Small Beta Research Articles

Phase 1/2 study of elraglusib (9-ING-41), a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, alone or with irinotecan, temozolomide/irinotecan or cyclophosphamide/topotecan in pediatric patients with refractory malignancies: Interim results.

e22015 Background: GSK-3β overexpression is associated with aggressive malignancies, treatment resistance and poor prognosis. The GSK-3β inhibitor Elraglusib induces apoptosis via NFΚB and p53 pathways and has potent anti-fibrotic and immunomodulatory activity. Adult studies of elraglusib demonstrate clinical activity in pancreatic cancer, melanoma, lymphoma and sarcoma as a single agent or in combination with cytotoxic chemotherapy. Elraglusib is active in in vivo models of neuroblastoma (NBL) and malignant glioma. This first-in-pediatrics study (NCT04239092) is evaluating the safety, pharmacokinetics (PK), and efficacy of elraglusib monotherapy and in combination with chemotherapy in patients with refractory malignancies. Methods: Elraglusib is given intravenously (IV) twice-weekly at 3 dose levels (DL) (9.3, 12.4 and 15 mg/kg) as a single agent or in combination with irinotecan, cyclophosphamide/topotecan or temozolomide/irinotecan in 21-day cycles. A cohort of pts with refractory NBL will be treated at the recommended phase 2 dose (RP2D) of elraglusib with temozolomide/irinotecan. Results: As of January 2022, 23 pts (n = 7 female, median age 14.2 years) have received at least one dose of elraglusib. Tumor types: 5 NBL, 3 diffuse midline glioma (DMG), 3 osteosarcoma (OS), 3 ependymoma (EP), 2 alveolar rhabdomyosarcoma (aRMS), 1 angiosarcoma (AS), 1 Ewing sarcoma (ES), 1 glioblastoma (GBM), 1 hepatoblastoma (HB), 1 embryonal CNS tumor NOS, 1 NUT midline carcinoma, 1 pineoblastoma (PB). Median time from diagnosis is 26 months (range: 6.7 – 156.3) and median number of lines of prior systemic therapy is 2 (range 0-14). Two DLs of single agent (6 pts) have been completed (9.3 and 12.4 mg/kg) without elraglusib-attributable severe adverse events (SAEs). Of the 15 patients on the combination arm with irinotecan or cyclophosphamide/topotecan, a single adverse event (Grade 4 hypotension/infusion reaction) was reported. Grade 1/2 elraglusib attributable-AEs include: transient visual change (n = 10), nausea (n = 7), vomiting (n = 6), fatigue (n = 2), hypotension (n = 2) and infusion reaction (n = 1). One pt with recurrent ES had a radiographic and pathologic CR after 3 cycles of elraglusib/cyclophosphamide/topotecan. 6 pts (26.1%) had SD (2 NBL, 1 aRMS, 1 EP, 1 OS, 1 GBM). 8 pts (35%) remained on study treatment ≥ 3 months (2 NBL, 2 EP, 1 OS, 1 aRMS, 1 ES, 1 PB). Median treatment duration was 40 days (range 1 - 126). 4 pts remain on therapy. Conclusions: Elraglusib is well tolerated as a single agent and with several chemotherapy regimens in this heavily pretreated pediatric population with refractory cancers. It has encouraging antitumor activity, with 1 CR in a patient with recurrent ES. Enrollment is ongoing; a RPD2 has not been reached. Clinical trial information: NCT04239092.

De novo design of small beta barrel proteins

De novo design of small beta barrel proteins

Beam loss study for the implementation of corrugated structure at the European XFEL

The European XFEL is a free-electron laser facility based on superconducting linac with high repetition rate of up to 4.5 MHz. A corrugated structure is planned to be installed in front of the SASE beam line at the European XFEL, which can be used as a kicker for fresh-slice schemes or a dechirper to control the bandwidth of SASE radiation. When the beam passes through the corrugated structure module, strong longitudinal and transverse wakefields can be excited to introduce a correlated energy chirp and/or a kick along the bunch. However, due to the relatively small gap of the corrugated structure, beam halo particles experience large betatron oscillations after hitting the corrugated structure, which can lead to energy deposition in the undulator beam line. This may cause demagnetization of the undulators especially at high repetition rate. For this reason, we have performed beam loss simulations using BDSIM for two different configurations: double-plate corrugated structure with nominal FODO optics and single-plate corrugated structure with small beta optics. Our simulation results showed that the latter configuration can help us not only to relax the tolerance on beam halo extension, but also to reduce the peak radiation doses by more than factor 2. Besides, the possibility of adding a collimator downstream of the corrugated structure has also been studied, which can further help us to reduce the loss in the downstream cells by factor 100.

Brain Health and the EEG: Toward Personalized Anesthesia Care for Older Patients

Your Patient's Brain| May 2022 Brain Health and the EEG: Toward Personalized Anesthesia Care for Older Patients Patrick L. Purdon, PhD; Patrick L. Purdon, PhD Search for other works by this author on: This Site PubMed Google Scholar Daniel J. Cole, MD, FASA Daniel J. Cole, MD, FASA Search for other works by this author on: This Site PubMed Google Scholar ASA Monitor May 2022, Vol. 86, 1–9. https://doi.org/10.1097/01.ASM.0000830784.65419.6c Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn MailTo Cite Icon Cite Get Permissions Search Site Citation Patrick L. Purdon, Daniel J. Cole; Brain Health and the EEG: Toward Personalized Anesthesia Care for Older Patients. ASA Monitor 2022; 86:1–9 doi: https://doi.org/10.1097/01.ASM.0000830784.65419.6c Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll PublicationsASA Monitor Search Advanced Search Topics: anesthesia care, brain, electroencephalography, older adult The brain under anesthesia is a marvel to behold. Although the electroencephalogram (EEG) is not a routine part of clinical anesthesia care, there is growing evidence that readily visible changes in the anesthesia-induced EEG are intimately linked to perioperative brain health. Induction of general anesthesia with propofol produces stereotyped oscillations or waves in the EEG that change form in a dose-dependent manner related to the patient's state of consciousness (Anesthesiology 2015;123:937-60). After administering an induction dose of propofol, as a patient becomes sedated, the EEG begins to show small beta oscillations, which alternate at a frequency between 12 to 25 cycles per second (Hz). Soon after, when the patient loses consciousness, a combination of alpha (8 to 12 Hz) and slow (~0.5 to 1 Hz) oscillations develop (PNAS 2013;110:E1142-51). Beyond this point, if the propofol concentration continues to rise, burst suppression may develop, characterized by flat... You do not currently have access to this content.

Prediction of Fluorophore Brightness in Designed Mini Fluorescence Activating Proteins

The de novo computational design of proteins with predefined three-dimensional structure is becoming much more routine due to advancements both in force fields and algorithms. However, creating designs with functions beyond folding is more challenging. In that regard, the recent design of small beta barrel proteins that activate the fluorescence of an exogenous small molecule chromophore (DFHBI) is noteworthy. These proteins, termed mini fluorescence activating proteins (mFAPs), have been shown to increase the brightness of the chromophore more than 100-fold upon binding to the designed ligand pocket. The design process created a large library of variants with different brightness levels but gave no rational explanation for why one variant was brighter than another. Here, we use quantum mechanics and molecular dynamics simulations to investigate how molecular flexibility in the ground and excited states influences brightness. We show that the ability of the protein to resist dihedral angle rotation of the chromophore is critical for predicting brightness. Our simulations suggest that the mFAP/DFHBI complex has a rough energy landscape, requiring extensive ground-state sampling to achieve converged predictions of excited-state kinetics. While computationally demanding, this roughness suggests that mFAP protein function can be enhanced by reshaping the energy landscape toward conformations that better resist DFHBI bond rotation.

Penilaian returns investasi saham dengan Augmented Three Factor model pada kondisi political uncertainty di Indonesia

This study aims to analyze the market factor portfolio beta, small minus big portfolio beta, high minus low portfolio beta, market volatility beta portfolio effect on investment returns with the Fama and French augmented three factor model in the manufacturing industry under conditions of political uncertainty. This research is a quantitative research with the hypothesis that there is an effect of market factor portfolio beta, small minus big portfolio beta, high minus low beta portfolio, market volatility beta portfolio on investment returns with the Fama and French augmented three factor model in the manufacturing industry under political conditions uncertainty. The variables used in this study include the dependent variable, namely investment returns and the independent variables include market factor portfolio beta, small minus big beta portfolio, high minus low portfolio beta, market volatility portfolio beta. The measurement results with small minus big and market volatility have an effect on stock returns, while high minus low and market factors have no effect on investment returns. This study only focuses on the assessment of investment returns with the augmented three factor model of the Fama and French models, so for future researchers it would be better if they could use another model as a comparison.

Development of amyloid beta gold nanorod aggregates as optoacoustic probes.

Propagation of small amyloid beta (Aβ) aggregates (or seeds) has been suggested as a potential mechanism of Alzheimer’s disease progression. Monitoring the propagation of Aβ seeds in an organism would enable testing of this hypothesis and, if confirmed, provide mechanistic insights. This requires a contrast agent for long-term tracking of the seeds. Gold nanorods combine several attractive features for this challenging task, in particular, their strong absorbance in the infrared (enabling optoacoustic imaging) and the availability of several established protocols for surface functionalisation. In this work, polymer-coated gold nanorods were conjugated with anti-Aβ antibodies and attached to pre-formed Aβ seeds. The resulting complexes were characterised for their optical properties by UV/Vis spectroscopy and multispectral optoacoustic tomography. The complexes retained their biophysical properties, i.e. their ability to seed Aβ fibril formation. They remained stable in biological media for at least 2 days and showed no toxicity to SH-SY5Y neuroblastoma cells up to 1.5 nM and 6 μM of gold nanorods and Aβ seeds, respectively. Taken together, this study describes the first steps in the development of probes for monitoring the spread of Aβ seeds in animal models.

Maternal lipid profiles vs. fetal growth and cord blood hematopoietic cells: weak associations in healthy Korean newborn-mother pairs.

We aimed to define the maternal lipid profiles that are associated with fetal growth and cord blood (CB) hematopoietic cells in healthy Korean full-term newborns. A total of 608 fetal-maternal pairs were enrolled; mothers voluntarily donated CB with informed consent. We analyzed birth weight (BW) as a marker of fetal growth, and we examined total nucleated cells (TNCs) and CD34+ cell concentrations of CB as markers of hematopoietic progenitor cell (HPC) contents. We also analyzed maternal lipid levels and investigated their associations with BW, TNCs and CD34+ cells. Maternal triglycerides (TG) showed a significant positive association with BW and CD34+ cells, and low-density lipoprotein (LDL) showed a negative association with BW and CD34+ cells. Though not statistically significant, higher maternal TG showed a tendency toward higher levels of TNCs. Maternal TG was independently and positively correlated with BW, and maternal LDL was independently and negatively correlated with CD34+ cells, although the impacts were not as strong, as indicated by small beta coefficients (0.157 and -0.226, respectively). We were able to investigate the association of maternal lipid profiles with BW and CB HPCs in healthy Korean newborn-mother pairs in this study. Both BW and the HPC contents showed independent associations with maternal TG and LDL, although the effect of maternal lipid levels on fetal growth and HPCs was not strong in the normal healthy population. Because maternal lipid levels were assessed once in the healthy fetal-maternal pairs, we could not investigate those associations across pregnancy.

Phase 2 study of 9-ING-41, a small molecule selective glycogen synthase kinase-3 beta (GSK-3β) inhibitor, with gemcitabine/nab-paclitaxel (GnP) in first-line advanced pancreatic ductal adenocarcinoma (PDAC).

578 Background: GSK-3β overexpression is associated with worse prognosis and chemotherapy resistance in PDAC. GSK-3β inhibition reverses chemotherapy-resistance by inhibiting chemotherapy-induced, ATR-mediated, DNA damage response. 9-ING-41 has significant anti-tumor activity through apoptosis induction, anti-fibrotic activity and NK/T-cell effector stimulation. We hypothesized that 9-ING-41 in combination with GnP chemotherapy would lead to anti-tumor activity, with improved tumor responses in patients with advanced PDAC in the first line setting. Methods: Primary endpoint is disease control rate (DCR). DCR = confirmed complete response (CR), partial response (PR), or stable disease (SD) ≥ 16 weeks (wks). Secondary endpoints are safety and ORR (overall response rates). Eligibility: Advanced PDAC, ECOG PS 0-2, no prior therapy in the metastatic setting and no systemic therapy in prior 6 months. Pts received 9-ING-41 15mg/kg IV twice-weekly with G 1,000 mg/m2 and nP 125 mg/m2 on days 1,8,15 of a 28-day cycle. Simon 2-Stage Design for DCR of 65% and null hypothesis of 50% (historical control), 80% power and 2 sided-significance level of.05. Up to 23 fully evaluable pts planned for stage 1 and if ≥ 12 evaluable patients achieve a DCR 37 additional pts will be enrolled on a second stage or a randomized study commenced. Results: As of Sept 27, 2021, 42 pts enrolled. Median age: 67. 24 females, 18 males. 38 pts with metastatic and 4 with locally advanced disease. Prior adjuvant therapy: 4 pts each FOLFIRINOX and gemcitabine-based. No 9-ING-41-attributable SAEs to date. 9-ING-41 attributed AEs: visual disturbance: 24 (75%) G1/2, 1 (3%) G3; infusion reactions 9 (28%) G1/2. Chemotherapy-related AEs: anemia 13 (40%) G1/2, 1 (3%) G3; neutropenia 2 (6%) G1/2, 13 (40%) G3/4; thrombocytopenia 9 (28%) G1/2, 2 (6%) G3/4; diarrhea 8 (25%) G1/2, 4 (13%) G3; fatigue 9 (28%) G1/2, 3 (9%) G3; nausea/vomiting 24 (75%) G1/2, 1 (3%) G3; constipation 9 (28%) G1/2; febrile neutropenia 5 (16%) G3/4. In 21 pts currently evaluable for response, DCR was 62% and ORR 43%. There were 2 confirmed CRs, 6 confirmed and 1 unconfirmed PRs, 4 SD and 8 disease progressions were observed. Amongst responder’s median duration of response has not yet been reached. Conclusions: 9-ING-41 plus GnP demonstrated encouraging clinical activity but chemotherapy-related AEs were significant. Based on efficacy data to date, including confirmed CRs, we have commenced a randomized phase 2 study, evaluating 9-ING-41 plus GnP vs Gn P alone. Enrollment to the randomized study is now open (NCT03678883). Clinical trial information: NCT03678883.

A seven-bend-achromat lattice option for the HALF storage ring

The Hefei Advanced Light Facility (HALF) is a soft X-ray diffraction-limited storage ring being designed with an energy of about 2.2 GeV and an emittance goal of less than 100 pm·rad. The present HALF lattice is a modified hybrid six-bend-achromat (6BA) lattice with a long and a short straight section in each cell. In this paper, a 7BA lattice is designed for HALF as a promising option, which follows the main feature of hybrid 7BA lattice, but to have a compact configuration and lower emittance, all bends in this lattice are combined-function bends and reverse bends. The designed HALF storage ring has a circumference of 388.8 m and 20 identical cells. Two solutions with different betatron tunes are studied for this lattice. One with smaller tunes has better nonlinear dynamics performance allowing for off-axis injection, which has a natural emittance of 67 pm·rad. The other with larger tunes has very small beta functions at the straight section as well as lower natural emittance of 59 pm·rad, which can enhance the brightness of insertion device (ID) radiation. The intra-beam scattering effect and ID radiation properties are also presented in this paper.

Furfural acetalization with ethanol over conventional and hierarchical beta zeolites

Hierarchical and conventional beta zeolites were tested in the acetalization of furfural with ethanol. Application of the synthesized hierarchical material consisting of fused small beta crystallites (20 nm) in the studied reaction leads to the formation of furfural diethyl acetal with the highest yield (77%). The highest catalytic activity of the hierarchical material compared to the conventional ones in terms of the initial reaction rate and TON values is associated with its lower acidity and developed mesoporosity (Vmeso 0.71 cm3/g) facilitating the diffusion of the reagent to and from the active sites.

Dothidea kunmingensis, a novel asexual species of Dothideaceae on Jasminum nudiflorum (winter jasmine) from Southwestern China

During a survey of saprobic microfungi in Southwest China, a coelomycetous fungus was found on dead twigs of Jasminum nudiflorum in Kunming, Yunnan Province. Based on a detailed morphological characterization coupled with multi-locus phylogenetic analyses, the fungus was identified as a new species in the genus Dothidea. Phylogenetic analyses using a combined matrix consisting of internal transcribed spacer (ITS), large subunit rRNA (LSU), small subunit rRNA (SSU), beta tubulin (tub2) and translation elongation factor-1 alpha (tef1-α) confirmed its placement in Dothideaceae and revealed a sister relationship to Dothidea eucalypti. The new species is characterized by pycnidial conidiomata, ampulliform or doliiform conidiogenous cells as well as aseptate, subglobose to ovoid, hyaline to pale-brown conidia. Comprehensive descriptions and illustrations are provided. Morphological characteristics of asexual morph taxa in Dothideaceae are also summarized and discussed.

Platelet Endothelial Cell Adhesion Molecule 1 (CD31) Is Essential for Clostridium perfringens Beta-Toxin Mediated Cytotoxicity in Human Endothelial and Monocytic Cells.

Beta toxin (CPB) is a small hemolysin beta pore-forming toxin (β-PFT) produced by Clostridium perfringens type C. It plays a central role in the pathogenesis of necro-hemorrhagic enteritis in young animals and humans via targeting intestinal endothelial cells. We recently identified the membrane protein CD31 (PECAM-1) as the receptor for CPB on mouse endothelial cells. We now assess the role of CD31 in CPB cytotoxicity against human endothelial and monocytic cells using a CRISPR/Cas9 gene knockout and an antibody blocking approach. CD31 knockout human endothelial and monocytic cells were resistant to CPB and CPB oligomers only formed in CD31-expressing cells. CD31 knockout endothelial and monocytic cells could be selectively enriched out of a polyclonal cell population by exposing them to CPB. Moreover, antibody mediated blocking of the extracellular Ig6 domain of CD31 abolished CPB cytotoxicity and oligomer formation in endothelial and monocytic cells. In conclusion, this study confirms the role of CD31 as a receptor of CPB on human endothelial and monocytic cells. Specific interaction with the CD31 molecule can thus explain the cell type specificity of CPB observed in vitro and corresponds to in vivo observations in naturally diseased animals.

The Stimulatory Effects of Intracellular α-Synuclein on Synaptic Transmission Are Attenuated by 2-Octahydroisoquinolin-2(1H)-ylethanamine.

α-Synuclein (αSyn) species can be detected in synaptic boutons, where they play a crucial role in the pathogenesis of Parkinson’s Disease (PD). However, the effects of intracellular αSyn species on synaptic transmission have not been thoroughly studied. Here, using patch-clamp recordings in hippocampal neurons, we report that αSyn oligomers (αSynO), intracellularly delivered through the patch electrode, produced a fast and potent effect on synaptic transmission, causing a substantial increase in the frequency, amplitude and transferred charge of spontaneous synaptic currents. We also found an increase in the frequency of miniature synaptic currents, suggesting an effect located at the presynaptic site of the synapsis. Furthermore, our in silico approximation using docking analysis and molecular dynamics simulations showed an interaction between a previously described small anti-amyloid beta (Aβ) molecule, termed M30 (2-octahydroisoquinolin-2(1H)-ylethanamine), with a central hydrophobic region of αSyn. In line with this finding, our empirical data aimed to obtain oligomerization states with thioflavin T (ThT) and Western blot (WB) indicated that M30 interfered with αSyn aggregation and decreased the formation of higher-molecular-weight species. Furthermore, the effect of αSynO on synaptic physiology was also antagonized by M30, resulting in a decrease in the frequency, amplitude, and charge transferred of synaptic currents. Overall, the present results show an excitatory effect of intracellular αSyn low molecular-weight species, not previously described, that are able to affect synaptic transmission, and the potential of a small neuroactive molecule to interfere with the aggregation process and the synaptic effect of αSyn, suggesting that M30 could be a potential therapeutic strategy for synucleinopathies.

An interplay between beam–beam and beam coupling impedance effects in the Future Circular e$$^+$$e$$^-$$ Collider

In order to reach high luminosity, the Future Circular e\(^+\)e\(^-\) Collider will need very intense beams with small emittances and small beta functions in the interaction points. This is achieved with a large Piwinski angle combined with the crab waist collision scheme. Under these conditions, the luminosity and the beam–beam tune shifts are strongly influenced by the bunch length. On the other hand, in this machine, the beamstrahlung effect is dominant too, leading to an increase of bunch length and energy spread. Moreover, due to the extreme beam parameters, new important beam–beam instabilities have been found, such as the so-called coherent X-Z instability. Finally, the bunch length and energy spread are also affected by collective effects. In this paper, we study the beam–beam interaction, by focusing on the X-Z instability for FCC-ee, in the lowest energy configuration (45.6 Gev, Z-resonance), by taking into account, self-consistently, the combined effects of beamstrahlung and the machine impedance model that has been evaluated so far. Finally, we also discuss some possible mitigation methods.

HspB1 Overexpression Improves Life Span and Stress Resistance in an Invertebrate Model.

To explore the role of the small heat shock protein beta 1 (HspB1, also known as Hsp25 in rodents and Hsp27 in humans) in longevity, we created a Caenorhabiditis elegans model with a high level of ubiquitous expression of the naked mole-rat HspB1 protein. The worms showed increased life span under multiple conditions and also increased resistance to heat stress. RNAi experiments suggest that HspB1-induced life extension is dependent on the transcription factors skn-1 (Nrf2) and hsf-1 (Hsf1). RNAseq from HspB1 worms showed an enrichment in several skn-1 target genes, including collagen proteins and lysosomal genes. Expression of HspB1 also improved functional outcomes regulated by SKN-1, specifically oxidative stress resistance and pharyngeal integrity. This work is the first to link a small heat shock protein with collagen function, suggesting a novel role for HspB1 as a hub between canonical heat response signaling and SKN-1 transcription.

FCC-ee: the synthesis of a long history of e+e- circular colliders

The design of FCC-ee is relying on the accumulated experience of mathrm {e^{+}e^{-}} colliders that have been designed, constructed and operated in the past 40 years. FCC-ee will surpass the 26.7 km long Large Electron Positron collider LEP by a factor 4 in size. Like for LEP the large size is justified by the need to control the synchrotron radiation losses that for both machines reach a few percent per turn. To that end LEP had the first large super-conducting (SC) RF system with around 3.8 GV of accelerating voltage. LEP achieved for the first time very large beam-beam parameters of around 0.08, and it relied on transversely polarized beams to determine accurately the beam energy for the experiments. The DAvarPhi NE collider, together with PEP II and KEKB split the two beams into separate vacuum chambers to reach much higher Ampere-level beam currents. To overcome beam-beam lifetime and performance issues DAvarPhi NE used for the first time the Crab Waist concept for the interaction region (IR) optics. The B-factories, PEP-II and KEKB have verified the double-ring mathrm {e^{+}e^{-}} collider with multi-ampere stored currents for over 1000 bunches, small beta ^*, top-up injection, and achieved then-highest luminosity. KEKB has applied 22-mrad crossing angle at the IP with crab crossing. Both machines inherited accelerator techniques from their predecessors, PEP and TRISTAN, which was a small-scale LEP. Currently the next generation SuperKEKB collider is starting up. It has already achieved some milestones required for FCC-ee such as small beta ^* (0.8 mm) and virtual crab-waist scheme with a large Piwinski angle (>10).

THE SPILLOVER, RISK AND LEVERAGE EFFECTS OF SMART BETA MANAGEMENT EXCHANGE-TRADED FUND (ETF)

This research uses two different GARCH models to measure spillover, risk, and leverage effects of active, passive, and smart beta management Exchange-traded Funds (ETFs). The increase in popularity of ETFs and new categories within them, specifically the growth of smart beta management, means asset managers and investors have new metrics to account for when determining portfolio exposure following the Adaptive Investment Approach (AIA). The results show significant relationships among all groups regarding the spillover. A trend of positive multi-lateral spillover of returns among the three management types including passive, active and small beta is observed with smart beta showing the highest percentage of a bi-lateral positive effect. The strongest spillover of volatility effects is among the actively managed ETFs. The testing of risk results is insignificant, but the leverage effect results are consistent with the past studies showing the significant negative bi-lateral effect.

Exploring the low tan beta region of two Higgs doublet models at the LHC

Current interpretations of the LHC results on two Higgs doublet models (2HDM) underestimate the sensitivity due to neglecting higher order effects. In this work, we revisit the impact of these effects using the current cross-section times branching ratio limits of the Arightarrow hZ, H rightarrow VV and Hrightarrow hh channels. With a degenerate heavy Higgs mass m_varPhi , we find that the LHC searches gain sensitivity to the small tan beta region after including loop corrections, even close to cos (beta -alpha )=0 which is not reachable at tree level for all types of 2HDM. For a benchmark point with m_varPhi =300 GeV, tan beta <1.8(1.2) can be probed for the Type-I(II) 2HDM model for cos (beta -alpha )=0. When the deviation from cos (beta -alpha )=0 is larger, the region for which current searches have exclusion potential becomes larger.

Pancreatic protection elicited by platelet-rich plasma and cinnamon combination in a rat model of type 1 diabetes: is it a new era in islet cell regeneration and insulin signalling genes?

Enhancement of islet cell regeneration is a great demand that worth the attention of researchers and healthcare providers to replace the risk of β-cell transplantation in type 1 diabetic patients. Evaluation of the regenerative and therapeutic potential of cinnamon (CMN) and platelet-rich plasma (PRP) either alone or combined on the reversal of the pancreatic ultrastructure and insulin signalling pathway in STZ-induced diabetic rats.Materials and methods: Fifteen adult male albino rats were used for obtaining PRP and the remaining 35 rats were used as control, diabetic (STZ, 65mg/kg, IV), diabetic CMN-treated (200 mg/kg, oral), diabetic PRP-treated (0.2 ml/kg, ip), and diabetic combined-treatment groups. Pancreatic specimens were arranged for biochemical analysis, processed for light and electron microscopic studies, and were prepared for molecular analysis of the gene expression of insulin receptor-B (IR-B), insulin receptor substrate-1 (IRS-1) and PI3-kinase as a marker for phosphatidylinositol-3 kinase signalling pathway. Results: Specimens of the diabetic group showed islet atrophy with apoptotic cellular changes, in addition to cellular depletion and vacuolar changes in some sections. Insulin immunostained sections showed weak immunoreactions. Electron microscopy showed small pyknotic beta cells’ nuclei, numerous immature secretory granules, swelling of the mitochondria and endoplasmic reticulum, and cytoplasmic rarefactions. In contrast, noticeable improvement was seen in monotherapy groups with a remarkable restoration in the combination group. Noteworthy, potential islet cell regeneration was evident in the PRP-treated group and became more prominent in the combined treatment group. The individual use of each treatment showed satisfying results, regarding the islet structure and function, which qualify them to be used as an adjunctive therapy in the field of integrative medicine to manage type 1 DM. However, the use of both combined had a synergistic action, showed a better islet regeneration, and might be a proper alternative for the burden of frequent insulin dosing and adjustment.