading eptifibatide bolus (180 mcg/kg) at the time of stenting, followed by a maintenance infusion of 1 mcg/kg/min, then oral or nasogastric loading of dual antiplatelet agents. RESULTS: 80 patients were included for analysis. Median presenting NIHSS was 17. Sixty-six patients (83%) had a tandem intracranial occlusion. Six (7.5%) patients developed symptomatic intracranial hemorrhage (sICH). Those who received intravenous thrombolysis were not more likely to develop sICH (10% vs 5%, p = 0.40). Those patients with a presenting ASPECTS <8 were significantly more likely to develop sICH than those with ASPECTS 8-10 (25% vs 3%, p = 0.004). CONCLUSIONS: Eptifibatide may have a role in the management of acute stroke requiring carotid stenting. Caution may be required in those with established infarct on presentation imaging.

Tyrosine kinases compete for growth hormone receptor binding and regulate receptor mobility and degradation.

Growth hormone (GH) acts via JAK2 and LYN to regulate growth, metabolism, and neural function. However, the relationship between these tyrosine kinases remains enigmatic. Through an interdisciplinary approach combining cell biology, structural biology, computation, and single-particle tracking on live cells, we find overlapping LYN and JAK2 Box1-Box2-binding regions in GH receptor (GHR). Our data implicate direct competition between JAK2 and LYN for GHR binding and imply divergent signaling profiles. We show that GHR exhibits distinct mobility states within the cell membrane and that activation of LYN by GH mediates GHR immobilization, thereby initiating its nanoclustering in the membrane. Importantly, we observe that LYN mediates cytokine receptor degradation, thereby controlling receptor turnover and activity, and this applies to related cytokine receptors. Our study offers insight into the molecular interactions of LYN with GHR and highlights important functions for LYN in regulating GHR nanoclustering, signaling, and degradation, traits broadly relevant to many cytokine receptors.

Investigating potential mechanisms of obesity by metabolomics.

Obesity is a serious health problem with an increased risk of several common diseases including diabetes, cardiovascular disease, and cancer. Metabolomics is an emerging analytical technique for systemic determination of metabolite profiles, which is useful for understanding the biochemical changes in obesity or related diseases both in individual organs and at the organism level. Increasingly, this technology has been applied to the study of obesity, complementing transcriptomics and/or proteomics analyses. Indeed, the alterations of metabolites in biofluids/tissues are direct indicators of variations in physiology or pathology. In this paper, we will examine the obesity-related alterations in significant metabolites that have been identified by metabolomics as well as their metabolic pathway associations. Issues concerning the screening of biologically significant metabolites related to obesity will also be discussed.