From nature to creation: Going around in circles,the art of peptide cyclization

Cyclic peptides and cyclotides are becoming common identities within the present efforts seen in peptide engineering – as we seek approaches to achieve potent biological activity, pharmacological selectivity, structurally stability and oral bioavailability. Yet this unique family of peptides has faced uncommon hurdles in their discovery, synthesis and bioengineering, retaining to characteristics that truly deviate these from their linear counterparts. In this mini-review we take a board spectrum approach to introduce this novel family of biomolecules and the troubles that they face in their sequence and disulfide connectivity assignment, together highlighting the present combined strategies involved in cyclic peptide/cyclotide synthesis and modification. These efforts have circumvented otherwise impossible hurdles in their manipulation and production that are only now advancing cyclic peptides/cyclotides as research probes and future pharmaceutical templates.     

Vasectomy reversal in Nepal

Data from 157 men in Nepal who had vasectomy reversal are analysed. Most sought reversal within 5 years of vasectomy. Half of the men sought reversal because of the death of a male child, and about one-fourth because of the loss of a female child. Re-marriage was the primary reason for only 10% of the men. Those having reversal because of the loss of a male child were generally younger, and for almost half of this group, the age of their last child at the time of their vasectomy was under 2 years. The results suggest that the demand for reversal could be considerably reduced by more careful screening of the potential vasectomy acceptors.     

Structural features and oligomeric nature of human podocin domain

Podocytes are crucial cells of the glomerular filtration unit and plays a vital role at the interface of the blood-urine barrier. Podocyte slit-diaphragm is a modified tight junction that facilitates size and charge-dependent permselectivity. Several proteins including podocin, nephrin, CD2AP, and TRPC6 form a macromolecular assembly and constitute the slit-diaphragm. Podocin is an integral membrane protein attached to the inner membrane of the podocyte via a short transmembrane region (101–125). The cytosolic N- and C-terminus help podocin to attain a hook-like structure. Podocin shares 44% homology with stomatin family proteins and similar to the stomatin proteins, podocin was shown to associate into higher-order oligomers at the site of slit-diaphragm. However, the stoichiometry of the homo-oligomers and how it partakes in the macromolecular assemblies with other slit-diaphragm proteins remains elusive. Here we investigated the oligomeric propensity of a truncated podocin construct (residues:126–350). We show that the podocin domain majorly homo-oligomerizes into a 16-mer. Circular dichroism and fluorescence spectroscopy suggest that the 16-mer oligomer has considerable secondary structure and moderate tertiary packing.     

Calpain Inhibitors as Potential Therapeutic Modulators in Neurodegenerative Diseases

It is considered a significant challenge to understand the neuronal cell death mechanisms with a suitable cure for neurodegenerative disorders in the coming years. Calpains are one of the best-considered “cysteine proteases activated” in brain disorders. Calpain is an important marker and mediator in the pathophysiology of neurodegeneration. Calpain activation being the essential neurodegenerative factor causing apoptotic machinery activation, it is crucial to develop reliable and effective approaches to prevent calpain-mediated apoptosis in degenerating neurons. It has been recently seen that the “inhibition of calpain activation” has appeared as a possible therapeutic target for managing neurodegenerative diseases. A systematic literature review of PubMed, Medline, Bentham, Scopus, and EMBASE (Elsevier) databases was conducted. The present article reviews the basic pathobiology and role of selective calpain inhibitors used in various neurodegenerative diseases as a therapeutic target.

Graphical Abstract

     

Pinealectomy and LL Abolished Circadian Perching Rhythms but Did Not Alter Circannual Reproductive or Fattening Rhythms in Finches

In the subtropical finch, spotted munia (Lonchura punctulata) circannual rhythms (of gonads, fattening, feeding) have been demonstrated in an information-free environment of continuous illumination (LL), rendering it an ideal model for research on the physiology of the circannual clock. In an attempt to understand the involvement, if any, of the circadian system in the genesis of circannual rhythms, we studied the effect of pinealectomy (LL 15 lux) and strong continuous illumination (LL 300 lux), both known to abolish circadian rhythms, on the circadian perch-hopping rhythm and on the circannual rhythm of reproduction and fattening in the same birds. While both pinealectomy and LL 300 lux treatments abolished the circadian rhythm of motor activity, they had no effect on the circannual rhythms of gonadal size and fattening. If the endogenous circadian rhythm in perch-hopping can be taken to reflect the circadian clock mechanism associated with gonadal functioning, present results suggest that circannual rhythm of reproduction in spotted munia is independent of circadian events.     

A pregnane ester triglycoside from Sarcostemma brevistigma

A new pregnane ester glycoside, brevine, was isolated from the dried twigs of Sarcostemma brevistigma. Its chemical and spectroscopic properties were consistent with the structure 11-O-benzoyl-sarcogenin-3-O-α-L-diginopyranosyl (1 → 4)-O-α-L-diginopyranosyl(1 → 4)-O-α-L-diginopyranoside.     

Detecting Amyloid-β Aggregation with Fiber-Based Fluorescence Correlation Spectroscopy

Soluble aggregates critically influence the chemical and biological aspects of amyloid protein aggregation, but their population is difficult to measure, especially in vivo. We take an optical fiber-based fluorescence correlation spectroscopy (FCS) approach to characterize a solution of aggregating amyloid-β molecules. We find that this technique can easily resolve aggregate particles of size 100 nm or greater in vitro, and the size distribution of these particles agrees well with that obtained by conventional FCS techniques. We propose fiber FCS as a tool for studying aggregation in vivo.     

Ethnic differentials in early childhood mortality in Nepal

This paper investigates the association of early childhood mortality (between birth and second birthday) with ethnicity in Nepal, based on data from the 1976 Nepal Fertility Survey, which was part of the World Fertility Survey. The approach is through a series of hazard models, which incorporate ethnicity, year of birth, mother's illiteracy, father's illiteracy, rural-urban residence, region, sex, maternal age, survival of previous birth, previous birth interval, and breast-feeding as covariates. Ethnic differentials in early childhood mortality are not explained by the other socioeconomic and demographic covariates, except for a modest effect of illiteracy, but the remaining covariates explain a great deal of variability in early childhood mortality itself. Analysis using an improved specification of breast-feeding as an age-varying covariate indicates, on average, that breast-feeding, relative to not breast-feeding, reduces age-specific mortality risks during the first 2 years of life by 76%, a very large effect.