Humanized Mice Are Instrumental to the Study of Plasmodium falciparum Infection

Research using humanized mice has advanced our knowledge and understanding of human haematopoiesis, non-adaptive and adaptive immunity, autoimmunity, infectious disease, cancer biology, and regenerative medicine. Challenges posed by the human-malaria parasite Plasmodium falciparum include its complex life cycle, the evolution of drug resistance against anti-malarials, poor diagnosis, and a lack of effective vaccines. Advancements in genetically engineered and immunodeficient mouse strains, have allowed for studies of the asexual blood stage, exoerythrocytic stage and the transition from liver-to-blood stage infection, in a single vertebrate host. This review discusses the process of “humanization” of various immunodeficient/transgenic strains and their contribution to translational biomedical research. Our work reviews the strategies employed to overcome the remaining-limitations of the developed human-mouse chimera(s)

Liposome-Mediated Immunosuppression Plays an Instrumental Role in the Development of “Humanized Mouse” to Study Plasmodium falciparum

The material world has been getting prone toward infectious diseases, and therefore novel strategies should be devised to treat chronic infectious disorders. The translational biomedical research scientists made early attempts to develop mouse-human chimera (humanized mouse) through the reconstitution of immunodeficient mouse with engraftment of human cells and tissues. Although the humanized mouse proved to be an effective tool in understanding various diseases such as human malaria and hepatitis, however, drug administration, retention capacity of the administered drug, toxicity, and ethical constraints are some of the major issues and need to be objectively addressed. The “humanization” of immunodeficient mouse needs pharmacological immunomodulatory reagents to control the excessively recruited cells of monocyte-macrophage lineage. Therefore, administration of liposome loaded with hydrophobic drug (clodronate) to induce selective apoptosis through “suicidal approach” in myeloid cells plays an instrumental role for controlling residual nonadaptive immune response of the host. Liposomes are spherical and hollow—structures consisting of lipid bilayer—and are used for the delivery of drug and vaccine candidates. The surface-engineered liposomes (ligand anchored) are used for targeted and controlled delivery. Clodronate-loaded liposomes play a pivotal role in developing humanized mouse. This mouse holds relevance to study pathophysiology and immunopathology of human malaria parasite, P. falciparum. The liposomal delivery of clodronate administered in immunodeficient mice to modulate their innate immune system is an amenable strategy with the minimal/acceptable range of systemic toxicity

Stable Artesunate Resistance in A Humanized Mouse Model of <em>Plasmodium falciparum</em>

Plasmodium falciparum, the most devastating human malaria parasite, confers higher morbidity and mortality. Although efforts have been made to develop an effective malaria vaccine, stage- and species-specific short-lived immunity crippled these efforts. Hence, antimalarial drug treatment becomes a mainstay for the treatment of malaria infection in the wake of the unavailability of an effective vaccine. Further, there has been a wide array of antimalarial drugs effective against various developmental stages of P. falciparum due to their different structures, modes of action, and pharmacodynamics as well as pharmacokinetics. The development of resistance against almost all frontline drugs by P. falciparum indicates the need for combination therapy (artemisinin-based combination therapy; ACT) to treat patients with P. falciparum. A higher pool of parasitemia under discontinuous in vivo artemisinin drug pressure in a developed humanized mouse allows the selection of artesunate resistant (ART-R) P. falciparum. Intravenously administered artesunate, using either single flash doses or a 2-day regimen, to the P. falciparum-infected human blood chimeric NOD/SCID.IL-2Rγ−/− immunocompromised (NSG) mice, with progressive dose increments upon parasite recovery, was the strategy deployed to select resistant parasites. Parasite susceptibility to artemisinins and other antimalarial compounds was characterized in vitro and in vivo. P. falciparum has shown to evolve extreme artemisinin resistance as well as co-resistance to antimalarial drugs. Overall, the present information shall be very useful in devising newer therapeutic strategies to treat human malaria infection

LncRNA VEAL2 regulates PRKCB2 to modulate endothelial permeability in diabetic retinopathy

Long non‐coding RNAs (lncRNAs) are emerging as key regulators of endothelial cell function. Here, we investigated the role of a novel vascular endothelial‐associated lncRNA (VEAL2) in regulating endothelial permeability. Precise editing of veal2 loci in zebrafish (veal2 (gib005Δ8/+)) induced cranial hemorrhage. In vitro and in vivo studies revealed that veal2 competes with diacylglycerol for interaction with protein kinase C beta‐b (Prkcbb) and regulates its kinase activity. Using PRKCB2 as bait, we identified functional ortholog of veal2 in humans from HUVECs and named it as VEAL2. Overexpression and knockdown of VEAL2 affected tubulogenesis and permeability in HUVECs. VEAL2 was differentially expressed in choroid tissue in eye and blood from patients with diabetic retinopathy, a disease where PRKCB2 is known to be hyperactivated. Further, VEAL2 could rescue the effects of PRKCB2‐mediated turnover of endothelial junctional proteins thus reducing hyperpermeability in hyperglycemic HUVEC model of diabetic retinopathy. Based on evidence from zebrafish and hyperglycemic HUVEC models and diabetic retinopathy patients, we report a hitherto unknown VEAL2 lncRNA‐mediated regulation of PRKCB2, for modulating junctional dynamics and maintenance of endothelial permeability

Assessment of dimensional stability, biodegradability, and fracture energy of bio composites reinforced with novel pine cone

In this investigation, biodegradable composites were fabricated with polycaprolactone (PCL) matrix reinforced with pine cone powder (15%, 30%, and 45% by weight) and compatibilized with graphite powder (0%, 5%, 10%, and 15% by weight) in polycaprolactone matrix by compression molding technique. The samples were prepared as per ASTM standard and tested for dimensional stability, biodegradability, and fracture energy with scanning electron micrographs. Water-absorption and thickness-swelling were performed to examine the dimensional stability and tests were performed at 23 °C and 50% humidity. Results revealed that the composites with 15 wt % of pine cone powder (PCP) have shown higher dimensional stability as compared to other composites. Bio-composites containing 15–45 wt % of PCP with low graphite content have shown higher disintegration rate than neat PCL. Fracture energy for crack initiation in bio-composites was increased by 68% with 30% PCP. Scanning electron microscopy (SEM) of the composites have shown evenly-distributed PCP particles throughout PCL-matrix at significantly high-degrees or quantities of reinforcing

Increasing frailty is associated with higher prevalence and reduced recognition of delirium in older hospitalised inpatients: results of a multi-centre study

Purpose: Delirium is a neuropsychiatric disorder delineated by an acute change in cognition, attention, and consciousness. It is common, particularly in older adults, but poorly recognised. Frailty is the accumulation of deficits conferring an increased risk of adverse outcomes. We set out to determine how severity of frailty, as measured using the CFS, affected delirium rates, and recognition in hospitalised older people in the United Kingdom. Methods: Adults over 65 years were included in an observational multi-centre audit across UK hospitals, two prospective rounds, and one retrospective note review. Clinical Frailty Scale (CFS), delirium status, and 30-day outcomes were recorded. Results: The overall prevalence of delirium was 16.3% (483). Patients with delirium were more frail than patients without delirium (median CFS 6 vs 4). The risk of delirium was greater with increasing frailty [OR 2.9 (1.8–4.6) in CFS 4 vs 1–3; OR 12.4 (6.2–24.5) in CFS 8 vs 1–3]. Higher CFS was associated with reduced recognition of delirium (OR of 0.7 (0.3–1.9) in CFS 4 compared to 0.2 (0.1–0.7) in CFS 8). These risks were both independent of age and dementia. Conclusion: We have demonstrated an incremental increase in risk of delirium with increasing frailty. This has important clinical implications, suggesting that frailty may provide a more nuanced measure of vulnerability to delirium and poor outcomes. However, the most frail patients are least likely to have their delirium diagnosed and there is a significant lack of research into the underlying pathophysiology of both of these common geriatric syndromes

Sequential Product Positioning Under Differential Costs

This paper examines the product positioning decisions of firms that enter a market sequentially and that have potentially different cost structures. It shows that if the first mover knows the second mover to have a lower production cost, it positions away from the most attractive location in the market; further, the larger the second-mover's cost advantage, the farther away the first mover positions from the most attractive location. The paper also models uncertainty in the first-mover's mind about the later-entrant's cost structure, and shows that an increase in this uncertainty (in the sense of mean-preserving spread) also makes the first mover position farther from the most attractive location in the market. Overall, this paper suggests that unless the first entrant in a market is certain that the later entrant will not have a superior cost structure, it may be better off leaving the best position in the market vacant and having a niche or fringe product.product positioning, sequential entry, first-mover advantage, Game Theory