A New Species of the Genus Tylototriton(Amphibia: Urodela: Salamandridae) from Eastern Himalaya

A new species of the genus Tylototriton is described from eastern Himalaya based on molecular and morphological comparisons. The new species is diagnosable from the closely-related species by having light brown colouration in dorsal region in life, flat and blunt snout, greatly separated dorsolateral bony ridges on head and straightthick tailfin. In addition to head morphology, the new species is also morphologically distinguishable from its closelyrelated species Tylototriton shanorum by having 16 dorsal warts and average smaller Snout Vent Length（SVL）.

Genetic and phenotypic heterogeneity in tropical calcific pancreatitis

Tropical calcific pancreatitis(TCP)is a form of chronic non-alcoholic pancreatitis initially reported in the developing parts of the tropical world.The clinical phenotype of TCP has undergone marked changes since its first description in 1968.The disease is now seen in relatively older people with less severe symptoms.In addition,there are varying reports on the proportion of cases presenting with imaging abnormalities like calcification,ductal dilation,and glandular atrophy.Significant progress has also been made in understanding the etiopathology of TCP.The role of malnutrition and cassava toxicity in its pathogenesis is disproven and few studies have focused on the role of micronutrient deficiency and oxidative stress in the etiopathogenesis of TCP.Emerging evidence support an important role for genetic risk factors in TCP.Several studies have shown that,rather than mutations in trypsinogens,variants in serine protease inhibitor kazal type 1,cathepsin B,chymotrypsin C,cystic fibrosis transmembrane regulator,and carboxypeptidase A1,predict risk of TCP.These studies also provided evidence of mutational heterogeneity between TCP and chronic pancreatitis in Western populations.The current review summarizes recent advances that have implications in the understanding of the pathophysiology and thus,heterogeneity in genotype-phenotype correlations in TCP.

Bioengineered functional humanized livers： An emerging supportive modality to bridge the gap of organ transplantation for management of end-stage liver diseases

End stage liver diseases （ESLD） represent a major, neglected global public health crisis which requires an urgent action towards fnding a proper cure. Orthotro-pic liver transplantation has been the only definitive treatment modality for ESLD. However, shortage of donor organs, timely unavailability, post-surgery related complications and financial burden on the patients li-mits the number of patients receiving the transplants. Since last two decades cell-based therapies have revolu-tionized the feld of organ/tissue regeneration. However providing an alternative organ source to address the donor liver shortage still poses potential challenges. The developments made in this direction provide useful futuristic approaches, which could be translated into preclinical and clinical settings targeting appropriate applications in specific disease conditions. Earlier studies have demonstrated the applicability of this particular approach to generate functional organ in rodent system by connecting them with portal and hepatic circulatory networks. However, such strategy requires very high level of surgical expertise and also poses the technical and financial questions towards its future applicability. Hence, alternative sites for generating secondary organs are being tested in several types of disease conditions. Among different sites, omentum has been proved to be more appropriate site for implanting several kinds of functional tissue constructs without eliciting much immunological response. Hence, omentum may be con-sidered as better site for transplanting humanized bio-engineered ex vivo generated livers, thereby creating a secondary organ at intra-omental site. However, the expertise for generating such bioengineered organs are limited and only very few centres are involved for inve-stigating the potential use of such implants in clinical practice due to gap between the clinical transplant surgeons and basic scientists working on the concept evolution. Herein we discuss the recent advances and challenges to create functional secondary organs thr-ough intra-omental transplantation of ex vivo genera-ted bioengineered humanized livers and their further application in the management of ESLD as a supportive bridge for organ transplantation.

Long-term and non-invasive in vivo tracking of DiD dye-labeled human hepatic progenitors in chronic liver disease models

BACKGROUND Chronic liver diseases(CLD)are the major public health burden due to the continuous increasing rate of global morbidity and mortality.The inherent limitations of organ transplantation have led to the development of stem cell-based therapy as a supportive and promising therapeutic option.However,identifying the fate of transplanted cells in vivo represents a crucial obstacle.AIM To evaluate the potential applicability of DiD dye as a cell labeling agent for longterm,and non-invasive in vivo tracking of transplanted cells in the liver.METHODS Magnetically sorted,epithelial cell adhesion molecule positive(1×106 cells/mL)fetal hepatic progenitor cells were labeled with DiD dye and transplanted into the livers of CLD-severe combined immunodeficiency(SCID)mice.Near-infrared(NIR)imaging was performed for in vivo tracking of the DiD-labeled transplanted cells along with colocalization of hepatic markers for up to 80 d.The existence of human cells within mouse livers was identified using Alu polymerase chain reaction and sequencing.RESULTS NIR fluorescence imaging of CLD-SCID mice showed a positive fluorescence signal of DiD at days 7,15,30,45,60,and 80 post-transplantation.Furthermore,positive staining of cytokeratin,c-Met,and albumin colocalizing with DiD fluorescence clearly demonstrated that the fluorescent signal of hepatic markers emerged from the DiD-labeled transplanted cells.Recovery of liver function was also observed with serum levels of glutamic-oxaloacetic transaminase,glutamate-pyruvate transaminase,and bilirubin.The detection of human-specific Alu sequence from the transplanted mouse livers provided evidence for the survival of transplanted cells at day 80.CONCLUSION DiD-labeling is promising for long-term and non-invasive in vivo cell tracking,and understanding the regenerative mechanisms incurred by the transplanted cells.

Pretreatment of caffeine leads to partial neuroprotection in MPTP model of Parkinson＇s disease

Parkinson＇s disease （PD） is disorder affecting more than a common neurodegenerative 1% people above 60 years of age worldwide, manifesting as the impaired motor function such as tremors, rigidity, akinesia/bradykinesia and postural inefficiency with a reduced life expectancy （Dorsey et al., 2007）. PD is believed to be the end result of the progressive death of dopaminergic neurons in the substantia nigra pars compacta （SNc）.

Natural product based novel small molecules with promising neurotrophic,neurogenic and anti-neuroinflammatory actions can be developed as stroke therapeutics

Stroke is the world’s second leading cause of death and a major cause of adult disability.Among the different kinds of stroke,ischemic stroke is the most widely prevalent type,causing high morbidity and mortality worldwide（Moskowitz et al.,2010）.

Development of peptidomimetic hydroxamates as PfA-M1 and PfA-M17 dual inhibitors: Biological evaluation and structural characterization by cocrystallization

Plasmodium parasites causing malaria have developed resistance to most of the antimalarials in use,in-cluding the artemisinin-based combinations,which are the last line of defense against malaria.This ne-cessitates the discovery of new targets and the development of novel antimalarials.Plasmodium falciparum alanyl aminopeptidase(PfA-M1)and leucyl aminopeptidase(PfA-M17)belong to the M1 and M17 family of metalloproteases respectively and play critical roles in the asexual erythrocytic stage of development.These enzymes have been suggested as potential antimalarial drug targets.Herein we describe the devel-opment of peptidomimetic hydroxamates as PfA-M1 and PfA-M17 dual inhibitors.Most of the compounds described in this study display inhibition at sub-micromolar range against the recombinant PfA-M1 and PfA-M17.More importantly,compound 26 not only exhibits potent malarial aminopeptidases inhibitory activities(PfA-M1 K i=0.11±0.0002μmol/L,PfA-M17 K_(i)=0.05±0.005μmol/L),but also possesses remarkable selectivity over the mammalian counterpart(pAPN K_(i)=17.24±0.08μmol/L),which endows 26 with strong inhibition of the malarial parasite growth and negligible cytotoxicity on human cell lines.Crystal structures of PfA-M1 at atomic resolution in complex with four different compounds including compound 26 establish the structural basis for their inhibitory activities.Notably,the terminal ureidoben-zyl group of 26 explores the S2' region where differences between the malarial and mammalian enzymes are apparent,which rationalizes the selectivity of 26.Together,our data provide important insights for the rational and structure-based design of selective and dual inhibitors of malarial aminopeptidases that will likely lead to novel chemotherapeutics for the treatment of malaria.

Development of islet organoids from human induced pluripotent stem cells in a cross-linked collagen scaffold

Islets organoids would have value in the cell replacement therapy for diabetes apart from usual personalized drug screening routes.Generation of a large number of Islets like clusters,with ability to respond to glucose stimulation appears to be an ideal choice.In this study we have generated islet organoids with the ability to respond to glucose stimulation by insulin release.The source of the cells was an iPSC cell line differentiated into the pancreatic progenitors.These cells were assembled in matrigel or cross-linked collagen scaffold and compared for their efficacy to release insulin upon stimulation with glucose.The assembled organoids were examined by immunohistochemistry and expression of the relevant marker genes.The organoids showed expression of islet like markers in both-matrigel and crosslinked collagen scaffold.The islet organoids in both the cases showed release of insulin upon stimulation with glucose.The crosslinked collagen scaffold is quite stable and supports islet cells growth and function.