Exploring human-animal host interactions and emergence of COVID-19: Evolutionary and ecological dynamics

The novel coronavirus disease (COVID-19) that emerged in December 2019 had caused substantial morbidity and mortality at the global level within few months. It affected economies, stopped travel, and isolated individuals and populations around the world. Wildlife, especially bats, serve as reservoirs of coronaviruses from which the variant Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) emerged that causes COVID-19. In this review, we describe the current knowledge on COVID-19 and the significance of wildlife hosts in its emergence. Mammalian and avian coronaviruses have diverse host ranges with distinct lineages of coronaviruses. Recombination and reassortments occur more frequently in mixed-animal markets where diverse viral genotypes intermingle. Human coronaviruses have evolved through gene gains and losses primarily in interfaces where wildlife and humans come in frequent contact. There is a gap in our understanding of bats as reservoirs of coronaviruses and there is a misconception that bats periodically transmit coronaviruses to humans. Future research should investigate bat viral diversity and loads at interfaces between humans and bats. Furthermore, there is an urgent need to evaluate viral strains circulating in mixed animal markets, where the coronaviruses circulated before becoming adapted to humans. We propose and discuss a management intervention plan for COVID-19 and raise questions on the suitability of current containment plans. We anticipate that more virulent coronaviruses could emerge unless proper measures are taken to limit interactions between diverse wildlife and humans in wild animal markets.     

Synthesis,anti-inflammatory,analgesic and antioxidant activities of some tetrasubstituted thiophenes

Sets of tetrasubstituted thiophene esters 4a-4g, 5a-5f and 6a-6e were synthesized by reaction of 1-(α-Carbomethoxy-β-aminothiocrotonoyl)-aryl/aroyl amines (3) with 3-(bromoacetyl)coumarin, 1,4-dibromodiacetyl and chloroacetone respectively. The compound 3 were synthesized by nucleophilic addition of aryl/aroylisothiocyanate and enamine (2). The synthesized targeted compounds (4a-4g, 5a-5f and 6a-6e) were evaluated for their in vivo anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at three graded doses employed at 10, 20 and 40 mg/kg body weight using mefanamic acid, ibuprofen and in vivo analgesic activity in acetic acid induced writhing response model at 10 mg/kg dose using ibuprofen as standard drug. The compounds 4a-4f, 5c, 5f, 6c and 6e were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay at the concentrations of 5, 10, 15, 20, 25, 30 and 35 μg/mL using ascorbic acid as standard drug. Among all the targeted compounds 4c showed maximum anti-inflammatory activity of 71% protection at 10 mg/kg and 77% protection at 20 mg/kg to inflamed paw and analgesic activity of 56% inhibition and also maximum in vitro nitric oxide radical scavenging activity having IC₅₀ value 31.59 μg/mL.     

Repeated oral administration of capsaicin increases anxiety-like behaviours with prolonged stress-response in rats

This study was conducted to examine the psycho-emotional effects of repeated oral exposure to capsaicin, the principal active component of chili peppers. Each rat received 1 mL of 0.02% capsaicin into its oral cavity daily, and was subjected to behavioural tests following 10 daily administrations of capsaicin. Stereotypy counts and rostral grooming were significantly increased, and caudal grooming decreased, in capsaicin-treated rats during the ambulatory activity test. In elevated plus maze test, not only the time spent in open arms but also the percent arm entry into open arms was reduced in capsaicin-treated rats compared with control rats. In forced swim test, although swimming duration was decreased, struggling increased in the capsaicin group, immobility duration did not differ between the groups. Repeated oral capsaicin did not affect the basal levels of plasma corticosterone; however, the stress-induced elevation of plasma corticosterone was prolonged in capsaicin treated rats. Oral capsaicin exposure significantly increased c-Fos expression not only in the nucleus tractus of solitarius but also in the paraventricular nucleus. Results suggest that repeated oral exposure to capsaicin increases anxiety-like behaviours in rats, and dysfunction of the hypothalamic-pituitary-adrenal axis may play a role in its pathophysiology.     

Development of indole/indazole-aminopyrimidines as inhibitors of c-Jun N-terminal kinase (JNK): Optimization for JNK potency and physicochemical properties

A novel series of indole/indazole-aminopyrimidines was designed and synthesized with an aim to achieve optimal potency and selectivity for the c-Jun kinase family or JNKs. Structure guided design was used to optimize the series resulting in a significant potency improvement. The best compound (17) has IC₅₀ of 3 nM for JNK1 and 20 nM for JNK2, with greater than 40-fold selectivity against other kinases with good physicochemical and pharmacokinetic properties.     

Effect of weight loss and exercise on angiogenic factors in the circulation and in adipose tissue in obese subjects

Background:

Vascular growth is a prerequisite for adipose tissue (AT) development and expansion. Some AT cytokines and hormones have effects on vascular development, like vascular endothelial growth factor (VEGF‐A), angiopoietin (ANG‐1), ANG‐2 and angiopoietin‐like protein‐4 (ANGPTL‐4).

Methods:

In this study, the independent and combined effects of diet‐induced weight loss and exercise on AT gene expression and proteins levels of those angiogenic factors were investigated. Seventy‐nine obese males and females were randomized to: 1. Exercise‐only (EXO; 12‐weeks exercise without diet‐restriction), 2. Hypocaloric diet (DIO; 8‐weeks very low energy diet (VLED) + 4‐weeks weight maintenance diet) and 3. Hypocaloric diet and exercise (DEX; 8‐weeks VLED + 4‐weeks weight maintenance diet combined with exercise throughout the 12 weeks). Blood samples and fat biopsies were taken before and after the intervention.

Results:

Weight loss was 3.5 kg in the EXO group and 12.3 kg in the DIO and DEX groups. VEGF‐A protein was non‐significantly reduced in the weight loss groups. ANG‐1 protein levels were significantly reduced 22‐25% after all three interventions (P < 0.01). The ANG‐1/ANG‐2 ratio was also decreased in all three groups (P < 0.05) by 27‐38%. ANGPTL‐4 was increased in the EXO group (15%, P < 0.05) and 9% (P < 0.05) in the DIO group. VEGF‐A, ANG‐1, and ANGPTL‐4 were all expressed in human AT, but only ANGPTL‐4 was influenced by the interventions.

Conclusions:

Our data show that serum VEGF‐A, ANG‐1, ANG‐2, and ANGPTL‐4 levels are influenced by weight changes, indicating the involvement of these factors in the obese state. Moreover, it was found that weight loss generally was associated with a reduced angiogenic activity in the circulation.     

Chiral separation of Frovatriptan isomers by HPLC using amylose based chiral stationary phase

A stereospecific HPLC method for separation of Frovatriptan enantiomers in bulk drug and pharmaceutical formulations was developed and validated on a normal-phase amylose derivertized chiral column. The effects of the organic modifiers namely 2-propanol, ethanol and diethyl amine (DEA) in the mobile phase were optimized to obtain the best enantiomeric separation. Calibration curves were linear over the range of 200-6150 ng/mL, with a regression coefficient (R(2)) of 0.9998. The limit of detection (LOD) and limit of quantification (LOQ) were 65 ng/mL and 200 ng/mL, respectively. The method was accurate and precise and suitable for the intended purpose. Analysis results were compared with the results obtained by using a validated chiral CE method and found to be in very good agreement. This method can be successfully applied to the enantiomeric purity analysis of Frovatriptan in pharmaceutical bulk drug samples and formulations.     

Maxillary reconstruction: functional and aesthetic considerations

Maxillary reconstruction is a challenging endeavor in functional and aesthetic restoration. Given its central location in the midface and its contributions to the key midfacial elements--the orbits, the zygomaticomaxillary complex, the nasal unit, and the stomatognathic complex--the maxilla functions as the keystone of the midface and unifies these elements into a functional and aesthetic unit. Maxillary defects are inherently complex because they generally involve more than one midfacial component. In addition, most maxillary defects are composite in nature, and they often require skin coverage, bony support, and mucosal lining for reconstruction. In the reconstruction of maxillary defects secondary to trauma, ablative tumor surgery, or congenital deformities, the following goals must be met: (1) obliteration of the defect; (2) restoration of essential functions of the midface, such as mastication and speech; (3) provision for adequate structural support to each of the midfacial units; and (4) aesthetic reconstruction of the external features. This review will discuss the pertinent anatomic considerations, the historical approaches to maxillary reconstruction, and the merits of the techniques in use today, with an emphasis on state-of-the-art reconstruction and dental rehabilitation of extensive maxillary defects.     

Interaction of the estrogen receptors with the Fas ligand promoter in human monocytes

The predominance of autoimmune diseases among women suggests that estrogen may modulate immune function. Monocytes and macrophages are important in initiating, maintaining, and resolving inflammatory responses through cell-signaling molecules, which control immune cell survival. One important mechanism of cell survival is mediated by the Fas/Fas ligand (FasL) system. In this study, the link between estrogen, monocytes/macrophages, and the Fas/FasL system was investigated. Estrogen treatment increased FasL expression in monocytes through the binding of the estrogen receptors (ER) to the estrogen recognizing elements and AP-1 motifs present at the FasL promoter. Furthermore, estrogen induced apoptosis in monocytes expressing ERbeta, but not in monocyte-differentiated macrophages expressing ERalpha. The expression of either ERalpha or ERbeta and their response to estrogen in monocytes was found to be dependent on the their stage of cell differentiation. Previously, we have shown that estrogen replacement therapy in postmenopausal women decreased the number of circulating monocytes. In this study, we have characterized the molecular mechanism by which estrogen regulates monocytes homeostasis. These findings indicate that estrogen may regulate immune cell survival through the Fas/FasL system. There is biological relevance to these findings in view of studies showing that accumulation of activated monocytes is involved in the pathogenesis of conditions such as vasculititis, arteriosclerosis, and rheumatoid arthritis.     

Treatment of Kienbock's disease with capitohamate arthrodesis: pain relief with minimal morbidity

Despite the large number of procedures available for treatment of Kienbock's disease, no single method has emerged as being clearly superior. Ultimately, the goal of treatment must be the relief of pain and maintaining wrist range of motion. The authors' experience with 45 consecutive wrists that had undergone capitohamate fusion for treatment of Lichtman's stage 1, 2, or 3 Kienbock's disease is presented. Average follow-up was 32 months (range, 4 to 107 months). All arthrodeses healed with an average time to fusion of 1.9 months. Postoperatively, 93 percent of patients had either no pain or less pain than they had preoperatively, with preservation of wrist range of motion and improved grip strength (52 percent of normal preoperatively to 72 percent of normal postoperatively). The authors conclude that capitohamate arthrodesis relieves pain in 93 percent of patients with stage 1, 2, or 3 Kienbock's disease and is an effective treatment for this disease.     

Importance of the depressor septi nasi muscle in rhinoplasty: anatomic study and clinical application

An active depressor septi muscle can accentuate a drooping nasal tip and shorten the upper lip on animation. We have found that dissection and transposition of the depressor septi muscle during rhinoplasty can improve the tip-upper lip relationship in appropriately selected patients. Although the anatomy of the depressor septi muscle has been described, the anatomic variations of this muscle have not been previously reported. The goals of this study were two-fold: (1) to define the anatomic variations of the depressor septi muscle using 55 fresh cadaver dissections and (2) to develop a clinically applicable algorithm for modification of this muscle during rhinoplasty in those patients with a short upper lip and/or tip-upper lip imbalance. Fifty-five fresh cadavers were dissected, and the anatomic variations of the depressor septi muscle were recorded. Three variations of the depressor septi muscle were delineated: type I inserted fully into the orbicularis oris (62 percent); type II inserted into the periosteum and incompletely into the orbicularis oris (22 percent); and type III showed no, or rudimentary, depressor septi muscle (16 percent). Sixty-two patients over a 4-year period (from 1995 to 1999) were identified preoperatively with a hyperactive depressor septi diagnosed by a descending nasal tip and shortened upper lip on animation. These patients underwent dissection and transposition (not resection) of the paired depressor septi during rhinoplasty with improvement or correction of the tip-upper lip imbalance in 88 percent of cases. The anatomic study, surgical indications, rationale for the operative technique, and clinical cases are presented. Dissection and transposition of the depressor septi is a valuable adjunct to rhinoplasty in patients with a type I or II muscle variant.