Proline at the P2 position in protein C is important for calcium- mediated regulation of protein C activation and secretion

Protein C is a vitamin K-dependent plasma serine protease zymogen, which upon activation, functions as an anticoagulant. Protein C activation is catalyzed by a complex of thrombin (T) with thrombomodulin (TM). This activation is Ca(2+)-dependent, but Ca2+ inhibits protein C activation by thrombin alone. In most proteases, specificity is determined primarily by the residues that lie near the scissile bond. In protein C, the P2 position is Pro, whereas in the fibrinogen A chain, P2 is Val. We have expressed a Pro-->Val mutant of protein C (P168V) in mammalian cells. At saturating Ca2+, the P168V and wild-type proteins were activated by the T-TM complex equivalently, but half maximal rates of activation were obtained at 50 mumol/L Ca2+ for wild type and approximately 5 mmol/L Ca2+ for the P168V mutant. In the absence of TM, Ca2+ no longer inhibited the activation of the P168V mutant. These results indicate that Pro168 influences the Ca(2+)- dependent conformational changes in protein C that control activation. Recently, a patient with thrombotic complications has been identified with a Pro168-->Leu substitution. Both the P168V and the P168L mutation lead to impaired secretion caused by retention within the cell.     

The Effectiveness of Preventative Mass Vaccination Regimes Against the Incidence of Highly Pathogenic Avian Influenza on Java Island,Indonesia

We conducted an operational research study involving backyard and semicommercial farms on Java Island, Indonesia, between April 2008 and September 2009 to evaluate the effectiveness of two preventive mass vaccination strategies against highly pathogenic avian influenza (HPAI). One regimen used Legok 2003 H5N1 vaccine, while the other used both Legok 2003 H5N1 and HB1 Newcastle disease (ND) vaccine. A total of 16 districts were involved in the study. The sample size was estimated using a formal power calculation technique that assumed a detectable effect of treatment as a 50% reduction in the baseline number of HPAI‐compatible outbreaks. Within each district, candidate treatment blocks with village poultry populations ranging from 80 000 to 120 000 were created along subdistrict boundary lines. Subsequently, four of these blocks were randomly selected and assigned one treatment from a list that comprised control, vaccination against HPAI, vaccination against HPAI + ND. Four rounds of vaccination were administered at quarterly intervals beginning in July 2008. A vaccination campaign involved vaccinating 100 000 birds in a treatment block, followed by another 100 000 vaccinations 3 weeks later as a booster dose. Data on disease incidence and vaccination coverage were also collected at quarterly intervals using participatory epidemiological techniques. Compared with the unvaccinated (control) group, the incidence of HPAI‐compatible events declined by 32% (P = 0.24) in the HPAI‐vaccinated group and by 73% (P = 0.00) in the HPAI‐ and ND‐vaccinated group. The effect of treatment did not vary with time or district. Similarly, an analysis of secondary data from the participatory disease and response (PDSR) database revealed that the incidence of HPAI declined by 12% in the HPAI‐vaccinated group and by 24% in the HPAI + ND‐vaccinated group. The results suggest that the HPAI + ND vaccination significantly reduced the incidence of HPAI‐compatible events in mixed populations of semicommercial and backyard poultry.     

The combined association of depression and socioeconomic status with length of post-operative hospital stay following coronary artery bypass graft surgery: Data from a prospective cohort study

Objective

To understand the association between pre-operative depression symptoms, including cognitive and somatic symptom subtypes, and length of post-operative stay in patients undergoing coronary artery bypass graft (CABG) surgery, and the role of socioeconomic status (SES).

Methods

We measured depression symptoms using the Beck Depression Inventory (BDI) and household income in the month prior to surgery in 310 participants undergoing elective, first-time, CABG. Participants were followed-up post-operatively to assess the length of their hospital stay.

Results

We showed that greater pre-operative depression symptoms on the BDI were associated with a longer hospital stay (hazard ratio = 0.978, 95% CI 0.957–0.999, p = .043) even after controlling for covariates, with the effect being observed for cognitive symptoms of depression but not somatic symptoms. Lower SES augmented the negative effect of depression on length of stay.

Conclusions

Depression symptoms interact with socioeconomic position to affect recovery following cardiac surgery and further work is needed in order to understand the pathways of this association.     

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).