Operational Tolerance Research Articles

Clinical parameters and biomarkers predicting spontaneous operational tolerance after liver transplantation: a scoping review protocol.

Objective: This scoping review aims at systematically mapping reported prognostic factors for spontaneous immunosuppression (IS) free allograft tolerance (operational tolerance, OT) in non-viral hepatitis and non-autoimmune disease liver transplant (LT) recipients who are undergoing immunosuppression withdrawal (ISW). The results may inform the subsequent conduct of a systematic review with a more specific review question. Background: LT is currently the most effective treatment for end-stage liver diseases. Whereas the short-term outcomes after LT have dramatically improved over the last decades, the long-term outcomes remain unsatisfactory, mainly because of side effects of lifelong IS, such as infections, cardiovascular diseases, malignancies, and nephrotoxicity. ISW studies have shown that OT can be achieved by a subset of LT recipients and recent research has identified biomarkers of OT in these patients. However, an evidence-based selection algorithm for patients that can predictably benefit from ISW is not available to date. The planned review will, therefore, map existing knowledge on prognostic clinical parameters and biomarkers for OT. Inclusion criteria: We will consider studies that record any clinical parameter or biomarker before the initiation of ISW in paediatric or adult non-viral hepatitis and non-autoimmune disease LT recipients and analyse their possible association with ISW outcomes (OT or non-tolerance). Studies addressing the effectiveness of OT-inducing treatments will be excluded. Methods: Embase, MEDLINE, and Cochrane Library will be searched for relevant articles or conference abstracts. Full-texts of selected abstracts will be independently screened for inclusion by two reviewers. References and citing articles of included records will be screened for additional relevant records. Clinical trial registries will be searched for ongoing studies, and their investigators contacted for the sharing of unpublished data. Data from included records will be independently extracted by two reviewers using a prespecified data extraction table and presented in both tabular and narrative form.

Clinical parameters and biomarkers predicting spontaneous operational tolerance after liver transplantation: a scoping review protocol

Objective: This scoping review aims at systematically mapping reported prognostic factors for spontaneous immunosuppression (IS) free allograft tolerance (operational tolerance, OT) in non-viral hepatitis and non-autoimmune disease liver transplant (LT) recipients who are undergoing immunosuppression withdrawal (ISW). The results may inform the subsequent conduct of a systematic review with a more specific review question. Background: LT is currently the most effective treatment for end-stage liver diseases. Whereas the short-term outcomes after LT have dramatically improved over the last decades, the long-term outcomes remain unsatisfactory, mainly because of side effects of lifelong IS, such as infections, cardiovascular diseases, malignancies, and nephrotoxicity. ISW studies have shown that OT can be achieved by a subset of LT recipients and recent research has identified biomarkers of OT in these patients. However, an evidence-based selection algorithm for patients that can predictably benefit from ISW is not available to date. The planned review will, therefore, map existing knowledge on prognostic clinical parameters and biomarkers for OT. Inclusion criteria: We will consider studies that record any clinical parameter or biomarker before the initiation of ISW in paediatric or adult non-viral hepatitis and non-autoimmune disease LT recipients and analyse their possible association with ISW outcomes (OT or non-tolerance). Studies addressing the effectiveness of OT-inducing treatments will be excluded. Methods: Embase, MEDLINE, and Cochrane Library will be searched for relevant articles or conference abstracts. Full-texts of selected abstracts will be independently screened for inclusion by two reviewers. References and citing articles of included records will be screened for additional relevant records. Clinical trial registries will be searched for ongoing studies, and their investigators contacted for the sharing of unpublished data. Data from included records will be independently extracted by two reviewers using a prespecified data extraction table and presented in both tabular and narrative form.

Toward an Integrated View of Operational Tolerance in Human Renal Transplantation: A Systems Biology Perspective.

Operational tolerance (OT) is the phenomenon occurring in human renal and liver transplantation in which the body does not reject the organ after discontinuing immunosuppression for at least a year. We revisited the data generated by The Brazilian Multicenter Study on Operational Tolerance involving different conceptual fields - antigen-specific cytokine response, immune cell numbers and repertoire, signaling pathways, and epigenetics. We integrated our data to pave the way to systems biology thinking and harness debate on potential mechanisms in OT. We present original data on systems biology in OT, connecting potential mechanistic players. Using bioinformatics, we identified three dominant features that discriminate OT from its opposing clinical outcome, chronic rejection (CR). The OT-CR discriminative molecules were FOXP3, GATA3 and STAT6, each corresponding to a differential profile: (1) In FOXP3, OT presents preserved regulatory T cell (Treg) numbers but decreased numbers in CR; (2) in GATA3, increased expression is seen in OT; and (3) in STAT6, decreased monocyte activation is seen in OT. With these variables, we built molecular networks to identify interactions related to OT versus CR. Our first systems biology endeavor gave rise to novel potentially relevant interconnected players in OT mechanisms: FOXP3 connecting to interleukin-9 (IL-9) and IL-35 signaling, suggesting their immunoregulatory involvement in OT. Likewise, GATA3/FOXP3 interactions incrementing/stabilizing FOXP3 transcription suggest participation in keeping healthy FOXP3+ Tregs in OT. We envision that systems biology thinking will greatly contribute to advancing knowledge in human transplantation tolerance in an interactive perspective.

The cross-disciplinary approach to analysis and forecast of operational damage tolerance of the oil pipeline system – part 1

The paper presents the cross-disciplinary approach to the analysis of the oil pipeline system based on the methodologies of tribo-fatigue and mechanothermodynamics. The pipeline section is analyzed as a complex system pipe-soil- flow of liquid subject to the set of mechanical, thermal and friction loads. It is shown that theses loads are mainly repeatedly-alternated, and the pipe metal works in the multi-cycle fatigue conditions. The procedure of resonance accelerated fatigue tests is proposed, and their results are presented. Also, the unorthodox method of integrated wear-fatigue tests of the pipeline steel was proposed with the model of simultaneous pressure and wall friction actions. The presented field test results of pipes subject to the long-term operation showed that their fracture may occur not only in the near-weld zone, but also in the vicinity of internal corrosion damages. New models of three-dimensional stressstrain state and volumetric damage tolerance for the system pipe-soil-liquid flow were developed. These models were applied with regard to the pipe internal corrosion damages, defined using the inline inspection technique. A new efficient method to describe static and cyclic elastic-plastic fracture of the pipe steel with crack using the transverse strain is proposed and tested. Results of the computer-simulated propagation of the crack-like damage are based upon the model of deformed solid with dangerous volume. The new model is proposed for risk and safety assessment with regard to the ultrasonic inspection data. The algorithm of the ‘oil line pipe’ problem solution is presented for drafting a short-term plan of particular R&D actions.

Application of KeyPort access to transanal endoscopic mircrosurgery

Objective: To explore the effectiveness of KeyPort access in transanal endoscopic mircrosurgery (TEM). Methods: A descriptive case series study was performed. Clinicopathological data of 20 patients undergoing KeyPort access TEM in Beijing Chaoyang Hospital of Capital Medical University from December 2016 to April 2018 were collected and analyzed retrospectively. Procedure of KeyPort access TEM: general anesthesia or combined spinal epidural anesthesia (CSEA); lithotomy or prone jack-knife position; anal dilation; placement of the KeyPortaccess; connection of TEM pneumoperitoneum device, light source and imaging equipment; placement of 5 mm dedicated endoscope; insufflation of CO2 with pressure of 1.6-2.0 kPa (12-15 mmHg); after rinsing the intestinal lumen, circular resection marginlabeled by the needle-shaped electrocautery;electric coagulation or ultrasonic knife used to perform a full-thickness resection with a 0.5 cm-1 cm margin along the marking line. Indications of KeyPort access TEM: (1) benign large sessile polyps which were difficult to resect under colonoscopy; (2) submucosal lesions with diameter <2 cm; (3) Tis and T1 stage rectal carcinoma without lymph node metastasis; (4) palliative resection of T2 stage rectal carcinoma without lymph node metastasis. Contraindications: (1) accompanying serious diseases without the tolerance of anesthesia and operation; (2) distance from lesion to anal verge >20 cm. Results: There were 10 males and 10 females with age of (63±15) years old and BMI of (24.5±3.3) kg/m(2). The diameter of the lesions was (2.0±1.3) cm, and the distance from lesion to anal verge was (6.2±2.2) cm. One patient had 3 lesions at different positions in rectum with diameters of 0.5 cm, 0.5 cm, and 1 cm, respectively. All operations were accomplished through the KeyPort access TEM and no case was transferred to other methods. The duration of surgery was 75 (30-220) minutes; intraoperative blood loss was 10 (0-30) ml. Two patients with rectal anterior wall lesions underwent full-thickness resection of the intestine wall reaching the peritoneal reflex with penetration into the peritonealcavity, and received suture closure immediately. For the patient with 3 rectal lesions, the 1.0 cm lesion received a full-thickness resection and the other 2 lesions received submucosal resection. No postoperative complication occurred. Postoperative pathology showed that there were 1 case of chronic inflammatory lesion, 4 cases of benign tumor, 3 cases of carcinoma in situ, 4 cases of neuroendocrine tumor, 6 cases of pT1 rectal cancer, 2 cases of pT2 rectal cancer (both invading the superficial muscle layer). The median hospital stay was 6 (3-7) days. The postoperative follow-up was (7.2±3.8) months. No postoperative complication or recurrence was observed. Conclusion: TEM with KeyPort access is safe, rapid and effective in the treatment of rectal tumors.

Розробка когнітивної моделі для аналізу впливу загроз на рівень захищеності комп’ютерної мережі

It is impossible to imagine modern life without the use of computer networks, which offer many opportunities for their users. However, computer networks and their resources are constantly at risk of being infected by malware or from various types of network attacks. Therefore, for the proper functioning of the network and the provision of quality services, special attention is paid to the organization of network security. To solve problems related to the protection of computer networks, it is convenient to apply a cognitive approach based on the creation and analysis of a fuzzy cognitive map that reflects the status of the situation under study. Considering the importance of this issue, a cognitive model has been developed that reflects the security level of a computer network when exposed to potential threats. A matrix of interaction of concepts is formed and on the basis of it the basic system indicators are calculated, such as: consonance, dissonance and influence of concepts on the system. The analysis of these indicators revealed the most dangerous threats to network security such as: malware, physical impact on the network by the attacker, unintentional actions and errors of network users. Increasing the impact of these concepts on the network, various scenarios have been simulated, resulting in a relative change in the security level of the network. It is revealed that with increased influence of the concept of «unintentional actions, mistakes of network users» the security will be reduced the most, and with the increase of the concept of «physical influence on the network by the attacker» the fault tolerance of network operation will worsen as much as possible. The results of this study will contribute to the implementation of the necessary mechanisms to prevent, protect and control access at the appropriate levels of network infrastructure. Tabl.: 2. Fig.: 5. Refs: 13 titles.

Clinical parameters and biomarkers predicting spontaneous operational tolerance after liver transplantation: a scoping review protocol

Objective: This scoping review aims at systematically identifying prognostic factors for spontaneous immunosuppression (IS) free allograft tolerance (operational tolerance, OT) in non-viral hepatitis and non-autoimmune disease liver transplant (LT) recipients who are undergoing immunosuppression withdrawal (ISW). The results may inform the subsequent conduct of a systematic review with a more specific review question. Background: LT is currently the most effective treatment for end-stage liver diseases. Whereas the short-term outcomes after LT have dramatically improved over the last decades, the long-term outcomes remain unsatisfactory, mainly because of side effects of lifelong IS, such as infections, cardiovascular diseases, malignancies, and nephrotoxicity. ISW studies have shown that OT can be achieved by a subset of LT recipients and recent research has identified biomarkers of OT in these patients. However, an evidence-based selection algorithm for patients that can predictably benefit from ISW is not available to date. The planned review will, therefore, map existing knowledge on prognostic clinical parameters and biomarkers for OT. Inclusion criteria: We will consider studies that record any clinical parameter or biomarker before the initiation of ISW in non-viral hepatitis and non-autoimmune disease LT recipients and analyse their possible association with ISW outcomes (OT or non-tolerance). Studies addressing the effectiveness of OT-inducing treatments will be excluded. Methods: Embase, MEDLINE, and Cochrane Library will be searched for relevant articles or conference abstracts. Full-texts of selected abstracts will be independently screened for inclusion by two reviewers. References and citing articles of included records will be screened for additional relevant records. Clinical trial registries will be searched for ongoing studies, and their investigators contacted for the sharing of unpublished data. Data from included records will be independently extracted by two reviewers using a prespecified data extraction table and presented in both tabular and narrative form.

Pd-Catalyzed Enantioselective Double Heck Reaction.

An asymmetric Pd-catalyzed intramolecular followed by an intermolecular double Heck reaction of arenediazonium salts with simple alkenes is disclosed. This reaction features mild reaction conditions, simple operation, and excellent functional group tolerance and provides a rapid access to functionalized dihydrobenzofurans bearing all-carbon quaternary centers in good regioselectivity (>95/5) and enantioselectivity (90-99% ee).

Identifying Actionable Compromises: Navigating Multi‐City Robustness Conflicts to Discover Cooperative Safe Operating Spaces for Regional Water Supply Portfolios

AbstractRegional cooperation among water utilities can improve the robustness of urban water supply systems to challenging and deeply uncertain futures. Through coordination mechanisms such as water transfers and regional demand management, water utilities can improve the efficiency of resource allocation and delay the need for new infrastructure investments. Though cooperation provides utilities with the potential for reduced cost strategies for improving the reliability of their services, two important challenges are worthy of careful consideration. First, regional utilities often have to navigate robustness conflicts stemming from potential asymmetries in their risk exposure, demand dynamics, and the availability of supply resources. Second, successful implementation of candidate compromise water portfolios requires that cooperating utilities understand their operational tolerances to deviations from the recommended regional actions (“imperfect implementation”). This study contributes a framework for identifying compromises across regional robustness conflicts and quantifying tolerances to implementation uncertainties. The framework is demonstrated on a system of four interdependent but institutionally independent water utilities in the Research Triangle region of North Carolina that are confronting robustness conflicts given asymmetries in their vulnerabilities to growing demands and hydroclimatic uncertainties. Our findings highlight that seemingly balanced compromise management strategies can yield significant and potentially surprising unintended consequences that could degrade regional cooperation. Moreover, asymmetries in regional robustness can be amplified with modest deviations from their agreed upon actions. Results of this analysis are broadly applicable to water supply regionalization as a global challenge and provide insights for discovering robust compromises and safe operating spaces for multi‐actor water supply systems.

TRACK GAUGE STABILITY UNDER EFFECT OF SLEEPER THERMAL EXPANSION

Railway sleepers are traditionally made of hardwood, pre-stressed concrete or steel. However, emerging advanced materials, including polymers or composites, are investigated for a possible employment in the sleeper production. The main function of sleepers is to distribute forces they carry onto the trackbed, to support rails and keep the spacing between them, called the track gauge. The operating tolerance of the track gauge is critical for safety and is set by regulations. Generally, it is advisable to keep the track gauge deviation, as well as the sleeper length deviation influencing it, as low as reasonably practicable. In this article, the recommended limit values of the thermal expansion coefficient characterizing possible sleeper length deviation were evaluated. The recommendation considered allowed track gauge tolerance and the experimentally determined temperatures of a sleeper measured in the trackbed for a year. In addition, thermal expansion of a selected polymer in laboratory conditions was determined, representing an alternative material for the sleeper production. Consequently, it was compared with the limit and conservatively used materials. Furthermore, the same tested polymer, but utilizing chopped glass fibres to reduce the thermal expansion of the polymer, was also tested. Results show a positive impact of the glass reinforcement on the thermal expansion coefficient. The applicability of the selected polymer in the railway sleeper production from the perspective of the thermal expansion was discussed in the paper.

Editorial introductions

Editorial introductions

Clinical Operational Tolerance and Immunosuppression Minimization in Kidney Transplantation: Where Do We Stand?

The 20th century represents a breakthrough in the transplantation era, since the first kidney transplantation between identical twins was performed. This was the first case of tolerance, since the recipient did not need immunosuppression. However, as transplantation became possible, an immunosuppression-free status became the ultimate goal, since the first tolerance case was a clear exception from the hard reality nowadays represented by rejection. A plethora of studies was described over the past decades to understand the molecular mechanisms responsible for rejection. This review focuses on the most relevant studies found in the literature where renal tolerance cases are claimed. Contrasting, and at the same time, encouraging outcomes are herein discussed and a glimpse on the main renal biomarkers analyzed in this field is provided. The activation of the immune system has been shown to play a central role in organ failure, but also it seems to induce a tolerance status when an allograft is performed, despite tolerance is still rare to register. Although there are still overwhelming challenges to overcome and various immune pathways remain arcane; the immunosuppression minimization might be more attainable than previously believed. . Multiple biomarkers and tolerance mechanisms suspected to be involved in renal transplantation have been investigated to understand their real role, with still no clear answers on the topic. Thus, the actual knowledge provided necessarily leads to more in-depth investigations, although many questions in the past have been answered, there are still many issues on renal tolerance that need to be addressed.

Unilateral approach painless vertebroplasty for osteoporotic vertebral compression fractures of critically ill patients under lateral decubitus position

Objective To investigate the clinical efficacy of unilateral approach painless vertebral augmentation in the treatment of severe osteoporotic vertebral compression fractures (OVCFs) in the critically ill patients under lateral decubitus postition. Methods A retrospective case series study was conducted to analyze 97 patients with severe vertebral fractures admitted to the Henan Provincial People's Hospital from April 2004 to January 2017. There were 27 males and 70 females, aged 59-99 years [(78.5±13.2)years]. There were 11 patients with three-segment fracture, nine patients with two-segment fracture and 77 patients with single fracture. All patients were treated with lateral decubitus unilateral approach for painless vertebral augmentation and received postoperative rehabilitation training guided by physicians. Preoperative and intraoperative blood loss were recorded. Preoperative and postoperative respiratory rate, heart rate, systolic pressure, oxygen saturation and acute physiology and chronic health evaluation score II (APACHE II) , height of vertebral compression site, and injured vertebrae Cobb angle were evaluated. The visual analogue scale (VAS) and Oswestry dysfunction index (ODI) were assessed to define function improvement. Meanwhile, the occurrence of re-fracture and complications were recorded. Results All patients were followed up for 3-8 months [(6.3±2.9)months]. The operation time was (69.2±25.9)minutes, and the amount of intraoperative bleeding was (7.5±2.6)ml. There were no significant differences in respiratory rate, heart rate, systolic blood pressure or oxygen saturation before operation and after operation (P>0.05). No surgical discontinuation or deterioration occurred. The APACHE II score was (15.2±3.7)points before operation and (8.4±0.7)points at 24 hours after operation (P 0.05). The Cobb angle was (25.6±9.3)° before operation, (20.7±2.5)° at one week after operation and (18.5±3.1)° at the last follow-up (P>0.05). The VAS score was (8.5±1.2)points before operation, (2.1±0.3)points at one week after operation, and (3.2±1.1)points at the last follow-up, respectively. The VAS scores at 1 week and the last follow-up were significantly improved compared with preoperative VAS (P 0.05). The ODI value was 39.9±3.4 before operation, 20.2±5.2 at one week after operation, and 17.2±2.0 at the last follow-up . The ODI values 1 week after operation and at the last follow-up were significantly improved compared with preoperative ODI (P<0.05), showing improvement trend during the follow-up (P<0.05). No re-fracture occurred during the follow-up. No serious complications such as nerve injury, pulmonary embolism or death occurred during the operation and postoperative follow-up. Conclusions The unilateral approach painless vertebral augmentation for the treatment of severe OVCFs in critically ill patients under lateral decubitus position can improve the patient's operative tolerance and satisfaction, shorten the operation time, relieve postoperative pain and promote functional recovery. It is an alternative surgical procedure for the treatment of severe OVCFs in internal medicine. Key words: Spinal fractures; Osteoporotic fractures; Vertebral augmentation

Immunologic benefit of maternal donors in pediatric living donor liver transplantation.

Long-term follow-up has suggested that pediatric LDLT may have superior outcomes compared to deceased donor recipients. In this review, we describe the subset of LDLT recipients with maternal donors that have lower reported rates of rejection and improved allograft survival. Pediatric LDLT recipients, particularly those with a primary diagnosis of biliary atresia who receive grafts from their mothers, have been reported to have lower rates of acute cellular rejection post-transplant and graft failure. Maternal-fetal microchimerism and the persistence of regulatory T cells may be related to improved outcomes observed in recipients with maternal donors. Further, recent studies have shown that up to 60% of pediatric LDLT recipients can undergo intentional withdrawal of immunosuppression and achieve long-term operational tolerance. The impact of graft type on operational tolerance has not been thoroughly investigated; however, investigation of tolerant pediatric LDLT patients with maternal donors may provide key insights into the mechanisms of immune tolerance. While excellent outcomes can be achieved in pediatric LDLT, there is still a measurable decrease in graft and patient survival over time post-transplant. Recipients of maternal donor liver transplants are a subset of patients who may be advantaged toward improved outcomes by means of immune tolerance.

Current state of organ transplant tolerance.

Immunological tolerance has long been considered the 'holy grail' of organ transplantation. Although tolerance has been an active area of research for 70 years, its clinical application has only been possible in the last two decades and widespread use remains an, as yet, unattained goal. Recent advances in the understanding of immune regulation have identified many new approaches to tolerance induction and several clinical trials are currently aimed at bringing this treatment to more patients. Mixed chimerism remains the most successful approach to tolerance induction. However, many treatments, including adoptive transfer of regulatory T cells, regulatory B cells, and immune suppressive dendritic cells and myeloid derived suppressor cells have shown great promise in preclinical models. Recent clinical studies have found that both kidney and liver operational tolerance are achievable in the appropriate settings. Furthermore, combining multiple tolerance approaches has shown potential to produce durable and safer tolerance. Tolerance to protect kidney and liver allografts has become a valuable therapy in the correct circumstances. Through further clinical trials and an improved understanding of immune regulatory components, tolerance is poised to have a significant impact on transplantation in the years to come.

Regulatory/inflammatory cellular response discrimination in operational tolerance

Antigen-specific cellular response is essential in immune tolerance. We tested whether antigen-specific cellular response is differentially modulated in operational tolerance (OT) in renal transplantation with respect to critical antigenic challenges in allotransplantation-donor antigens, pathogenic antigens and self-antigens. We analysed the profile of immunoregulatory (REG) and pro-inflammatory (INFLAMMA) cytokines for the antigen-specific response directed to these three antigen groups, by Luminex. We showed that, in contrast to chronic rejection and healthy individuals, OT gives rise to an immunoregulatory deviation in the cellular response to donor human leucocyte antigen DR isotype peptides, while preserving the pro-inflammatory response to pathogenic peptides. Cellular autoreactivity to the N6 heat shock protein 60 (Hsp60) peptide also showed a REG profile in OT, increasing IL4, IL-5, IL-10 and IL-13. The REG shift of donor indirect alloreactivity in OT, with inhibition of interleukin (IL)-1B, IL-8, IL-12, IL-17, granulocyte colony-stimulating factor, Interferon-γ and monocyte chemoattractant protein-1, indicates that this may be an important mechanism in OT. In addition, the differential REG profile of cellular response to the Hsp60 peptide in OT suggests that REG autoimmunity may also play a role in human transplantation tolerance. Despite cross-reactivity of antigen-specific T cell responses, a systemic functional antigen-specific discrimination takes place in OT.

P4.33: Operational tolerance can be achieved after intestinal transplant: first report and mechanistic analysis

Introduction: Transplantation tolerance is a highly sought and rarely achieved state in clinical medicine. Defined as long-term stable and acceptable graft tolerance without immunosuppression and with an otherwise competent immune system, tolerance maximizes graft survival and function and decreases organ demand without the negative side effects of immunosuppression. While there have been prior reports of tolerance after liver and kidney transplantation, we herein report and mechanistically characterize the first case of tolerance after intestinal transplantation. Methods: Intestinal transplantation was performed using our standard method. Immunosuppression for induction was thymoglobulin and steroids and for maintenance was tacrolimus. Graft and blood lymphocytes from the patient, 8 stable intestinal recipients, and 8 healthy controls (blood only) were analyzed using flow cytometry. Recipient T cell responses to donor and third party antigens were assessed by Pleximmune (proprietary). Results: We performed intestinal transplantation on a 14-year old male for severe pseudo-obstruction. Subsequently lost to follow up, he presented 7 years post-transplant and 3.5 years after stopping all immunosuppression with no graft problems. Biopsy showed pristine allograft histology. Given his history of GVHD, we hypothesized that central tolerance was mediated by chimerism. However, serial peripheral chimerism studies did not show donor chimerism. Thus, we speculated that he had peripheral tolerance mediated by regulatory T cells (Treg). This was confirmed by flow cytometric analysis showing that, compared to both sets of controls, the patient’s blood and graft had higher levels of naïve and lower levels of effector memory CD4/CD8 as well as higher Treg percentages. Demonstrating immunocompetence, recipient T cells robustly produced IL-17, TNF-α, and IFN-γ when stimulated by PMA/IO and highly upregulated antigen-specific CD154 expression in response to CMV and EBV antigen stimulation ex vivo. Critically, donor-specific hyporesponsiveness was confirmed by 2-fold higher CD8+CD154+ T cell response to 3rd party vs. donor lymphocytes in mixed lymphocyte reaction. Conclusion: This represents the first report of tolerance after intestinal transplantation. Mechanistic analysis demonstrates that peripheral tolerance mediated by increased Tregs and decreased effector memory cells in both graft and blood appears to play a role.

Effect of nozzle types on the laser cutting performance for 60-mm-thick stainless steel

The laser cutting of 60-mm-thick stainless steel using a 6-kW fiber laser was performed to investigate the effect of the geometric nozzle configuration on the operating tolerance of the stand-off distance. The stand-off distance is the distance between the nozzle tip and the top surface of the steel plate. Two types of nozzles—a subsonic nozzle with a convergent geometry and a supersonic nozzle with a convergent-divergent geometry—were used to comparatively evaluate the flow behavior through interferometric analysis. A laser cutting experiment was conducted in accordance with the interferometric analysis, focusing on the stand-off distance variation. The stand-off distance was varied from 1 to 60 mm in consideration of the melt-removal capability of the applied cutting nozzles. The throat diameters of the nozzles were 2 and 3 mm. According to the results, the supersonic nozzle has a better operating tolerance of the stand-off distance for the laser cutting of 60-mm-thick stainless steel.

Differential microRNA Profile in Operational Tolerance: A Potential Role in Favoring Cell Survival.

Background: Operational tolerance (OT) is a state of graft functional stability that occurs after at least 1 year of immunosuppressant withdrawal. MicroRNAs (microRNA) are small non-coding RNAs that downregulate messenger RNA/protein expression of innumerous molecules and are critical for homeostasis. We investigated whether OT in kidney transplantation displays a differential microRNA profile, which would suggest that microRNAs participate in Operational Tolerance mechanisms, and may reveal potential molecular pathways.Methods: We first compared serum microRNA in OT (n = 8) with chronic rejection (CR) (n = 5) and healthy individuals (HI) (n = 5), using a 768-microRNA qPCR-panel. We used the Thermo Fisher Cloud computing platform to compare the levels of microRNAs in the OT group in relation to the other study groups. We performed validation experiments for miR-885-5p, by q-PCR, in a larger number of study subjects (OT = 8, CR = 12, HI = 12), as individual samples.Results: We detected a differential microRNA profile in OT vs. its opposing clinical outcome—CR—suggesting that microRNAs may integrate transplantation tolerance mechanisms. Some miRNAs were detected at higher levels in OT: miR-885-5p, miR-331-3p, miR-27a-5p vs. CR; others, we found at lower levels: miR-1233-3p, miR-572, miR-638, miR-1260a. Considering highly predicted/experimentally demonstrated targets of these miRNAs, bioinformatics analysis revealed that the granzyme B, and death receptor pathways are dominant, suggesting that cell death regulation integrates transplantation tolerance mechanisms. We confirmed higher miR-885-5p levels in OT vs. CR, and vs. HI, in a larger number of subjects.Conclusions: We propose that epigenetics mechanisms involving microRNAs may integrate human transplantation tolerance mechanisms, and regulate key members of the cell death/survival signaling. miR-885-5p could favor cell survival in OT by diminishing the levels of CRADD/RAIDD and CASP3. Nonetheless, given the nature of any complex phenomenon in humans, only cumulative data will help to determine whether this microRNA differential profile may be related to the cause or consequence of operational tolerance.

Методические аспекты оценки эффективности активных систем ограничения предельных режимов полета самолетов при математическом моделировании и в летных испытаниях

В системе мероприятий по обеспечению безопасности полетов и повышению боевых возможностей современных летательных аппаратов важное значение придается оснащению их соответствующими техническими устройствами. Настоящая статья посвящена анализу применения на самолетах активных систем ограничения предельных режимов полета, предназначенных для предотвращения выхода самолета за допустимые значения угла атаки (перегрузки) при его боевом применении. В работе приведена математическая модель движение самолета с работающим активным автоматом ограничения предельных режимов полета, которая позволяет осуществлять предварительную оценку поведения самолета с работающим ограничителем на различных режимах полета, влияние изменений в пределах эксплуатационных допусков параметров автомата, центровки самолета и т. д. Изложены методические подходы оценки активных автоматов ограничения предельных режимов полета в летных испытаниях.