Antibody responses to a Cryptosporidium parvum rCP15/60 vaccine

Cryptosporidium parvum is a zoonotic apicomplexa-protozoan pathogen that causes gastroenteritis and diarrhoea in mammals worldwide. The organism is transmitted by ingestion of oocysts, which are shed in faeces, and completes its lifecycle in a single host.^1^ C. parvum is ubiquitous on dairy operations worldwide and is one of the leading causes of diarrhoea in calves on these farms.^2,3^ Here, for the first time, we describe the antibody response in a large group of cows to a recombinant C. parvum oocyst surface protein (rCP15/60) vaccine and the antibody response in calves fed rCP15/60-immune colostrum produced by these vaccinated cows. Results of recent genotype surveys indicate that calves are the only major reservoir for C. parvum infections in humans.^4^ Human C. parvum infections are particularly prevalent and often fatal in neonates in developing countries and to immunocompromised people, such as AIDs patients.^4^ Drug therapy against cryptosporidiosis is limited and not wholly efficacious in either humans or calves^5^, making development of an effective vaccine of paramount importance. To date, there is no commercially available effective vaccine against C. parvum, although passive immunization utilizing different zoite surface (glyco)proteins has showed promise.^6-9^ All cows we vaccinated produced an antibody response to the rCP15/60 vaccine and the magnitude of response correlated strongly with the subsequent level of antibody in their colostrum. All calves fed rCP15/60-immune colostrum showed a dose-dependent absorption of antibody. Our results demonstrate that vaccination of cows with rCP15/60 successfully induces antibodies against CP15/60 in their serum and colostrum and that these antibodies are then well absorbed when fed to neonatal calves. With further research, this C. parvum vaccine may well be a practical method of conferring passive protection to calves against cryptosporidiosis. Furthermore, a specifically targeted immune-colostrum may be valuable in protection and treatment of immunocompromised human patients with cryptosporidiosis

National Emission Standards for Hazardous Air Pollutants for Major Sources: Industrial, Commercial, and Institutional Boilers; Guidance for Calculating Efficiency Credits Resulting from Implementation of Energy Conservation Measures

The purpose of this document is to provide guidance for developing a consistent approach to documenting efficiency credits generated from energy conservation measures in the Implementation Plan for boilers covered by the Boiler MACT rule (i.e., subpart DDDDD of CFR part 63). This document divides Boiler System conservation opportunities into four functional areas: 1) the boiler itself, 2) the condensate recovery system, 3) the distribution system, and 4) the end uses of the steam. This document provides technical information for documenting emissions credits proposed in the Implementation Plan for functional areas 2) though 4). This document does not include efficiency improvements related to the Boiler tune-ups

Recognition of Lyso-Phospholipids by Human Natural Killer T Lymphocytes

Natural killer T (NKT) cells are a subset of T lymphocytes with potent immunoregulatory properties. Recognition of self-antigens presented by CD1d molecules is an important route of NKT cell activation; however, the molecular identity of specific autoantigens that stimulate human NKT cells remains unclear. Here, we have analyzed human NKT cell recognition of CD1d cellular ligands. The most clearly antigenic species was lyso-phosphatidylcholine (LPC). Diacylated phosphatidylcholine and lyso-phosphoglycerols differing in the chemistry of the head group stimulated only weak responses from human NKT cells. However, lyso-sphingomyelin, which shares the phosphocholine head group of LPC, also activated NKT cells. Antigen-presenting cells pulsed with LPC were capable of stimulating increased cytokine responses by NKT cell clones and by freshly isolated peripheral blood lymphocytes. These results demonstrate that human NKT cells recognize cholinated lyso-phospholipids as antigens presented by CD1d. Since these lyso-phospholipids serve as lipid messengers in normal physiological processes and are present at elevated levels during inflammatory responses, these findings point to a novel link between NKT cells and cellular signaling pathways that are associated with human disease pathophysiology.</p

Palliative care early in the care continuum among patients with serious respiratory illness an official ATS/AAHPM/HPNA/SWHPN policy statement

Background: Patients with serious respiratory illness and their caregivers suffer considerable burdens, and palliative care is a fundamental right for anyone who needs it. However, the overwhelming majority of patients do not receive timely palliative care before the end of life, despite robust evidence for improved outcomes. Goals: This policy statement by the American Thoracic Society (ATS) and partnering societies advocates for improved integration of high-quality palliative care early in the care continuum for patients with serious respiratory illness and their caregivers and provides clinicians and policymakers with a framework to accomplish this. Methods: An international and interprofessional expert committee, including patients and caregivers, achieved consensus across a diverse working group representing pulmonary–critical care, palliative care, bioethics, health law and policy, geriatrics, nursing, physiotherapy, social work, pharmacy, patient advocacy, psychology, and sociology. Results: The committee developed fundamental values, principles, and policy recommendations for integrating palliative care in serious respiratory illness care across seven domains: 1) delivery models, 2) comprehensive symptom assessment and management, 3) advance care planning and goals of care discussions, 4) caregiver support, 5) health disparities, 6) mass casualty events and emergency preparedness, and 7) research priorities. The recommendations encourage timely integration of palliative care, promote innovative primary and secondary or specialist palliative care delivery models, and advocate for research and policy initiatives to improve the availability and quality of palliative care for patients and their caregivers. Conclusions: This multisociety policy statement establishes a framework for early palliative care in serious respiratory illness and provides guidance for pulmonary–critical care clinicians and policymakers for its proactive integration

HacA-Independent Functions of the ER Stress Sensor IreA Synergize with the Canonical UPR to Influence Virulence Traits in Aspergillus fumigatus

Endoplasmic reticulum (ER) stress is a condition in which the protein folding capacity of the ER becomes overwhelmed by an increased demand for secretion or by exposure to compounds that disrupt ER homeostasis. In yeast and other fungi, the accumulation of unfolded proteins is detected by the ER-transmembrane sensor IreA/Ire1, which responds by cleaving an intron from the downstream cytoplasmic mRNA HacA/Hac1, allowing for the translation of a transcription factor that coordinates a series of adaptive responses that are collectively known as the unfolded protein response (UPR). Here, we examined the contribution of IreA to growth and virulence in the human fungal pathogen Aspergillus fumigatus. Gene expression profiling revealed that A. fumigatus IreA signals predominantly through the canonical IreA-HacA pathway under conditions of severe ER stress. However, in the absence of ER stress IreA controls dual signaling circuits that are both HacA-dependent and HacA-independent. We found that a ΔireA mutant was avirulent in a mouse model of invasive aspergillosis, which contrasts the partial virulence of a ΔhacA mutant, suggesting that IreA contributes to pathogenesis independently of HacA. In support of this conclusion, we found that the ΔireA mutant had more severe defects in the expression of multiple virulence-related traits relative to ΔhacA, including reduced thermotolerance, decreased nutritional versatility, impaired growth under hypoxia, altered cell wall and membrane composition, and increased susceptibility to azole antifungals. In addition, full or partial virulence could be restored to the ΔireA mutant by complementation with either the induced form of the hacA mRNA, hacAi, or an ireA deletion mutant that was incapable of processing the hacA mRNA, ireAΔ10. Together, these findings demonstrate that IreA has both HacA-dependent and HacA-independent functions that contribute to the expression of traits that are essential for virulence in A. fumigatus

Determination of Cellular Lipids Bound to Human CD1d Molecules

CD1 molecules are glycoproteins that present lipid antigens at the cell surface for immunological recognition by specialized populations of T lymphocytes. Prior experimental data suggest a wide variety of lipid species can bind to CD1 molecules, but little is known about the characteristics of cellular ligands that are selected for presentation. Here we have molecularly characterized lipids bound to the human CD1d isoform. Ligands were eluted from secreted CD1d molecules and separated by normal phase HPLC, then characterized by mass spectroscopy. A total of 177 lipid species were molecularly identified, comprising glycerophospholipids and sphingolipids. The glycerophospholipids included common diacylglycerol species, reduced forms known as plasmalogens, lyso-phospholipids (monoacyl species), and cardiolipins (tetraacyl species). The sphingolipids included sphingomyelins and glycosylated forms, such as the ganglioside GM3. These results demonstrate that human CD1d molecules bind a surprising diversity of lipid structures within the secretory pathway, including compounds that have been reported to play roles in cancer, autoimmune diseases, lipid signaling, and cell death

A Role for the Unfolded Protein Response (UPR) in Virulence and Antifungal Susceptibility in Aspergillus fumigatus

Filamentous fungi rely heavily on the secretory pathway, both for the delivery of cell wall components to the hyphal tip and the production and secretion of extracellular hydrolytic enzymes needed to support growth on polymeric substrates. Increased demand on the secretory system exerts stress on the endoplasmic reticulum (ER), which is countered by the activation of a coordinated stress response pathway termed the unfolded protein response (UPR). To determine the contribution of the UPR to the growth and virulence of the filamentous fungal pathogen Aspergillus fumigatus, we disrupted the hacA gene, encoding the major transcriptional regulator of the UPR. The ΔhacA mutant was unable to activate the UPR in response to ER stress and was hypersensitive to agents that disrupt ER homeostasis or the cell wall. Failure to induce the UPR did not affect radial growth on rich medium at 37°C, but cell wall integrity was disrupted at 45°C, resulting in a dramatic loss in viability. The ΔhacA mutant displayed a reduced capacity for protease secretion and was growth-impaired when challenged to assimilate nutrients from complex substrates. In addition, the ΔhacA mutant exhibited increased susceptibility to current antifungal agents that disrupt the membrane or cell wall and had attenuated virulence in multiple mouse models of invasive aspergillosis. These results demonstrate the importance of ER homeostasis to the growth and virulence of A. fumigatus and suggest that targeting the UPR, either alone or in combination with other antifungal drugs, would be an effective antifungal strategy

Palliative care early in the care continuum among patients with serious respiratory illness - An official ATS/AAHPM/HPNA/SWHPN policy statement

Background: Patients with serious respiratory illness and their caregivers suffer considerable burdens, and palliative care is a fundamental right for anyone who needs it. However, the overwhelming majority of patients do not receive timely palliative care before the end of life, despite robust evidence for improved outcomes. Goals: This policy statement by the American Thoracic Society (ATS) and partnering societies advocates for improved integration of high-quality palliative care early in the care continuum for patients with serious respiratory illness and their caregivers and provides clinicians and policymakers with a framework to accomplish this. Methods: An international and interprofessional expert committee, including patients and caregivers, achieved consensus across a diverse working group representing pulmonary–critical care, palliative care, bioethics, health law and policy, geriatrics, nursing, physiotherapy, social work, pharmacy, patient advocacy, psychology, and sociology. Results: The committee developed fundamental values, principles, and policy recommendations for integrating palliative care in serious respiratory illness care across seven domains: 1) delivery models, 2) comprehensive symptom assessment and management, 3) advance care planning and goals of care discussions, 4) caregiver support, 5) health disparities, 6) mass casualty events and emergency preparedness, and 7) research priorities. The recommendations encourage timely integration of palliative care, promote innovative primary and secondary or specialist palliative care delivery models, and advocate for research and policy initiatives to improve the availability and quality of palliative care for patients and their caregivers. Conclusions: This multisociety policy statement establishes a framework for early palliative care in serious respiratory illness and provides guidance for pulmonary–critical care clinicians and policymakers for its proactive integration

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio