Current perspectives and the future of disease-modifying therapies in type 1 diabetes

Use of immunomodulating agents to prevent the progression of autoimmuneβ-cell damage leading to type 1 diabetes mellitus(T1DM)is an interesting area for research.These include non-specific anti-inflammatory agents,immunologic vaccination and anti-inflammatory agents targeting specific immune cells or cytokines.Teplizumab is an anti-CD3-molecule that binds to and leads to the disappearance of the CD3/TCR complex and rendering the T cell anergic to its target antigen.Preclinical and clinical trials have demonstrated its efficacy in reducing the decline in serum C-peptide levels and the need for insulin therapy if used early in the disease process of T1DM.The benefits have been apparent as early as six months to as long as seven years after therapy.It has recently been approved by the Food and Drug Administration to delay the onset of clinical(stage 3)type 1 diabetes in children above 8 years of age.In their recent metaanalysis published in the World Journal of Diabetes,Ma et al found that those in the teplizumab treatment group have a greater likelihood of reduction in insulin use,change in C-peptide response,and better glycemic control compared to the control group with a good safety profile.However,all the included randomized control trials have been conducted in high-income countries.High cost of therapy and unknown utility of the molecule in stage 3 disease limit its widespread use.

Blood glucose changes surrounding initiation of tumor-necrosis factor inhibitors and conventional disease-modifying anti-rheumatic drugs in veterans with rheumatoid arthritis

AIM To determine the scope of acute hypoglycemic effects for certain anti-rheumatic medications in a large retrospective observational study. METHODS Patients enrolled in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were selected who, during follow-up, initiated treatment with tumor necrosis factor inhibitors (TNFi's, including etanercept, adalimumab, infliximab, golimumab, or certolizumab), prednisone, or conventional disease-modifying anti-rheumatic drugs(DMARDs), and for whom proximate random blood glucose (RBG) measurements were available within a window 2-wk prior to, and 6 mo following, medication initiation. Similar data were obtained for patients with proximate values available for glycosylated hemoglobin A1C values within a window 2 mo preceding, and 12 mo following, medication initiation. RBG and A1C measurements were compared before and after initiation events using paired t-tests, and multivariate regression analysis was performed including established comorbidities and demographics.RESULTS Two thousands one hundred and eleven patients contributed at least one proximate measurement surrounding the initiation of any examined medication. A significant decrease in RBG was noted surrounding 653 individual hydroxychloroquine-initiation events(-3.68 mg/dL, P = 0.04), while an increase was noted for RBG surrounding 665 prednisone-initiation events(+5.85 mg/d L, P < 0.01). A statistically significant decrease in A1C was noted for sulfasalazine initiation, as measured by 49 individual initiation events(-0.70%, P < 0.01). Multivariate regression analyses, using methotrexate as the referent, suggest sulfasalazine (β =-0.58, P = 0.01) and hydroxychloroquine(β =-5.78, P = 0.01) use as predictors of lower post-medicationinitiation RBG and A1C values, respectively. Analysis by drug class suggested prednisone (or glucocorticoids) as predictive of higher medication-initiation event RBG among all start events as compared to DMARDs, while this analysis did not show any drug class-level effect for TNFi. A diagnosis of congestive heart failure(β = 4.69, P = 0.03) was predictive for higher post-initiation RBG values among all medication-initiation events.CONCLUSION No statistically significant hypoglycemic effects surrounding TNFi initiation were observed in this large cohort. Sulfasalazine and hydroxychloroquine may have epidemiologically significant acute hypoglycemic effects.

Modifying agent selection for Al-7Si alloy by Miedema model

To determine the modifying agents for Al-7Si alloys, microstructure observation and mixing enthalpy analysis using Miedema model for Al-7Si alloy with additions of different rare earth elements were performed, and the effects of rare earth elements on the modifica-tion of eutectic silicon morphology were investigated. The results of mixing enthalpy analysis show that these four rare earth elements, La, Sm, Pr, and Ce, which have the large negative mixing enthalpies with Si, can be selected as modifying agents for eutectic silicon morphology. The element with the largest negative mixing enthalpy is Ce. Furthermore, the microstructures indicate that these four elements can effec-tively modify the eutectic （α）Al-Si crystals in Al-7Si alloy, and the most effective one is also Ce. Differential scanning calorimetry （DSC） results show that the eutectic temperature depressions due to the additions of modifying agents are the important reasons for the modification of eutectic （α）Al-Si crystals.

SHP2 regulates skeletal cell fate by modifying SOX9 expression and transcriptional activity

Chondrocytes and osteoblasts differentiate from a common mesenchymal precursor, the osteochondroprogenitor（OCP）, and help build the vertebrate skeleton. The signaling pathways that control lineage commitment for OCPs are incompletely understood. We asked whether the ubiquitously expressed protein-tyrosine phosphatase SHP2（encoded by Ptpn11） affects skeletal lineage commitment by conditionally deleting Ptpn11 in mouse limb and head mesenchyme using ＂Cre-lox P＂-mediated gene excision.SHP2-deficient mice have increased cartilage mass and deficient ossification, suggesting that SHP2-deficient OCPs become chondrocytes and not osteoblasts. Consistent with these observations, the expression of the master chondrogenic transcription factor SOX9 and its target genes Acan, Col2a1, and Col10a1 were increased in SHP2-deficient chondrocytes, as revealed by gene expression arrays, q RT-PCR, in situ hybridization, and immunostaining. Mechanistic studies demonstrate that SHP2 regulates OCP fate determination via the phosphorylation and SUMOylation of SOX9, mediated at least in part via the PKA signaling pathway. Our data indicate that SHP2 is critical for skeletal cell lineage differentiation and could thus be a pharmacologic target for bone and cartilage regeneration.

Study on the Influence of Ni Modifying on Phase Transformation and Photocatalytic Activity of TiO_2

The Ni-modified TiO2 was synthesized using two methods including co-precipitation(Ni doped TiO2, Ni-TiO2) and wet impregnation(Ni loaded TiO2, Ni/TiO2). The surface and bulk crystalline phases of Ni-modified TiO2 were investigated by using X-ray diffractometry(XRD), UV Raman spectroscopy, TEM, and SEM. It is observed that Ni doping can promote the phase transition and grain size growth of TiO2. Moreover, the propagation of the rutile phase from the bulk into the surface region of TiO2 is increased when the Ni doping amount reaches up to 3%. However, in Ni/TiO2, it is found out that the surface and bulk phase transformation of TiO2 can be inhibited after impregnation of 1% of Ni on the TiO2. Compared with the co-precipitation method, Ni species may be more enriched in the surface of the Ni/TiO2 sample upon adoption of the impregnation method, and the direct contact of anatase particles of TiO2 is avoided. As a consequence, the phase transition in the surface and bulk region of TiO2 can be effectively inhibited by Ni loading. Additionally, the activity of the photocatalytic degradation of RhB on the 3Ni-TiO2-600 ℃ sample is higher than that on the 3 Ni/TiO2-600 ℃ sample. The phase junction formed between anatase and rutile in the surface region of 3Ni-TiO2-600 ℃ may the main reason for its high photocatalytic activity.

Observation on the modifying activity of the protein from Elytrzgia repens rhizome for ice crystal

In winter, spring and summer, the rhizome of wild Elytrzgia repens of Heilongjiang Province was selected to extract the soluble which whole protein and the apoplastic protein, and analyzed by SDS-PAGE. The result indicated that there were two specific polypeptides in two types protein from winter; their relative molecular weight were identified as 52 ku and 26 ku by analyzing software; the apoplastic protein from winter had the ability of modifing the growth of ice crystal which appeared hexagonal in shape observed with the phase-contrast photomicroscope. So the apoplastic protein from winter has the antifreeze characters and the 52 ku protein is more likely the antifreeze protein

Novel anti-AD dimeric leads:from relieving symptoms to modifying diseases via multi-targets

Alzheimer disease(AD) has now become the most common brain disorder among the older population. In addition, the currently existing therapeutics only offer temporary symptomatic relieves. Therefore, further research and development of more efficacious and disease-modifying agents for the prevention, treatment and restoration of AD will have tremendous value from both scientific, and economic standpoints. Over the past few years, our series of studies have identified several highly promising anti-AD dimeric leads, with disease-modifying potentials. In this presentation, the latest progress on the neuroprotective and disease modifying effects and the underlying mechanisms of those candidates will be comprehensively illustrated and discussed.

Modifying Effect of Rare Earths and Titanium on Austenitic Manganese Steel

By means of thermodynamic calculations, optical microscope, sweep electron microscope(SEM), transimssion electron microscope(TEM) and microcomposition detection, the modifying effect of RE and Ti on austenitic manganese steel was investigated The results show that the constitutional supercooling of austenitic manganese steel during solidification can be improved and the dendritic crystals can be grown facilely, melted, isolated and multiplied by adding RE(Ce) In the melt the alloying elements Ti and C can form TiC directly which acts as nucleus of cementite and causes both primary and eutectic cementite to be granulated and refined so that the cementite network in this steel can be eliminated

Experiments of Applying the Rare-Earth Modifying Agents in New Dental Materials Preparation

Harmless rare-earth modifying agents were prepared by orthogonal experiments. A new resin material was synthesized with the qualities such as rigidity, rubbing abrasion, aging, luster and plasticity better than the dental resin materials in common used. It could be used as the substitutes for the applied resin teeth materials.

Amyotrophic lateral sclerosis disease modifying therapeutics:a cell biological perspective

Amyotrophic lateral sclerosis（ALS）is a progressively fatal neuromuscular disorder classically characterized by loss of upper and lower motor neurons from the cortex to the spinal cord Diagnosed patients have a median survival of about 3 years and death usually results from eventual respiratory failure.

A New Approach to Refining and Modifying Cast Aluminum Alloys with Rare Earth Alloys

The effects of rare earth (RE) alloys on the refining and modifying of cast aluminum alloys were investigated. Compared to other substances in common use, rare earth alloys maintain the refining and modifying effects of the aluminum alloys for a longer time. RE alloys can also reduce environmental pollution in the melting process. These effects of RE alloys make them become a superior choice for the applications in aluminum foundry.

Improving Local Temperature Rise in Rotational Incremental Sheet Forming Process by Modifying Forming Parameters Using Response Surface Method

In rotational incremental sheet forming( RISF) process,the friction heating of rotational tool could lead to local temperature rise of the sheet and cause the improvement of sheet's formability.Lightweight metal,such as magnesium alloy,could be deformed by RISF without additional heating. The objective of this study is to investigate the effects of forming parameters,namely,tool rotational speed,feed-rate,step size and wall angle,on the local temperature rise. Using response surface methodology and central composite design( CCD) experimental design,the significance,sequence of parameters and regression models would be analyzed with AZ31 B as the experimental material,and 3D response surface plots would be shown. Combined with actual processing conditions,the measures to improve the local temperature rise by modifying each parameter would be discussed in the end. The results showed that hierarchy of the parameters with respect to the significance of their effects on the local temperature at the side wall was: feed-rate,step size,and rotational speed,while at the bottom it was: feed-rate,step size,wall angle, and rotational speed, and no significant interaction appeared. It was found that the most significant parameter was not rotational speed,but feed-rate,followed by step size,for both test positions. In addition, the local temperature would increase by elevating step size,wall angle,rotating rate,and bringing down of feed-rate.

Study on the Adsorption Capability of Fe Modifying Sepiolite on Cr(Ⅵ)

[ Objective] The research aimed to study the adsorption capability of Fe modifying sepiolite on Cr（Vl）. [ Method] FeCl3 solution with different concentrations was used to modify sepiolite. By static adsorption experiment, the adsorption capability of Fe modifying sepiolite on Cr（VI ） was studied. [Result] Under the condition of initial Cr（VI） concentration of 90 mg/L, 10.0% IMS dosage of 5 g/L, pH of 4.5, adsorption time of 90 min, and temperature of 25 ℃ the equilibrium adsorption quantity of Fe modifying sepiolite was 6.5 mg/g. [Conclusion] The research provided an effective pathway for the application of Fe modifying sepiolite in Cr（VI）-containing wastewater treatment.

Modifying Plant Oils for Use as Fuel in Rural Contexts Tanzania: Techno-Economic Analysis

Techno-economic analysis of a small-scale Modified Plant Oil (MPO) production plant that has an annual production capacity of 15,072,741 kg of MPO (batch process) was carried out to estimate the capital and operating costs of a plant. The analysis was done by using a computer model that was designed and simulated with an aid of SuperPro Designer (Version 4.32) software. The specified feedstock was crude Jatropha oil (JO) and the main product was MPO. The major processes involved were degumming, neutralisation and blending. Degumming involved the removal of gums or phospholipids, and two methods were used: water degumming and acid degumming, whereas blending involved mixing of degummed or purified JO with natural gas condensate (NGC) modifier to lower the viscosity of JO. From techno-economic analysis of the process, it was found that the total capital investment of a plant was about US $ 10,222,000 and the predicted unit production cost of MPO was US $ 1.315/kg at a value of US $ 1.0/kg of JO. The economic feasibility of MPO production was found to be highly influenced by the price of feedstock, which contributed about 95% of the total annual production cost. The relationship between plant throughput and unit cost of producing MPO showed that unit production cost was very sensitive to production rate at low annual throughputs. The MPO cost showed a direct linear relationship with the cost of JO, with a change of US $ 0.50/kg of MPO in MPO cost in every change of US $ 0.50/kg of JO in JO price. The process technology simulated was found to be economically viable and can be implemented in rural setting, taking into consideration Tanzania’s rural situation.

Effects of rare earth modifying inclusions on the pitting corrosion of 13Cr4Ni martensitic stainless steel

In this study,the pitting corrosion behavior of 13Cr4Ni martensitic stainless steel(BASE)and that modified with rare earth(REM)in 0.1 mol/L Na Cl solution were characterized.Techniques such as automatic secondary electron microscope(ASPEX PSEM detector),scanning electron microscope(SEM),transmission electron microscope(TEM),scanning Kelvin probe force microscope(SKP),potentiodynamic and potentiostatic polarizations were employed.The results obtained indicate that BASE steel contains Al_(2)O_(3)/Mn S,Al_(2)O_(3) and Mn S inclusions,while REM steels contain(La,Ce,Cr,Fe)-O and(La,Ce,Cr,Fe)-O-S inclusions.Compared with BASE steel,REM steel is more susceptible to induce the metastable pitting nucleation and repassivation,whereas it restrains the transition from metastable pitting to stable pitting.Adding 0.021%rare earth element to BASE steel can reduce the number and area of inclusions,while that of 0.058%can increase the number and enlarged the size of inclusions,which is also the reason that pitting corrosion resistance of 58 REM steel is slightly lower than that of 21 REM steel.In the process of pitting corrosion induced by Al_(2)O_(3)/Mn S inclusions,Mn S is preferentially anodic dissolved,and also the matrix contacted with Al_(2)O_(3) is subsequently anodic dissolved.For REM steels,anodic dissolution preferentially occurs at the boundary between inclusions and matrix,while(La,Ce,Cr,Fe)-O inclusions chemically dissolve in local acidic environment or are separated from steel matrix.The chemically dissolved substance(La^(3+) and Ce^(3+))of(La,Ce,Cr,Fe)-O inclusions are concentrated in pitting pits,which inhibits its continuous growth.

Genome-wide identification and analysis of sulfatase and sulfatase modifying factor genes in Bemisia tabaci (Hemiptera: Aleyrodidae)

The invasive pest whitefly(Bemisia tabaci)is a complex species,of which Middle East-Minor Asia 1(MEAM1)and Mediterranean(MED)are the two most damaging members.Previous research showed that cabbage is frequently infested with MEAM1 but seldomly with MED,and this difference in performance is associated with glucosi-nolate(GS)content.Some insects can modify GS using glucosinolate sulfatase(SULF),the activity of which is regulated by sulfatase modifying factor 1(SUMF1);therefore,to increase our understanding of different performances of MEAM1 and MED on cabbage plants,we identified and compared nine putative SULFs and one SUMF in MEAM1 and MED.We found that the lengths of two genes,BtSulf2 and BtSulf4,differed between MEAM1 and MED.The messenger RNA levels of BtSulf4 increased more than 20-fold after MEAMl and MED adults were exposed to GS,but BtSulJ2 expression was only induced by GS in MEAM1.Knockdown of BtSulf2 and BtSulf4 in MEAM1 resulted in a substantial increase in the mortality of GS-treated adults but not in MED.These results indicate that differences in BtSulJ2 and BtSulf4 sequences and/or expression may explain why MEAM1 performs better than MED on cabbage.Our results provide a basis for future functional research on SULF and SUMF in B.tabaci.

Nucleoside modified mRNA-lipid nanoparticles as a new delivery platform for the repair of the injured spinal cord

Spinal cord injury and treatment opportunities:The adult mammalian spinal cord has a very limited capacity for spontaneous regeneration due to various intrinsic molecular and cellular factors.Although the spinal cord neurons have the capacity to regenerate their axons,the expression of growth inhibitory factors,lack or suppression of proper guidance cues,and profound inflammatory responses do not permit successful regeneration(Khyeam et al.,2021).

Preparation of high acidity coefficient slag wool fiber with blast furnace slag and modifying agents

Preparation of high acidity coefficient slag wool fiber with molten slag and modifying agents is considered to be a positive approach for value-added utilization of blast furnace slag. In order to achieve the multi-purposes of fiber-forming, energy saving, and waste heat recovery, the modifying agents that can improve the acidity coefficient of slag effectively, economically, and environmentally were investigated. Three agents with different acidity coefficients were adopted to modify slag and manufacture wool fibers. The effect of agent and slag proportion on the melting temperature and viscosity of molten slag was studied at a fixed acidity coefficient of 1.8 and 2.0. The results indicate that the sample modified with high acidity coefficient agent and high slag proportion has lower melting temperature and viscosity. The effect of agent and slag temperature on the fiber diameter was also investigated when the acidity coefficient of slag is 2.0. At a fixed slag proportion of 50 wt.%, the mean diameter decreases with increasing temperature and decreasing viscosity coefficient. Besides, the temperature drops caused by the addition of agents and energy consumption of samples for heating the slag were also analyzed.

Experimental Study and a Modified Model for Temperature-Recovery Stress of Shape Memory Alloy Wire under Different Temperatures

To investigate the performance of utilizing the shape memory effect of SMA(Shape Memory Alloy)wire to generate recovery stress,this paper performed single heating recovery stress tests and reciprocating heating-cooling recovery stress tests on SMA wire under varying initial strain conditions.The effects of various strains and different energized heating methods on the recovery stress of SMA wires were explored in the single heating tests.The SMA wire was strained from 2%to 8%initially,and two distinct heating approaches were employed:one using a large current interval for rapid heating and one using a small current interval for slower heating.The experimental outcomes reveal that during a single heating cycle,the temperature-recovery stress relationship of SMA wire exhibits three distinct stages:the martensite phase stage,the transition stage from martensite to austenite phase,and the austenite phase stage.Notably,the choice of heating method does not influence the maximum recovery stress value,and the correlation between initial strain and maximum recovery stress is predominantly linear.Moreover,conducting the reciprocating temperature rise and fall performance test is important to better simulate the scenario in practical engineering where multiple recovery stress in SMA wires for structural repair.In this test,two temperature cycling methods were studied:interval rise and fall,as well as direct rise and fall.In the case of utilizing the interval temperature rise and fall method,it was observed that the recovery stress associated with cooling was significantly higher than that corresponding to heating at the same temperature.Furthermore,the recovery stress was lower upon subsequent heating than that measured during the previous heating cycle.Based on the experimental results,a prediction model for the temperature-recovery stress relationship has been proposed to simplify numerical calculations.It is hoped that an approximate temperaturerecovery stress curve can be obtained from the parameters of the SMA wire.The calculated values derived from this model show good alignment with the measured values,indicating its reliability.