Antibodies to the polymeric immunoglobulin receptor with different binding and trafficking patterns

The polymeric immunoglobulin receptor (pIgR) has been proposed as a therapeutic target, but its potential depends on the efficiency of uptake and trafficking of the receptor ligand. Mouse monoclonal antibodies (Mabs) directed against pIgR, selected for strong binding to secretory component (SC) and secretory IgA (sIgA), were tested in a transcytosis assay in 16HBEo--cells (human bronchial epithelial cell line) transfected with human pIgR. Intracellular trafficking was followed by confocal microscopy. Mabs fell into two classes. For two Mabs, transcytosis from basolateral to apical surface is rapid, unidirectional, and little Mab is retained in the cell. For three Mabs, basolateral to apical transcytosis occurs to a significantly lesser extent, reverse transcytosis is permitted, and some of the Mab is retained in the perinuclear region even after 24 h. When tested for their ability to recognize and immunoprecipitate pIgR with systematic truncations and deletions of the five immunoglobulin (Ig)-like domains, all Mabs bound to the fifth Ig-like domain, but three of them also bound to the C-terminal region of pIgR near the plasma membrane. Different binding sites probably account for the different trafficking of these Mabs and may predict differential therapeutic utility.     

Mechanical efficiency of pure positive and pure negative work with special reference to the work intensity

The mechanical efficiencies of pure positive (eta) and pure negative (eta-) work were investigated on a special "sledge ergometer" with 25 and 36 subjects, respectively. The work intensities varied in positive work between 40% and 90% and in negative work from 30% to 120% of the maximum concentric exercise. In 54 exercises of positive work, eta was 17.1% +/- 2.2%, and its value correlated negatively with the work intensity (r = 0.367, P less than 0.01) and with the average knee angular velocity, omega+ (r = 0.359, P less than 0.01). In 103 eccentric exercises, eta- was on the average 80.2% +/- 31.8%, correlating positively with the work intensity (r = 0.396, P less than 0.01). Both inter- and intrasubject variations were large (32%-163%). The integrated electrical activity (IEMG) of the leg extensor muscles increased with an increase of work intensity both in the positive and in the negative work situations. Less efficient MU recruitment in higher positive work rates is suggested to be the reason for the decrease in eta, whereas better stiffness regulation via increased preactivation is speculated to cause high values of eta- in higher work intensities in eccentric exercise.     

Blockade of NMDA receptors located at the dorsomedial prefrontal cortex impairs spatial working memory in rats

We investigated the effects of NMDA and muscarinic acetylcholine receptor blockade in the rostral part of dorsomedial (dmPFC) and dorsolateral prefrontal cortex (dlPFC) on spatial working memory (SWM) (delayed non-matching to position task (DNMTP)). The NMDA antagonist, CPP (0.01, 0.03, 0.1 and 0.3 microg/hemisphere) and the muscarinic antagonist, scopolamine (10 microg/hemisphere) were locally infused into the brain of male Wistar rats. In the mPFC CPP 0.1 microg disrupted SWM delay-dependently and CPP 0.3 microg caused a delay-independent performance deficit. Scopolamine disrupted non-cognitive performance, but did not affect SWM accuracy. In the dlPFC, scopolamine or lower doses of CPP did not affect SWM accuracy, but CPP 0.3 microg disrupted non-cognitive performance. We concluded that the NMDA receptors in the dmPFC regulate SWM processes, whereas the muscarinic receptors in the dmPFC mediate non-cognitive performance in the DNMTP task.     

COVID‐19 lockdown consequences on body mass index and perceived fragility related to physical activity: A worldwide cohort study

BackgroundThis paper is a follow‐up study continuing the COVISTRESS network previous research regarding health‐related determinants.ObjectiveThe aim was to identify the main consequences of COVID‐19 lockdown on Body Mass Index and Perceived Fragility, related to Physical Activity (PA), for different categories of populations, worldwide.DesignThe study design included an online survey, during the first wave of COVID‐19 lockdown, across different world regions.Setting and participantsThe research was carried out on 10 121 participants from 67 countries. The recruitment of participants was achieved using snowball sampling techniques via social networks, with no exclusion criteria other than social media access.Main outcome measures Body Mass Index, Physical Activity, Perceived Fragility and risk of getting infected items were analysed. SPSS software, v20, was used. Significance was set at P < .05.Results Body Mass Index significantly increased during lockdown. For youth and young adults (18‐35 years), PA decreased by 31.25%, for adults (36‐65 years) by 26.05% and for the elderly (over 65 years) by 30.27%. There was a high level of Perceived Fragility and risk of getting infected for female participants and the elderly. Correlations between BMI, Perceived Fragility and PA were identified.Discussion and ConclusionsThe research results extend and confirm evidence that the elderly are more likely to be at risk, by experiencing weight gain, physical inactivity and enhanced Perceived Fragility. As a consequence, populations need to counteract the constraints imposed by the lockdown by being physically active.     

Central role of protein kinase Cepsilon in constitutive activation of ERK1/2 and Rac1 in the malignant cells of hairy cell leukemia

We have previously identified the presence of Ras/Raf-independent constitutive activation of extracellular signal-regulated kinase (ERK) in the hairy cells (HCs) of hairy cell leukemia. The aim of the present study was to characterize the signaling components involved in this activation and their relationship to the reported activation of Rac1. We found that both Rac1 and ERK activation in HCs are downstream of active Src and protein kinase C (PKC). Inhibition with toxin B showed that Rac1 plays no role in ERK activation in HCs. However, toxin B inhibited p60src and the Rac1-GEF Vav, demonstrating a positive feedback/activation of p60src by Rac1. Treatment with specific small interfering RNA for various PKC isoforms, or with PKC isoform-specific inhibitors, demonstrated a central role for PKCepsilon in the constitutive activation of Rac1 and ERK in HCs. PKCepsilon and active ERK were mutually associated and co-localized with mitochondria in HCs. Furthermore, active PKCepsilon was nitrated on tyrosine, pointing to a reactive oxygen species-dependent mechanism of activation. By being involved in activation of ERK and Rac1, PKCepsilon plays roles in both the survival of HCs and in the cytoskeletal dynamics responsible for the distinctive morphology and tissue homing of these cells. Our study therefore describes novel aspects of signaling important for the pathogenesis of hairy cell leukemia.     

Evolutionary adaptations in the flexor digitorum profundus muscle in Tamandua mexicana (Xenarthra,Myrmecophagidae)

The northern tamandua (Tamandua mexicana) is a neotropical mammal of the order Pilosa, suborder Vermilingua, and family Myrmecophagidae. This species has anatomical and functional adaptations in its forelimb for semiarboreal quadrupedal locomotion. Several studies have reported that the medial head of the triceps brachii and flexor digitorum profundus muscles are fused in species belonging to the family Myrmecophagidae. However, there is no reference to the innervation in these. The triceps brachii muscle is commonly innervated by the radial nerve and the flexor digitorum profundus muscle by the ulnar and median nerves. This study aims to describe the gross anatomy of the flexor digitorum profundus muscle in Tamandua mexicana with respect to the shape, origin, insertion, innervation, and arterial supply. Both forelimbs of nine specimens were used, which were dissected from superficial to deep layers. The formalin-fixed caudomedial forearm muscles were weighed, and the weight percentages of individual forearm muscle specimens were calculated. The flexor digitorum profundus had the highest weight among the forearm muscles and consisted of five heads (three humerals, one radial, and one ulnar). These heads were innervated by median and ulnar nerves; therefore, based on the innervation pattern, we concluded that the medial head of the triceps brachii muscle is not fused with the flexor digitorum profundus. Therefore, the flexor digitorum profundus muscle is highly developed in Tamandua and occupies the caudal part of the arm and forearm, which is an evolutionary adaptation that could have occurred during evolution from the common ancestor of Tamandua and Myrmecophaga.