Search

AbstractAs Black church leaders decried the arrival of Jim Crow segregation, many also celebrated the racial independence of their churches. They touted advancements such as women's ordination as examples of what Black churches could do when freed from white control. Other Black ministers defended remaining in majority-white denominations as a way to abolish the color line. This article argues that scholars miss much about Black religious history if we assume that Black churches’ resistance to racial subjugation started with a settled and uncontested racial autonomy. On the contrary, Black churches throughout the nineteenth century kept open a lively forum about the virtues and vices of such autonomy. Interracial cooperation often undermined Black autonomy, and Black Christians debated which better countered racial caste. To track the heated debates over racial independence and interracial cooperation within and between Black churches, this article analyzes Black newspapers, sermons, church minutes, and letters, mostly among Black Methodists but also among Black Baptists and Presbyterians throughout the late nineteenth century. It focuses on particular debates surrounding women's ordination, attempts to unite Methodists, and conflicts over Baptist education.

Building Automation Systems (BASs) are seeing increased usage in modern society due to the plethora of benefits they provide such as automation for climate control, HVAC systems, entry systems, and lighting controls. Many BASs in use are outdated and suffer from numerous vulnerabilities that stem from the design of the underlying BAS protocol. In this paper, we provide a comprehensive, up-to-date survey on BASs and attacks against seven BAS protocols including BACnet, EnOcean, KNX, LonWorks, Modbus, ZigBee, and Z-Wave. Holistic studies of secure BAS protocols are also presented, covering BACnet Secure Connect, KNX Data Secure, KNX/IP Secure, ModBus/TCP Security, EnOcean High Security and Z-Wave Plus. LonWorks and ZigBee do not have security extensions. We point out how these security protocols improve the security of the BAS and what issues remain. A case study is provided which describes a real-world BAS and showcases its vulnerabilities as well as recommendations for improving the security of it. We seek to raise awareness to those in academia and industry as well as highlight open problems within BAS security.

During thrombosis, procoagulant platelets expose phosphatidylserine (PS), which enhances local thrombin generation. Reducing platelet PS exposure could be a novel anti‐thrombotic approach. PS is confined to the inner leaflet of the plasma membrane in unstimulated platelets by ATP‐dependent “flippase” activity. Ca2+ionophores trigger all platelets to expose a high level of PS by activating a scramblase protein and inactivating the flippase. Although R5421 was previously shown to reduce Ca2+ionophore‐induced PS exposure, its mechanism of action is unknown. To determine the mechanism by which R5421 reduces platelet PS exposure. Washed human platelets were stimulated with the Ca2+ionophore, A23187, to induce procoagulant platelet formation while bypassing proximal receptor signalling. Platelets PS exposure was detected using annexin V or lactadherin in flow cytometry. NBD (7‐nitro‐2‐1,3‐benzoxadiazol‐4‐yl)‐PS was used to assess scramblase and flippase activity. Thrombin generation was monitored using a fluorogenic substrate. R5421 reduced the extent of A23187‐stimulated platelet PS exposure, as demonstrated with annexin V or lactadherin binding. R5421 also maintained flippase activity in procoagulant platelets. Although R5421 appeared to inhibit scramblase activity in procoagulant platelets, it did not once the flippase had been inhibited, demonstrating that scramblase activity is not directly inhibited. Furthermore, R5421 inhibited the contribution of A23187‐stimulated platelets to thrombin generation. Together these data demonstrate that R5421 reduces the extent of PS exposure in procoagulant platelets by maintaining flippase activity. Maintaining flippase activity in procoagulant platelets is a novel and effective approach to reducing thrombin generation.

There is very little published literature on Enhanced Recovery Principles (ERP) used in primary joint replacements applied to revision hip and knee arthroplasty (rTHA, rTKA).

The allogenic bone ring technique allows for horizontal and vertical bone augmentation with simultaneous implant placement in severely compromised sites. The aim of this report is to present a modified protocol for simultaneous placement of implant and allogenic bone ring graft using a computer‐guided surgery technique. Patient's chief complaint was to replace a missing lateral incisor. The implant site presented both vertical and horizontal tissue deficiencies. Study models and wax‐ups were digitally scanned to stl files and merged with the existing CBCT data in the implant planning software. A 3D representation of an allogenic bone ring was developed, and two digitally designed guides were created: a 5 mm sleeve guide for the implant site and a 7 mm sleeve guide for the allogenic bone ring trephine. Both the implant site and the allogenic bone ring recipient site were prepared using the computer‐generated guides. Once the ring was adapted into the recipient site, the implant was inserted through the allogenic bone ring. The healing was monitored and the implant was restored at 12 months. The accuracy of implant placement was measured and the difference in the final positioning was as follows: 0.6 mm at entry point, 0.55 mm vertical displacement, 1.94 mm at the apex, and angle discrepancy 6.1°. The use of computer‐guided technology for planning and placement of an allograft bone block with simultaneous implant insertion allows for a prosthetically driven team approach to compromised site grafting in addition to improving precision and accuracy when compared with non‐guided techniques.

Procoagulant platelets promote thrombin generation during thrombosis. Platelets become procoagulant in an all-or-nothing manner. We investigated how distinct Ca2+ signaling between platelet subpopulations commits some platelets to become procoagulant, using the high-affinity Ca2+ indicator Fluo-4, which may become saturated during platelet stimulation, or low-affinity Fluo-5N, which reports only very high cytosolic Ca2+ concentrations. All activated platelets had high Fluo-4 fluorescence. However, in Fluo-5N–loaded platelets, only the procoagulant platelets had high fluorescence, indicating very high cytosolic Ca2+. This finding indicates a novel, “supramaximal” Ca2+ signal in procoagulant platelets (ie, much higher than normally considered maximal). Supramaximal Ca2+ signaling and the percentage of procoagulant platelets were inhibited by cyclosporin A, a mitochondrial permeability transition pore blocker, and Ru360, an inhibitor of the mitochondrial Ca2+ uniporter, with no effect on Fluo-4 fluorescence. In contrast, Synta-66, an Orai1 blocker, reduced Fluo-4 fluorescence but did not directly inhibit generation of the supramaximal Ca2+ signal. Our findings show a distinct pattern of Ca2+ signaling in procoagulant platelets and provide a new framework to interpret the role of platelet signaling pathways in procoagulant platelets. This requires reassessment of the role of different Ca2+ channels and may provide new targets to prevent formation of procoagulant platelets and limit thrombosis.

The P7C3 class of neuroprotective aminopropyl carbazoles has been shown to block neuronal cell death in models of neurodegeneration. We now show that P7C3 molecules additionally preserve axonal integrity after injury, before neuronal cell death occurs, in a rodent model of blast-mediated traumatic brain injury (TBI). This protective quality may be linked to the ability of P7C3 molecules to activate nicotinamide phosphoribosyltransferase, the rate-limiting enzyme in nicotinamide adenine dinucleotide salvage. Initiation of daily treatment with our recently reported lead agent, P7C3-S243, 1 day after blast-mediated TBI blocks axonal degeneration and preserves normal synaptic activity, learning and memory, and motor coordination in mice. We additionally report persistent neurologic deficits and acquisition of an anxiety-like phenotype in untreated animals 8 months after blast exposure. Optimized variants of P7C3 thus offer hope for identifying neuroprotective agents for conditions involving axonal damage, neuronal cell death, or both, such as occurs in TBI.

Optical coherence tomography is routinely used clinically for the detection and management of ocular diseases as well as in research where the studies may involve animals. This routine use requires that the developed automated segmentation methods not only be accurate and reliable, but also be adaptable to meet new requirements. We have previously proposed the use of a graph-theoretic approach for the automated 3-D segmentation of multiple retinal surfaces in volumetric human SD-OCT scans. The method ensures the global optimality of the set of surfaces with respect to a cost function. Cost functions have thus far been typically designed by hand by domain experts. This difficult and time-consuming task significantly impacts the adaptability of these methods to new models. Here, we describe a framework for the automated machine-learning based design of the cost function utilized by this graph-theoretic method. The impact of the learned components on the final segmentation accuracy are statistically assessed in order to tailor the method to specific applications. This adaptability is demonstrated by utilizing the method to segment seven, ten and five retinal surfaces from SD-OCT scans obtained from humans, mice and canines, respectively. The overall unsigned border position errors observed when using the recommended configuration of the graph-theoretic method was 6.45 ± 1.87 μm, 3.35 ± 0.62 μm and 9.75 ± 3.18 μm for the human, mouse and canine set of images, respectively.

Patients with myeloproliferative disorders (MPDs), such as essential thrombocythemia (ET) have increased risk of thrombosis and bleeding, which are major sources of morbidity and mortality. Most MPD patients have a gain of function mutation in Janus kinase 2 (JAK2V617F), but little is known how JAK2V617F affects platelet function. Here, we demonstrate that platelets from ET patients have impaired SFLLRN-mediated fibrinogen binding and have lost the potentiating effect of thrombopoietin (which couples to JAK2) on this pathway. In contrast, SFLLRN-mediated P-selectin expression, ATP secretion, phosphorylation of the PKC substrate pleckstrin, and Ca2+ mobilization were unaffected in JAK2V617F positive platelets. In addition, thrombopoietin-mediated JAK2 phosphorylation was unchanged, suggesting that signaling pathways activated downstream of JAK2 are impaired. Indeed, we found that platelets from JAK2V617F-positive ET patients have significantly reduced phosphorylation of the PI3 kinase substrate Akt, and have reduced activation of Rap1 in response to thrombopoietin, IGF-1, ADP, SFLLRN, and thrombin. This effect was independent of Giα P2Y12 purinergic receptor function as ADP-mediated inhibition of VASP phosphorylation was unchanged. These results demonstrate that the PI3 kinase/Rap1 pathway is intrinsically impaired in platelets from JAK2V617F-positive ET patients, resulting in diminished thrombin and thrombopoietin-mediated integrin αIIbβ3 activation.

Patients with myeloproliferative disorders (MPDs), such as essential thrombocythemia (ET) have increased risk of thrombosis and bleeding, which are major sources of morbidity and mortality. Most MPD patients have a gain of function mutation in Janus kinase 2 (JAK2V617F), but little is known how JAK2V617F affects platelet function. Here, we demonstrate that platelets from ET patients have impaired SFLLRN-mediated fibrinogen binding and have lost the potentiating effect of thrombopoietin (which couples to JAK2) on this pathway. In contrast, SFLLRN-mediated P-selectin expression, ATP secretion, phosphorylation of the PKC substrate pleckstrin, and Ca2+mobilization were unaffected in JAK2V617F positive platelets. In addition, thrombopoietin-mediated JAK2 phosphorylation was unchanged, suggesting that signaling pathways activated downstream of JAK2 are impaired. Indeed, we found that platelets from JAK2V617F-positive ET patients have significantly reduced phosphorylation of the PI3 kinase substrate Akt, and have reduced activation of Rap1 in response to thrombopoietin, IGF-1, ADP, SFLLRN, and thrombin. This effect was independent of Giα P2Y12 purinergic receptor function as ADP-mediated inhibition of VASP phosphorylation was unchanged. These results demonstrate that the PI3 kinase/Rap1 pathway is intrinsically impaired in platelets from JAK2V617F-positive ET patients, resulting in diminished thrombin and thrombopoietin-mediated integrin αIIbβ3activation.

Platelets are highly specialized blood cells critically involved in hemostasis and thrombosis. Members of the protein kinase C (PKC) family have established roles in regulating platelet function and thrombosis, but the molecular mechanisms are not clearly understood. In particular, the conventional PKC isoform, PKCα, is a major regulator of platelet granule secretion, but the molecular pathway from PKCα to secretion is not defined. Protein kinase D (PKD) is a family of 3 kinases activated by PKC, which may represent a step in the PKC signaling pathway to secretion. In the present study, we show that PKD2 is the sole PKD member regulated downstream of PKC in platelets, and that the conventional, but not novel, PKC isoforms provide the upstream signal. Platelets from a gene knock-in mouse in which 2 key phosphorylation sites in PKD2 have been mutated (Ser707Ala/Ser711Ala) show a significant reduction in agonist-induced dense granule secretion, but not in α-granule secretion. This deficiency in dense granule release was responsible for a reduced platelet aggregation and a marked reduction in thrombus formation. Our results show that in the molecular pathway to secretion, PKD2 is a key component of the PKC-mediated pathway to platelet activation and thrombus formation through its selective regulation of dense granule secretion.

Antibody-mediated retinopathies may be widely present among the canine population. Early diagnosis and appropriate treatment are essential for visual preservation and reversal of blindness in these patients. The principal purpose of this review is to describe the mechanistic basis, clinical signs, diagnostic methods, and treatment options for retinal diseases causing sudden onset of blindness with absence of typical signs of intraocular inflammation or retinal degeneration—sudden acquired retinal degeneration syndrome and immune-mediated retinitis.

Remote navigation, popular in computer games and prevalent in areas such as clinical medicine and teleoperations of robots and drones, uses human-computer interfaces for control. Usability studies of remote navigation interfaces require good metrics for evaluating interfaces, assessing users' capabilities, and determining the difficulty of the navigational task. We studied the time proficient users took to navigate virtual hovercrafts through virtual hallways with corners of various widths and discovered that the time to negotiate corners is inversely proportional to corner width. We derive and evaluate two models for the index of difficulty for negotiating corners. Both models fit the data well, with r2greater than 0.85 for the mean time to negotiate corners verses corner width.

Background A 49-year old man initially underwent clam ileocystoplasty 14 years ago. A revision of this original procedure was required 11 years ago for intractable detrusor overactivity secondary to transverse myelitis; he experienced only temporary symptomatic improvement that lasted 6 months after each procedure. Despite the use of oral anticholinergic drugs, the patient subsequently needed to perform clean intermittent self-catheterization approximately 10 times every 24 h, and when he presented to our department, he still suffered from occasional episodes of urgency incontinence that required the regular use of a penile sheath.Investigations Symptom severity was assessed using a 4-day bladder diary.Diagnosis Cystometry confirmed the presence of terminal detrusor overactivity.Management After the patient provided his informed consent, he was treated as an outpatient with intradetrusor injections of botulinum toxin A, delivered under local anesthesia by a minimally invasive technique that used a flexible cystoscope. A significant improvement was noted in the patient's lower urinary tract symptoms, urodynamic parameters and quality of life, measured at 4 and 16 weeks after treatment. The patient was completely dry at both follow-up visits and was able to discontinue the use of anticholinergic drugs and the penile sheath for a total of 11 months.

Store-operated Ca2+entry (SOCE) is a major mechanism for Ca2+influx in platelets and other cells. De novo conformational coupling between elements in the plasma membrane and Ca2+stores, where the actin cytoskeleton plays an important regulatory role, has been proposed as the most likely mechanism to activate SOCE in platelets. Here we have examined for the first time changes in platelet F-actin levels on a subsecond time scale. Using stopped-flow fluorimetry and a quenched-flow approach, we provide evidence for the involvement of cofilin in actin filament reorganization and SOCE in platelets. Thrombin (0.1 U/mL) evoked an initial decrease in F-actin that commenced within 0.1 second and reached a minimum 0.9 second after stimulation, prior to the activation of SOCE. F-actin then increased, exceeding basal levels approximately 2.5 seconds after stimulation. Thrombin also induced cofilin dephosphorylation and activation, which paralleled the changes observed in F-actin, and rapid Btk activation. Inhibition of cofilin dephosphorylation by LFM-A13 resulted in the loss of net actin depolymerization and an increased delay in SOCE initiation. These results suggest that cofilin is important for the rapid actin remodeling necessary for the activation of SOCE in platelets through de novo conformational coupling.