Hematological profile of East African short-horn zebu calves from birth to 51 weeks of age

This paper is the first attempt to accurately describe the hematological parameters for any African breed of cattle, by capturing the changes in these parameters over the first 12 months of an animal’s life using a population-based sample of calves reared under field conditions and natural disease challenge. Using a longitudinal study design, a stratified clustered random sample of newborn calves was recruited into the IDEAL study and monitored at 5-weekly intervals until 51 weeks of age. The blood cell analysis performed at each visit included: packed cell volume; red cell count; red cell distribution width; mean corpuscular volume; mean corpuscular hemoglobin concentration; hemoglobin concentration; white cell count; absolute lymphocyte, eosinophil, monocyte, and neutrophil counts; platelet count; mean platelet volume; and total serum protein. The most significant age-related change in the red cell parameters was a rise in red cell count and hemoglobin concentration during the neonatal period. This is in contrast to what is reported for other ruminants, including European cattle breeds where the neonatal period is marked by a fall in the red cell parameters. There is a need to establish breed-specific reference ranges for blood parameters for indigenous cattle breeds. The possible role of the postnatal rise in the red cell parameters in the adaptability to environmental constraints and innate disease resistance warrants further research into the dynamics of blood cell parameters of these breeds.     

Using Psychological Principles to Narrow the Intention-Behavior Gap and Increase Participation in HIV Vaccine Trials

There is a pressing need to find an efficacious HIV vaccine and a concomitant need for the recruitment of participants in efficacy trials. These efforts are hampered, however, by a gap between what respondents say they will do regarding research participation, and whether they actually enroll. The current paper examines the size of this gap and proposes psychological reasons for it. Some reasons include the temporal stability of the intention, the time taken to consider its ramifications and plans to deal with them, and the social forces that affect the intention. From this analysis, recommendations are offered to improve recruitment efforts and the predictive power of expressions of willingness to participate.     

Context and hand posture modulate the neural dynamics of tool–object perception

Prior research has linked visual perception of tools with plausible motor strategies. Thus, observing a tool activates the putative action-stream, including the left posterior parietal cortex. Observing a hand functionally grasping a tool involves the inferior frontal cortex. However, tool-use movements are performed in a contextual and grasp specific manner, rather than relative isolation. Our prior behavioral data has demonstrated that the context of tool-use (by pairing the tool with different objects) and varying hand grasp postures of the tool can interact to modulate subjects' reaction times while evaluating tool-object content. Specifically, perceptual judgment was delayed in the evaluation of functional tool-object pairings (Correct context) when the tool was non-functionally (Manipulative) grasped. Here, we hypothesized that this behavioral interference seen with the Manipulative posture would be due to increased and extended left parietofrontal activity possibly underlying motor simulations when resolving action conflict due to this particular grasp at time scales relevant to the behavioral data. Further, we hypothesized that this neural effect will be restricted to the Correct tool-object context wherein action affordances are at a maximum.64-channel electroencephalography (EEG) was recorded from 16 right-handed subjects while viewing images depicting three classes of tool–object contexts: functionally Correct (e.g. coffee pot–coffee mug), functionally Incorrect (e.g. coffee pot–marker) and Spatial (coffee pot–milk). The Spatial context pairs a tool and object that would not functionally match, but may commonly appear in the same scene. These three contexts were modified by hand interaction: No Hand, Static Hand near the tool, Functional Hand posture and Manipulative Hand posture. The Manipulative posture is convenient for relocating a tool but does not afford a functional engagement of the tool on the target object. Subjects were instructed to visually assess whether the pictures displayed correct tool-object associations. EEG data was analyzed in time–voltage and time–frequency domains. Overall, Static Hand, Functional and Manipulative postures cause early activation (100–400 ms post image onset) of parietofrontal areas, to varying intensity in each context, when compared to the No Hand control condition. However, when context is Correct, only the Manipulative Posture significantly induces extended neural responses, predominantly over right parietal and right frontal areas [400–600 ms post image onset]. Significant power increase was observed in the theta band [4–8 Hz] over the right frontal area, [0–500 ms]. In addition, when context is Spatial, Manipulative posture alone significantly induces extended neural responses, over bilateral parietofrontal and left motor areas [400–600 ms]. Significant power decrease occurred primarily in beta bands [12–16, 20–25 Hz] over the aforementioned brain areas [400–600 ms].Here, we demonstrate that the neural processing of tool-object perception is sensitive to several factors. While both Functional and Manipulative postures in Correct context engage predominantly an early left parietofrontal circuit, the Manipulative posture alone extends the neural response and transitions to a late right parietofrontal network. This suggests engagement of a right neural system to evaluate action affordances when hand posture does not support action (Manipulative). Additionally, when tool-use context is ambiguous (Spatial context), there is increased bilateral parietofrontal activation and, extended neural response for the Manipulative posture. These results point to the existence of other networks evaluating tool-object associations when motoric affordances are not readily apparent and underlie corresponding delayed perceptual judgment in our prior behavioral data wherein Manipulative postures had exclusively interfered in judging tool-object content.     

Mechanoelectrical transduction in chondrocytes

Cartilage tissue lines the joints of mammals, helping to lubricate joint movement and distribute mechanical loads. This tissue is comprised of isolated cells known as chondrocytes which are embedded in an extracellular matrix. Chondrocytes produce and maintain the cartilage by sensing and responding to changing mechanical loads. Mechanosensitive ion channels have been implicated in chondrocyte mechanotransduction and recent studies have shown that both PIEZO1 and TRPV4 can be activated by mechanical stimuli in these cells. The 2 channels mediate separate but overlapping mechanoelectrical transduction pathways, PIEZO1 in response to stretch and substrate deflections and TRPV4 in response to substrate deflections alone. These distinct pathways of mechanoelectrical transduction suggest a mechanism by which chondrocytes can distinguish between different stimuli that arise in their complex mechanical environment.     

Romosozumab Enhances Vertebral Bone Structure in Women With Low Bone Density

Romosozumab monoclonal antibody treatment works by binding sclerostin and causing rapid stimulation of bone formation while decreasing bone resorption. The location and local magnitude of vertebral bone accrual by romosozumab and how it compares to teriparatide remains to be investigated. Here we analyzed the data from a study collecting lumbar computed tomography (CT) spine scans at enrollment and 12 months post-treatment with romosozumab (210 mg sc monthly, n = 17), open-label daily teriparatide (20 μg sc, n = 19), or placebo (sc monthly, n = 20). For each of the 56 women, cortical thickness (Ct.Th), endocortical thickness (Ec.Th), cortical bone mineral density (Ct.bone mineral density (BMD)), cancellous BMD (Cn.BMD), and cortical mass surface density (CMSD) were measured across the first lumbar vertebral surface. In addition, color maps of the changes in the lumbar vertebrae structure were statistically analyzed and then visualized on the bone surface. At 12 months, romosozumab improved all parameters significantly over placebo and resulted in a mean vertebral Ct.Th increase of 10.3% versus 4.3% for teriparatide, an Ec.Th increase of 137.6% versus 47.5% for teriparatide, a Ct.BMD increase of 2.1% versus a −0.1% decrease for teriparatide, and a CMSD increase of 12.4% versus 3.8% for teriparatide. For all these measurements, the differences between romosozumab and teriparatide were statistically significant (p < 0.05). There was no significant difference between the romosozumab-associated Cn.BMD gains of 22.2% versus 18.1% for teriparatide, but both were significantly greater compared with the change in the placebo group (−4.6%, p < 0.05). Cortical maps showed the topographical locations of the increase in bone in fracture-prone areas of the vertebral shell, walls, and endplates. This study confirms widespread vertebral bone accrual with romosozumab or teriparatide treatment and provides new insights into how the rapid prevention of vertebral fractures is achieved in women with osteoporosis using these anabolic agents. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Reactivation of cocaine reward memory engages the Akt/GSK3/mTOR signaling pathway and can be disrupted by GSK3 inhibition

Rational

Memories return to a labile state following their retrieval and must undergo a process of reconsolidation to be maintained. Thus, disruption of cocaine reward memories by interference with reconsolidation may be therapeutically beneficial in the treatment of cocaine addiction.

Objective

The objectives were to elucidate the signaling pathway involved in reconsolidation of cocaine reward memory and to test whether targeting this pathway could disrupt cocaine-associated contextual memory.

Methods

Using a mouse model of conditioned place preference, regulation of the activity of glycogen synthase kinase-3 (GSK3), mammalian target of Rapamycin complex 1 (mTORC1), P70S6K, β-catenin, and the upstream signaling molecule Akt, was studied in cortico-limbic-striatal circuitry after re-exposure to an environment previously paired with cocaine.

Result

Levels of phosporylated Akt-Thr308, GSK3α-Ser21, GSK3β-Ser9, mTORC1, and P70S6K were reduced in the nucleus accumbens and hippocampus 10 min after the reactivation of cocaine cue memories. Levels of pAkt and pGSK3 were also reduced in the prefrontal cortex. Since reduced phosphorylation of GSK3 indicates heightened enzyme activity, the effect of a selective GSK3 inhibitor, SB216763, on reconsolidation was tested. Administration of SB216763 immediately after exposure to an environment previously paired with cocaine abrogated a previously established place preference, suggesting that GSK3 inhibition interfered with reconsolidation of cocaine-associated reward memories.

Conclusions

These findings suggest that the Akt/GSK3/mTORC1 signaling pathway in the nucleus accumbens, hippocampus, and/or prefrontal cortex is critically involved in the reconsolidation of cocaine contextual reward memory. Inhibition of GSK3 activity during memory retrieval can erase an established cocaine place preference.     

Nitrate storage and retrieval in Beta vulgaris: Effects of nitrate and chloride on proton gradients in tonoplast vesicles

The fluorescent probes acridine orange and oxonol-V were used as indicators of pH gradients (ΔpH) and membrane potential differences (ΔΨ), respectively, in membrane vesicles believed to be derived from the tonoplast of Beta vulgaris L. Low concentrations of nitrate (1-5 mM) caused a partial dissipation of both ΔpH and ΔΨ at vesicle transport sites distinct from the H⁺-ATPase. In contrast, chloride dissipated only ΔΨ. A model is proposed in which nitrate and chloride enter the plant cell vacuole in response to a potential generated by the tonoplast H⁺-ATPase. Nitrate but not chloride may then be retrieved for metabolic use by the operation of a nitrate/proton symport at the tonoplast.     

Treatment of poor risk acute leukemia with sequential high-dose ARA-C and asparaginase

Resistance of leukemia cells to cytosine arabinoside (ARA-C) may be due to any one or combination of biochemical processes, which in certain instances may be substantially reversed by an appropriate increase in ARA-C dosage. Based on these and other laboratory observations indicating pharmacologic synergy between sequential high-dose ARA-C and asparaginase (HiDAC----ASNase), a therapeutic program was developed for the treatment of patients with acute nonlymphocytic leukemia (ANLL) refractory to conventional doses of ARA-C, as well as patients with high risk ANLL and advanced acute lymphocytic leukemia (ALL). Treatment consisted of 3-hr intravenous infusions of 3 g/sq m of ARA-C given at 12-hr intervals for 4 doses, followed by 6,000 IU/sq m ASNase given i.m. at hour 42. The same schedule was repeated on day 8. In 32 induction attempts, only 4 patients proved to be truly refractory, i.e., failed to achieve substantial leukemia cell cytoreduction. Complete remissions were achieved with HiDAC---- ASNase in 9 of 13 patients with refractory ANLL, 6 of 9 patients with antecedent hematologic disorders, and 3 of 10 patients with advanced ALL. These include 9 of 14 patients who had either failed induction or who had relapsed on active ARA-C therapy and 6 of 8 patients who had had no prior exposure to ARA-C. The median duration of unmaintained remission in ANLL was 5 mo. In a patient with central nervous system (CNS) leukemia, there was clearance of cerebral spinal fluid (CSF) blasts without intrathecal therapy, suggesting a role for HiDAC in CNS prophylaxis. In general, toxicity was tolerable and reversible. These data suggest that HiDAC----ASNase is an exceptionally effective and well tolerated regimen in leukemic patients with antecedent hematologic disorders and in those refractory to conventional doses of ARA-C.     

Critical roles for the actin cytoskeleton and cdc42 in regulating platelet integrin alpha2beta1

The modified two-site model for platelet activation by collagen requires tight binding of platelets to collagen through integrin alpha2beta1, after its prior activation by inside-out signals initiated by GP VI. The inside-out signalling to alpha2beta1 is not well characterized although it is currently accepted that GPVI initiates signals that lead to regulation of this integrin. The aim of the study was to determine the role played by actin polymerization and the Rho family GTPase cdc42 in the regulation of alpha2beta1 integrin. We first show that GPVI- and non-GPVI-dependent signals differentially regulate distribution of alpha2beta1 receptors, where binding of platelets to collagen leads to redistribution of the integrin to areas of contact between platelet and collagen fibre. Binding of platelets to collagen also leads to activation of alpha2beta1 integrin, which is dependent upon actin polymerization and cdc42 activity, since activation is blocked by cytochalasin D and secramine A respectively. Adhesion of platelets to collagen is markedly diminished in the presence of these inhibitors, whereas adhesion to CRP- or fibrinogen-coated surfaces is not affected. Platelet aggregation to collagen, but not CRP or thrombin, is also markedly dependent upon actin polymerization and cdc42 activity. In conclusion these data suggest that actin polymerization and cdc42 are required for activation of integrin alpha2beta1, but not alpha(IIb)beta3, thereby critically regulating platelet adhesion to and activation by collagen. We therefore suggest a further modification to the current two-site two-step model for activation of platelets by collagen, where actin polymerization and cdc42 mediate a critical step in modulating alpha2beta1 activation, possibly through a positive feedback pathway from alpha2beta1 itself.