Mathematical analysis of the pharmacokinetic-pharmacodynamic (PKPD) behaviour of monoclonal antibodies: predicting in vivo potency

We consider the relationship between the target affinity of a monoclonal antibody and its in vivo potency. The dynamics of the system is described mathematically by a target-mediated drug disposition model. As a measure of potency, we consider the minimum level of the free receptor following a single bolus injection of the ligand into the plasma compartment. From the differential equations, we derive two expressions for this minimum level in terms of the parameters of the problem, one of which is valid over the full range of values of the equilibrium dissociation constant K_D and the other which is valid only for a large drug dose or for a small value of K_D. Both of these formulae show that the potency achieved by increasing the association constant k_on can be very different from the potency achieved by decreasing the dissociation constant k_off. In particular, there is a saturation effect when decreasing k_off where the increase in potency that can be achieved is limited, whereas there is no such effect when increasing k_on. Thus, for certain monoclonal antibodies, an increase in potency may be better achieved by increasing k_on than by decreasing k_off.     

Properties of the isoforms of α-amylase from kilned and unkilned malted sorghum (Sorghum bicolor)

We have previously reported the presence of a relatively heat-stable α-amylase with a low K_m for starch in kilned malted sorghum. In order to establish the industrially useful and more efficient isoforms, we have separated this α-amylase into different isoforms using both cation and anion-exchange chromatographies. Unkilned malted α-amylase crude was separated into three different isoforms (a1, a2 and a3) whereas kilned samples were separated into two (a1 and a2). Apparently one isoform (a3) was lost during kilning due to heat lability. a1 isoform which appears to have a neutral pI and constitute about 60% of the total α-amylases protein that were induced during germination, have the lowest K_m for starch. They are more generally stable than other isoforms at all the temperatures studied. These isoforms lost only 10% activity at 80 °C for 30 min and still had some residual activity at 100 °C incubation for 30 min. a1 isoform could therefore be adapted for industrial starch conversion processes which are carried out within this range of gelatinizing temperatures because of its properties.     

Green Synthesis of Genistein-Fortified Zinc Ferrite Nanoparticles as a Potent Hepatic Cancer Inhibitor: Validation through Experimental and Computational Studies

In hepatic cancer, precancerous nodules account for damage and inflammation in liver cells. Studies have proved that phyto-compounds based on biosynthetic metallic nanoparticles display superior action against hepatic tumors. This study targeted the synthesis of genistein-fortified zinc ferrite nanoparticles (GENP) trailed by anticancer activity assessment against diethylnitrosamine and N-acetyl-2-aminofluorene induced hepatic cancer. The process of nucleation was confirmed by UV/VIS spectrophotometry, X-ray beam diffraction, field-emission scanning electron microscopy, and FT-IR. An in vitro antioxidant assay illustrated that the leaves of Pterocarpus mildbraedii have strong tendency as a reductant and, in the nanoformulation synthesis, as a natural capping agent. A MTT assay confirmed that GENP have a strong selective cytotoxic potential against HepG2 cancer cells. In silico studies of genistein exemplified the binding tendency towards human matrix metalloproteinase comparative to the standard drug marimastat. An in vivo anticancer evaluation showed that GENP effectively inhibit the growth of hepatic cancer by interfering with hepatic and non-hepatic biochemical markers.     

Phythonematoxic properties and nematicidal potential of Tithonia diversifolia extract and residue on Meloidogyne incognita infecting yam (Discoria rotundata)

A laboratory study and a screen house experiment were conducted to determine the phythonematoxic properties and nematicidal potential of extract and residue of Tithonia diversifolia (Hemsl.) A. Gray on Meloidogyne incognita, (Kofoid and White) Chitwood infecting yam. Alkaloids and saponins were found to be present in the constituents of Tithonia ethanol extract. Also, Tithonia water extract significantly (P ≤ 0.05) inhibits M. incognita egg hatch by 98% from 2 days after incubation (DAI) and was more evidenced with 100% inhibition at 9 DAI in the in vitro studies. M. incognita (5000 eggs/plant) reproduction, number of eggs and juveniles and galling were significantly (P ≤ 0.05) suppressed by Tithonia residue treatment at a rate of 30 tons/ha on yam (Discoria rotundata) in the screen house. The extract and residue of T. diversifolia have potential for the control of root-knot nematodes.     

Correction to: Mosquito Repellent and Antibacterial Efficiency of Facile and Low‑Cost Silver Nanoparticles Synthesized Using the Leaf Extract of Morinda Citrifolia

Plasmonics - A correction to this paper has been published: https://doi.org/10.1007/s11468-021-01439-0     

Accelerometer-Determined Physical Activity and Its Comparison with the International Physical Activity Questionnaire in a Sample of Nigerian Adults

Introduction

Accurate assessment of physical activity to identify current levels and changes within the population is dependent on the precision of the measurement tools. The aim of this study was to compare components of physical activity measured with an adapted version of the International Physical Activity Questionnaire (Hausa IPAQ-SF) and the accelerometer in a sample of Nigeria adults.

Methods

One hundred and forty-four participants (Mean age = 32.6±9.9 years, 40.3% women) in a cross-sectional study wore an accelerometer for seven consecutive days and completed the Hausa IPAQ-SF questionnaire on the eighth day. Total physical activity, time spent in moderate-to-vigorous activity (MVPA) and sedentary time assessed by Hausa IPAQ-SF and accelerometer were compared. The absolute and criterion- related validity of the Hausa IPAQ-SF was assessed by Bland-Altman analysis and Spearman Correlation Coefficients, respectively. Specificity and sensitivity were calculated to classify individuals according to the global standard guideline for sufficient physical activity.

Results

Compared with the accelerometer, higher time in MVPA and total physical activity were reported on the Hausa IPAQ-SF (p<0.001), while low to moderate correlations (Rs = 0.03–0.38) were found between the two methods. The 95% limits of agreement were wide between methods for total physical activity (−23019 to 20375 METmin.d⁻¹) and sedentary time (−510 to 150 min.d⁻¹). The sensitivity (76.2%) of Hausa IPAQ-SF to identify insufficiently active people was good, but its specificity (33.3%) to correctly classify sufficiently active people was low.

Conclusions

The Hausa IPAQ-SF overestimated components of physical activity among Nigerian adults, and demonstrated poor to moderate evidence of absolute and criterion validity. Further evaluation of IPAQ and other self-report physical activity instruments in other Africa populations could enhance accurate evaluation of physical activity data in the region countries.     

Anxiogenic effects of developmental bisphenol a exposure are associated with gene expression changes in the juvenile rat amygdala and mitigated by soy

Early life exposure to Bisphenol A (BPA), a component of polycarbonate plastics and epoxy resins, alters sociosexual behavior in numerous species including humans. The present study focused on the ontogeny of these behavioral effects beginning in adolescence and assessed the underlying molecular changes in the amygdala. We also explored the mitigating potential of a soy-rich diet on these endpoints. Wistar rats were exposed to BPA via drinking water (1 mg/L) from gestation through puberty, and reared on a soy-based or soy-free diet. A group exposed to ethinyl estradiol (50 μg/L) and a soy-free diet was used as a positive estrogenic control. Animals were tested as juveniles or adults for anxiety-like and exploratory behavior. Assessment of serum BPA and genistein (GEN), a soy phytoestrogen, confirmed that internal dose was within a human-relevant range. BPA induced anxiogenic behavior in juveniles and loss of sexual dimorphisms in adult exploratory behavior, but only in the animals reared on the soy-free diet. Expression analysis revealed a suite of genes, including a subset known to mediate sociosexual behavior, associated with BPA-induced juvenile anxiety. Notably, expression of estrogen receptor beta (Esr2) and two melanocortin receptors (Mc3r, Mc4r) were downregulated. Collectively, these results show that behavioral impacts of BPA can manifest during adolescence, but wane in adulthood, and may be mitigated by diet. These data also reveal that, because ERβ and melanocortin receptors are crucial to their function, oxytocin/vasopressin signaling pathways, which have previously been linked to human affective disorders, may underlie these behavioral outcomes.     

Purification and catalytic properties of glutathione transferase from the hepatopancreas of crayfish macrobrachium vollenhovenii (herklots)

Glutathione transferase from the hepatopancreas of fresh water crayfish Macrobrachium vollenhovenii was purified to apparent homogeneity by ion-exchange chromatography on DEAE-cellulose and by gel filtration on Sephadex G-100. The enzyme appeared to be a homodimer with molecular weight (Mr) of 46.0 +/- 1.4 kDa and a subunit Mr of 24.1 +/- 0.35 kDa. Chromatofocusing of the apparently pure enzyme revealed microheterogeneity and resolved it into two isozymic peaks, which were eluted at pH 8.36 and 8.22 respectively. Inhibition studies showed that the I50 value for cibacron blue, S-hexylglutathione, hematin, and N-ethylmaleimide (NEM) were 0.01 microM, 340 microM, 5 microM and 33 mM respectively. Out of the several substrates tested, only 1-chloro-2,4-dinitrobenzene (CDNB) and 7-chloro-4-nitrobenzo-2-oxa-1,3-diazole could be conjugated with glutathione. Chemical modification studies with DTNB revealed that two sulphydryl groups per dimer were essential to the activity of the enzymes. On the basis of structural and catalytic characteristics, M. vollenhovenii GST seems close, tentatively, to the omega and zeta classes of GST. Initial-velocity studies of the enzyme are consistent with a steady-state random kinetic mechanism. Denaturation and renaturation studies with guanidine HCl (Gdn-HCl) revealed that though low Gdn-HCl concentrations (less than 0.5 M) denatured the enzyme, the enzyme was able to renature completely (100%). At higher concentration of the denaturant (0.5-4 M), refolding studies indicated that complete renaturation was not achieved. The extent of renaturation was however a function of protein concentration. Our results are consistent with a three-state unfolding process.     

Enhancing enzyme-aided production of fermentable sugars from poplar pulp in the presence of non-ionic surfactants

Bioprocess and Biosystems Engineering - Addition of surfactants to enzymatic hydrolysis has been reported to enhance the hydrolytic potential of enzymes in the bioconversion of lignocellulosic...