Bi-allelic TTI1 variants cause an autosomal-recessive neurodevelopmental disorder with microcephaly.

Telomere maintenance 2 (TELO2), Tel2 interacting protein 2 (TTI2), and Tel2 interacting protein 1 (TTI1) are the three components of the conserved Triple T (TTT) complex that modulates activity of phosphatidylinositol 3-kinase-related protein kinases (PIKKs), including mTOR, ATM, and ATR, by regulating the assembly of mTOR complex 1 (mTORC1). The TTT complex is essential for the expression, maturation, and stability of ATM and ATR in response to DNA damage. TELO2- and TTI2-related bi-allelic autosomal-recessive (AR) encephalopathies have been described in individuals with moderate to severe intellectual disability (ID), short stature, postnatal microcephaly, and a movement disorder (in the case of variants within TELO2). We present clinical, genomic, and functional data from 11 individuals in 9 unrelated families with bi-allelic variants in TTI1. All present with ID, and most with microcephaly, short stature, and a movement disorder. Functional studies performed in HEK293T cell lines and fibroblasts and lymphoblastoid cells derived from 4 unrelated individuals showed impairment of the TTT complex and of mTOR pathway activity which is improved by treatment with Rapamycin. Our data delineate a TTI1-related neurodevelopmental disorder and expand the group of disorders related to the TTT complex.

TTI-101 targets STAT3/c-Myc signaling pathway to suppress cervical cancer progression: an integrated experimental and computational analysis.

BACKGROUND: Cervical cancer (CC) is a significant global health concern, demanding the consideration of novel therapeutic strategies. The signal transducer and activator of transcription 3 (STAT3) pathway has been implicated in cancer progression and is a potential target for therapeutic intervention. This study aimed to explore the therapeutic potential of TTI-101, a small molecule STAT3 inhibitor, in CC and investigate its underlying mechanisms. METHODS: Molecular docking studies and molecular dynamics simulations were performed to explore the binding interaction between TTI-101 and STAT3 and assess the stability of the STAT3-TTI-101 complex. Cell viability assays, wound healing assays, colony formation assays, flow cytometry analysis, and gene expression analysis were conducted. In vivo xenograft models were used to assess the antitumor efficacy of TTI-101. RESULTS: The in silico analysis shows a stable binding interaction between TTI-101 and STAT3. TTI-101 treatment inhibits cell viability, clonogenic ability, and cell migration in CC cells. Furthermore, TTI-101 induces apoptosis and cell cycle arrest. Analysis of apoptosis-related markers demonstrated dysregulation of Bax, Bcl-2, and Caspase-3 upon TTI-101 treatment. Moreover, TTI-101 caused G2/M phase arrest accompanied by a decrease in CDK1 and Cyclin B1 at mRNA levels. In the xenograft model, TTI-101 significantly inhibited tumor growth without adverse effects on body weight. CONCLUSION: TTI-101 exhibited anticancer effects by targeting the STAT3/c-Myc signaling pathway, inducing cell cycle arrest, and promoting apoptosis in CC cells. These findings provide valuable insights into the development of novel therapeutic strategies for cervical cancer. Further investigation is warranted to validate the clinical application of TTI-101.

International review of blood donation nucleic acid amplification testing.

BACKGROUND AND OBJECTIVES: Nucleic acid amplification testing (NAT), in blood services context, is used for the detection of viral and parasite nucleic acids to reduce transfusion-transmitted infections. This project reviewed NAT for screening blood donations globally. MATERIALS AND METHODS: A survey on NAT usage, developed by the International Society of Blood Transfusion Working Party on Transfusion-transmitted Infectious Diseases (ISBT WP-TTID), was distributed through ISBT WP-TTID members. Data were analysed using descriptive statistics. RESULTS: Forty-three responses were received from 32 countries. Increased adoption of blood donation viral screening by NAT was observed over the past decade. NAT-positive donations were detected for all viruses tested in 2019 (proportion of donations positive by NAT were 0.0099% for human immunodeficiency virus [HIV], 0.0063% for hepatitis C virus [HCV], 0.0247% for hepatitis B virus [HBV], 0.0323% for hepatitis E virus [HEV], 0.0014% for West Nile virus [WNV] and 0.00005% for Zika virus [ZIKV]). Globally, over 3100 NAT-positive donations were identified as NAT yield or solely by NAT in 2019 and over 22,000 since the introduction of NAT, with HBV accounting for over half. NAT-positivity rate was higher in first-time donors for all viruses tested except WNV. During 2019, a small number of participants performed NAT for parasites (Trypanosoma cruzi, Babesia spp., Plasmodium spp.). CONCLUSION: This survey captures current use of blood donation NAT globally. There has been increased NAT usage over the last decade. It is clear that NAT contributes to improving blood transfusion safety globally; however, there is a need to overcome economic barriers for regions/countries not performing NAT.

TTI1 promotes non-small-cell lung cancer progression by regulating the mTOR signaling pathway.

The role of TELO2-interacting protein 1 (TTI1) in the progression of several types of cancer has been reported recently. The aim of this study was to estimate the expression and potential value of TTI1 in non-small-cell lung cancer (NSCLC) patients. The expression of TTI1 and its prognostic value in NSCLC from The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database were analyzed. To verify the bioinformatics findings, a tissue microarray containing 160 NSCLC and paired peritumoral tissues from NSCLC patients was analyzed by immunohistochemistry for TTI1. Subsequently, the roles of TTI1 in NSCLC cells were investigated in vivo by establishing xenograft models in nude mice and in vitro by transwell, CCK-8, wound healing, and colony formation assays. In addition, quantitative real-time polymerase chain reaction and western blot were applied to explore the underlying mechanism by which TTI1 promotes tumor progression. Finally, the relationship between TTI1 and Ki67 expression level in NSCLC was probed, and Kaplan-Meier and Cox analyses were performed to assess the prognostic merit of TTI1 and Ki67 in NSCLC patients. We found that the expression of TTI1 was significantly upregulated in NSCLC tissues compared to paired peritumoral tissues, which coincides with the bioinformatics findings from the TCGA and GEO databases. TTI1 was highly expressed in NSCLC patients with large tumors, advanced tumor stage, and lymphatic metastasis. In addition, the prognostic analysis identified TTI1 as an independent indication for poor prognosis of NSCLC patients. In vitro, upregulation of TTI1 in NSCLC cells could facilitate cell invasion, metastasis, viability, and proliferation. Mechanistically, our study verified that TTI1 could regulate mTOR activity, which has a pivotal role in human cancer. Consistently, the expressions of TTI1 and Ki67 had a positive relationship in NSCLC cells and tissues. Notably, patients with overexpression of TTI1 or Ki67 had a shorter overall survival rate and a higher disease-free survival rate compared to patients with low expression of TTI1 or Ki67, and the combination of TTI1 and Ki67 was an independent parameter predicting the prognosis and recurrence of NSCLC patients. We conclude that TTI1 promotes NSCLC cell proliferation, metastasis, and invasion by regulating mTOR activity, and the combination of TTI1 and Ki67 is a valuable molecular biomarker for the survival and recurrence of NSCLC patients.

Systematic review of prevalence and risk factors of transfusion transmissible infections among blood donors, and blood safety improvements in Southern Africa.

Blood and blood products are listed as one of the essential medicines by the World Health Organization (WHO). In addition to inadequate supply, most sub-Saharan Africa (SSA) nations fail to meet their blood needs because many donated blood units are discarded because they are contaminated with transfusion-transmitted infections (TTIs). We sought to estimate the prevalence of TTIs, identify the risk factors for TTIs among blood donors, and identify the efforts and interventions that have been made to improve blood safety in Southern African nations, particularly the nations of the South African Development Community (SADC). We investigated the prevalence and risk factors for TTIs, blood safety interventions, and blood quality improvement in the SADC region from major PubMed/MEDLINE, Cochrane Library, and HINARI databases from 1 January 2011 to 31 April 2021. All investigations followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). In meta-analysis, we estimated the pooled TTIs prevalence and summarised the same using forest plots. A total of 180 articles published from the SSA region were identified covering our three targeted themes: TTI prevalence, risk factors for TTIs, and blood safety improvements. Of these 180 articles, only 27 (15%) focused on the SADC region. The overall pooled TTI prevalence estimate was 2.0% (95% CI: 1.0-3.0) and hepatitis B was the most prevalent TTI in the region (prevalence = 3.0; 95% CI: 2.0-5.0). The prevalence of HIV, HCV, and syphilis was 2.0% (95% CI: 1.0-4.0), 1.0% (95% CI: 0.0-2.0), and 2.0% (95% CI: 0.0-8.0), respectively. In general, replacement donors and first-time donors were more likely to be infected with TTIs than repeat donors. Twelve articles explored blood safety research in the region; however, they vary greatly highlighting the need for consistent and more comprehensive research. Few publications were identified that were from the SADC region, indicating lack of research or resources towards improving both quantity and quality of blood donation. TTI prevalence remains one of the highest in the world and blood safety recommendations vary across the region. More effort should be directed towards developing a cohesive regional blood transfusion policy and effective blood monitoring and evaluation strategies.

TTT (Tel2-Tti1-Tti2) Complex, the Co-Chaperone of PIKKs and a Potential Target for Cancer Chemotherapy.

The heterotrimeric Tel2-Tti1-Tti2 or TTT complex is essential for cell viability and highly observed in eukaryotes. As the co-chaperone of ATR, ATM, DNA-PKcs, mTOR, SMG1, and TRRAP, the phosphatidylinositol 3-kinase-related kinases (PIKKs) and a group of large proteins of 300-500 kDa, the TTT plays crucial roles in genome stability, cell proliferation, telomere maintenance, and aging. Most of the protein kinases in the kinome are targeted by co-chaperone Cdc37 for proper folding and stability. Like Cdc37, accumulating evidence has established the mechanism by which the TTT interacts with chaperone Hsp90 via R2TP (Rvb1-Rvb2-Tah1-Pih1) complex or other proteins for co-translational maturation of the PIKKs. Recent structural studies have revealed the α-solenoid structure of the TTT and its interactions with the R2TP complex, which shed new light on the co-chaperone mechanism and provide new research opportunities. A series of mutations of the TTT have been identified that cause disease syndrome with neurodevelopmental defects, and misregulation of the TTT has been shown to contribute to myeloma, colorectal, and non-small-cell lung cancers. Surprisingly, Tel2 in the TTT complex has recently been found to be a target of ivermectin, an antiparasitic drug that has been used by millions of patients. This discovery provides mechanistic insight into the anti-cancer effect of ivermectin and thus promotes the repurposing of this Nobel-prize-winning medicine for cancer chemotherapy. Here, we briefly review the discovery of the TTT complex, discuss the recent studies, and describe the perspectives for future investigation.

A data-driven decision support system with smart packaging in grocery store supply chains during outbreaks.

The unexpected emergence of the COVID-19 pandemic has changed how grocery shopping is done. The grocery retail stores need to ensure hygiene, quality, and safety concerns in-store shopping by providing "no-touch" smart packaging solutions for agri-food products. The benefit of smart packaging is to inform consumers about the freshness level of a packaged product without having direct contact. This paper proposes a data-driven decision support system that uses smart packaging as a smart product-service system to manage the sustainable grocery store supply chain during outbreaks to prevent food waste. The proposed model dynamically updates the price of a packaged perishable product depending on freshness level while reducing food waste and the number of rejected customers and maximising profit by increasing the inventory turnover rate of grocery stores. The model was tested on a hypothetical but realistic case study of a single product. The results of this study showed that stock capacities, freshness discount rate, freshness period, and quantity discounts significantly affect the performance of a grocery store supply chain during outbreaks.

Emerging drugs for the treatment of cutaneous T-cell lymphoma.

INTRODUCTION: Cutaneous T cell lymphoma (CTCL) is a rare and incurable group of non-Hodgkin lymphomas that manifest as patches, plaques, tumors, and/or erythroderma in the skin. Standard skin-directed therapies for CTCL are effective in patients with indolent early-stage disease, but more advanced/refractory stage patients require systemic therapies. However, none of the treatments are considered curative and most patients suffer from relapses. Biologic therapies and immunotherapy provide novel treatment options for patients with advanced or refractory disease. AREAS COVERED: This review provides a discussion of recently approved biological and novel therapeutics that are actively developed for the management of the heterogeneous group of CTCL. EXPERT OPINION: Mogamulizumab and brentuximab vedotin have reached the market and are approved for the treatment of CTCL, providing valuable options. Additionally, therapies utilizing immune checkpoint inhibitors, miRNA inhibitors, and peptide inhibitors show promising results in clinical trials. Durvalumab, pembrolizumab, TTI-621, BNZ-1, and MRG-106 are several of the emerging treatments still in trials. Further combinatorial studies are needed as none of the treatments have demonstrated long-term remissions.

Comparative evaluation of ADVIA Centaur® XP chemiluminescence system for screening of HBV, HCV, HIV and syphilis in Indian blood donors.

BACKGROUND: The introduction of chemiluminescent immunoassay (CLIA) in blood donor screening has led to a gradual replacement of enzyme-linked-immunosorbent assay (ELISA) as the former offers automation, higher sensitivity and lower turn-around-time. However, only a few CLIA platforms are used for blood donor screening in India. The present study evaluated one such newer platform viz., Adiva Centaur XP CLIA for screening of HBV, HCV, HIV and syphilis. MATERIAL AND METHODS: Prospective comparative study wherein 4843 whole blood donors were screened for HBsAg, Anti-HCV, HIV Ag-Ab and Anti-treponemal antibodies in both Advia Centaur XP and Architect i2000SR platforms. Additional tests were performed in samples which were reactive in only one of the platforms. The sensitivity, specificity, positive predictive value, negative predictive value, accuracy, false positive rate and false negative rate of both the platforms were compared. Kappa coefficient was calculated to determine the agreement between the testing platforms. RESULTS: The sensitivity of Advia Centaur platform for HBV, HCV, HIV and syphilis detection were 94.9 %, 100 %, 100 % and 100 % respectively as compared to 96.6 %, 100 %, 100 % and 100 % in Architect i2000SR platform. The specificity of both the platforms were 99.8-99.9 % for all the four tests. The agreement between the two platforms was almost perfect for HBV, HCV and syphilis testing; and fair for HIV testing. CONCLUSION: The Advia Centaur CLIA platform was found to be comparable with the Architect CLIA platform for blood donor screening. Unexpected finding was the occurrence of HBV false negatives in both the platforms, possibly due to HBsAg mutations.

Impact of delay in diagnosis and treatment-initiation on disease stage and survival in oral cavity cancer: a systematic review.

AIM/OBJECTIVES: This study aimed to systematically review the literature on the impact of delay in diagnosis and treatment of oral cavity cancer. METHODS: PubMed and Embase were systematically searched for articles reporting impact of delay in diagnosis and treatment on cancer-stage and survival of oral cavity cancer. Studies comprising at least ten patients, and published since the year 2000, were included. RESULTS: Sixteen studies (n = 45,001, range: 62-18,677 per study, 83% men), from Australia, Asia, Europe, North America and South America, met the inclusion criteria. Eleven studies (n = 1,460) examined delay in diagnosis, while five studies (n = 43,541) reported delay in treatment. Eight of the eleven studies, examining delay in diagnosis (n = 1,220), analyzed the correlation between delay in diagnosis and tumor stage at diagnosis. Three studies found a significant correlation between patient delay and advanced stage at diagnosis (p < 0.05), whereas three other studies did not. The studies reporting a significant correlation were from Asian countries, whereas the three studies that did not find a correlation were from other continents. Studies reporting on professional delay and total diagnostic delay, generally, did not find a significant correlation with advanced cancer at diagnosis. Time to treatment (TTI), defined as time from diagnosis to treatment, was found significantly correlated with survival in three studies (p < 0.01, p < 0.001, p < 0.05), and nonsignificant in two studies. CONCLUSION: A significant correlation between patient delay and advanced stage cancer was reported in Asian studies only, while professional delay and total diagnostic delay were generally found to be non-correlated with advanced stage cancer at diagnosis. TTI was in some studies reported to be correlated with poorer outcome, while other studies did not report a correlation. One study presented that there was no clear advantage in overall survival (OS) for patients treated within 30 days, compared to patients treated between 30 and 44 days.

Whole-exome sequencing identifies homozygous mutation in TTI2 in a child with primary microcephaly: a case report.

BACKGROUND: Primary microcephaly is defined as reduced occipital-frontal circumference noticeable before 36 weeks of gestation. Large amount of insults might lead to microcephaly including infections, hypoxia and genetic mutations. More than 16 genes are described in autosomal recessive primary microcephaly. However, the cause of microcephaly remains unclear in many cases after extensive investigations and genetic screening. CASE PRESENTATION: Here, we described the case of a boy with primary microcephaly who presented to a neurology clinic with short stature, global development delay, dyskinetic movement, strabismus and dysmorphic features. We performed microcephaly investigations and genetic panels. Then, we performed whole-exome sequencing to identify any genetic cause. Microcephaly investigations and genetic panels were negative, but we found a new D317V homozygous mutation in TELOE-2 interacting protein 2 (TTI2) gene by whole-exome sequencing. TTI2 is implicated in DNA damage response and mutation in that gene was previously described in mental retardation, autosomal recessive 39. CONCLUSIONS: We described the first French Canadian case with primary microcephaly and global developmental delay secondary to a new D317V homozygous mutation in TTI2 gene. Our report also highlights the importance of TTI2 protein in brain development.

Maize defective kernel mutant generated by insertion of a Ds element in a gene encoding a highly conserved TTI2 cochaperone.

We have used the newly engineered transposable element Dsg to tag a gene that gives rise to a defective kernel (dek) phenotype. Dsg requires the autonomous element Ac for transposition. Upon excision, it leaves a short DNA footprint that can create in-frame and frameshift insertions in coding sequences. Therefore, we could create alleles of the tagged gene that confirmed causation of the dek phenotype by the Dsg insertion. The mutation, designated dek38-Dsg, is embryonic lethal, has a defective basal endosperm transfer (BETL) layer, and results in a smaller seed with highly underdeveloped endosperm. The maize dek38 gene encodes a TTI2 (Tel2-interacting protein 2) molecular cochaperone. In yeast and mammals, TTI2 associates with two other cochaperones, TEL2 (Telomere maintenance 2) and TTI1 (Tel2-interacting protein 1), to form the triple T complex that regulates DNA damage response. Therefore, we cloned the maize Tel2 and Tti1 homologs and showed that TEL2 can interact with both TTI1 and TTI2 in yeast two-hybrid assays. The three proteins regulate the cellular levels of phosphatidylinositol 3-kinase-related kinases (PIKKs) and localize to the cytoplasm and the nucleus, consistent with known subcellular locations of PIKKs. dek38-Dsg displays reduced pollen transmission, indicating TTI2's importance in male reproductive cell development.

Enabling Medicine Reuse Using a Digital Time Temperature Humidity Sensor in an Internet of Pharmaceutical Things Concept.

Medicinal waste due to improper handling of unwanted medicines creates health and environmental risks. However, the re-dispensing of unused prescribed medicines from patients seems to be accepted by stakeholders when quality and safety requirements are met. Reusing dispensed medicines may help reduce waste, but a comprehensive validation method is not generally available. The design of a novel digital time temperature and humidity indicator based on an Internet of Pharmaceutical Things concept is proposed to facilitate the validation, and a prototype is presented using smart sensors with cloud connectivity acting as the key technology for verifying and enabling the reuse of returned medicines. Deficiency of existing technologies is evaluated based on the results of this development, and recommendations for future research are suggested.

Confirmation that variants in TTI2 are responsible for autosomal recessive intellectual disability.

TTI2 (MIM 614126) has been described as responsible for autosomal recessive intellectual disability (ID; MRT39, MIM:615541) in only two inbred families. Here, we give an account of two individuals from two unrelated outbred families harbouring compound heterozygous TTI2 pathogenic variants. Together with severe ID, progressive microcephaly, scoliosis and sleeping disorder are the most striking features in the two individuals concerned. TTI2, together with TTI1 and TELO2, encode proteins that constitute the triple T heterotrimeric complex. This TTT complex interacts with the HSP90 and R2TP to form a super-complex that has a chaperone function stabilising and maturing a number of kinases, such as ataxia-telangiectasia mutated and mechanistic target of rapamycin, which are key regulators of cell proliferation and genome maintenance. Pathogenic variants in TTI2 logically result in a phenotype close to that caused by TELO2 variants.

Influence of culture conditions on the technological properties of Carnobacterium maltaromaticum CNCM I-3298 starters.

AIM: The aim of this study is to investigate the effect of a broad spectrum of culture conditions on the acidification activity and viability of Carnobacterium maltaromaticum CNCM I-3298, the main technological properties that determine the shelf-life of biological time-temperature integrator (TTI) labels. METHODS AND RESULTS: Cells were cultivated at different temperatures (20-37°C) and pH (6-9·5) according to a modified central composite design and harvested at increasing times up to 10 h of stationary phase. Acidification activity and viability of freeze-thawed concentrates were assessed in medium mimicking the biological label. Acidification activity was influenced by all three culture conditions, but pH and harvest time were the most influential. Viability was not significantly affected by the tested range of culture conditions. CONCLUSIONS: Carnobacterium maltaromaticum CNCM I-3298 must be cultivated at 20°C, pH 6 and harvested at the beginning of stationary phase to exhibit fastest acidification activities. However, if slower acidification activities are pursued, the recommended culture conditions are 30°C, pH 9·5 and a harvest time between 4-6 h of stationary phase. SIGNIFICANCE AND IMPACT OF THE STUDY: Quantifying the impact of fermentation temperature, pH and harvest time has led to a predictive model for the production of biological TTI covering a broad range of shelf-lives.

Reflections on current status of blood transfusion transplant viral safety in UK/Europe and on novel strategies for enhancing donors/recipients healthcare in promising era of advanced cell therapy/regenerative medicine.

In this report, a personal view is provided on the current achievements and challenges with unresolved issues regarding the viral and transfusion safety of blood in the UK and Europe. Advances in plasma fractionation processes and the use of alternative strategies to reshape treatment of bleeding disorders are also explored. The relationships between the cellular storage lesion and transfusion outcomes using newer tools such as -omics are explored. The use of some newer developments in the promising areas of diagnosis, development, and research [DDR] strategies for improving healthcare of both donors and recipients are discussed using the current transfusion transplant practices in the UK as an example. Other key sections include: a concise presentation of the "Big Six Parameters" for enhancing the safety of transfusion / transplant practice; surmounting the unresolved issues of blood viral safety and food borne diseases, the circulatory role of the donor-gut microbiome in transfusion-induced immunomodulation, and the use of extracellular vesicles [EV] in routine aspects of the cell lesion and in the clinical performance of red cells. These topics are discussed together with the concept of using cell microparticles in drug delivery and the promising role of novel blood products such as serum eye drops and platelet lysates in regenerative medicine. It is hoped that the information conveyed in this overview would be of educational value and serve the transfusion/ transplant services and those involved in related clinical-DDR strategies worldwide and cultivate future talents capable of serving patients.

Seroprevalence of transfusion-transmissible infections (HBV, HCV, syphilis and HIV) among prospective blood donors in a tertiary health care facility in Calabar, Nigeria; an eleven years evaluation.

BACKGROUND: Provision of constant and safe blood has been a public health challenge in Sub-Saharan Africa with high prevalence of transfusion-transmissible infections (TTIs). This study was aimed at determining the trend and seroprevalence of HBV, HCV, syphilis and HIV across the years within study among prospective blood donors at blood bank in University of Calabar Teaching Hospital (UCTH), Calabar, Nigeria. METHODS: A retrospective analysis of blood donor data from January 2005 to December 2016 was conducted in Blood Bank/Donor Clinic of University of Calabar Teaching Hospital, Calabar, Nigeria. Sera samples were screened for hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus (HCV), human immunodeficiency virus (HIV) 1 and 2 and Treponema pallidum using commercially available immunochromatic based kits. RESULTS: Out of the 24,979 screened prospective donors in the 2005-2016 study period, 3739 (14.96%) were infected with at least one infective agent. The overall prevalence of HBV, HCV, syphilis and HIV were 4.1, 3.6, 3.1 and 4.2%, respectively. During the period of study, the percentage of all transfusion-transmissible infections declined significantly with remarkable decline in HIV. The study showed male dominated donor pool (98.7%) with higher prevalence (4.2%) of transfusion-transmissible infections than in female donors (0.0%). Commercial donors constituted majority (62.0%) of the donors and as well had the highest prevalence of transfusion-transmissible infections. Majority (62.9%) of the donors were repeat donors. CONCLUSION: HBV, HCV, syphilis and HIV have remained a big threat to safe blood transfusion in Nigeria and Sub-Saharan Africa at large. Strict adherence to selection criteria and algorithm of donor screening are recommended.

Advances on the Structure of the R2TP/Prefoldin-like Complex.

Cellular stability, assembly and activation of a growing list of macromolecular complexes require the action of HSP90 working in concert with the R2TP/Prefoldin-like (R2TP/PFDL) co-chaperone. RNA polymerase II, snoRNPs and complexes of PI3-kinase-like kinases, a family that includes the ATM, ATR, DNA-PKcs, TRAPP, SMG1 and mTOR proteins, are among the clients of the HSP90-R2TP system. Evidence links the R2TP/PFDL pathway with cancer, most likely because of the essential role in pathways commonly deregulated in cancer. R2TP forms the core of the co-cochaperone and orchestrates the recruitment of HSP90 and clients, whereas prefoldin and additional prefoldin-like proteins, including URI, associate with R2TP, but their function is still unclear. The mechanism by which R2TP/PFLD facilitates assembly and activation of such a variety of macromolecular complexes is poorly understood. Recent efforts in the structural characterization of R2TP have started to provide some mechanistic insights. We summarize recent structural findings, particularly how cryo-electron microscopy (cryo-EM) is contributing to our understanding of the architecture of the R2TP core complex. Structural differences discovered between yeast and human R2TP reveal unanticipated complexities of the metazoan R2TP complex, and opens new and interesting questions about how R2TP/PFLD works.

Preliminary Study on Biosensor-Type Time-Temperature Integrator for Intelligent Food Packaging.

A glucose biosensor was utilized as a platform for the time-temperature integrator (TTI), a device for intelligent food packaging. The TTI system is composed of glucose oxidase, glucose, a pH indicator, and a three-electrode potentiostat, which produces an electrical signal as well as color development. The reaction kinetics of these response variables were analyzed under isothermal conditions. The reaction rates of the electrical current and color changes were 0.0360 ± 0.0020 (95% confidence limit), 0.0566 ± 0.0026, 0.0716 ± 0.0024, 0.1073 ± 0.0028 µA/min, and 0.0187 ± 0.0005, 0.0293 ± 0.0018, 0.0363 ± 0.0012, 0.0540 ± 0.0019 1/min, at 5, 15, 25, and 35 °C, respectively. The Arrhenius activation energy of the current reaction (Eacurrent) was 25.0 ± 1.6 kJ/mol and the Eacolor of the color reactions was 24.2 ± 0.6 kJ/mol. The similarity of these Ea shows agreement in the prediction of food qualities between the electrical signal and color development. Consequently, the function of the new time-temperature integrator system could be extended to that of a biosensor compatible with any electrical utilization equipment.

Silent killers: Transfusion Transmissible Infections-TTI, among asymptomatic population of Pakistan.

OBJECTIVE: To analyse transfusion transmissible infections in asymptomatic population. METHODS: This study was conducted at the Allama Iqbal Medical College and Jinnah Hospital, Lahore, Pakistan, from December 2014 to November 2015, and comprised healthy asymptomatic blood donors.Every sample was screened for the presence of antibodies/antigens of hepatitis C virus, human immunodeficiency virus, treponemapallidum, hepatitis B virus and malaria parasite through rapid immunochromatographic technique. RESULTS: Of the 18,274 blood donors, 17,276(94.53%) were found healthy and 998(5.46%) were infected. Besides, 71(0.38%) had multiple infections. The overall frequency of anti-hepatitis C virus, treponemapallidum (syphilis), hepatitis B surface antigen, malaria parasite and anti-human immunodeficiency virus was 480(2.62%), 284(1.55%), 210(1.10%), 20(0.10%) and 4(0.02%), respectively. CONCLUSIONS: Blood transfusion was found to be a significant but preventable mode of spread of transfusion transmissible infections.