HLA-B*57:01 Allele Prevalence in HIV-infected North American Subjects and the Impact of Allele Testing on the Incidence of Abacavir-associated Hypersensitivity Reaction in HLA-B*57:01-negative Subjects

BACKGROUND: The presence of the HLA-B*57:01 allele in HIV-infected subjects is associated with a higher risk of abacavir-associated hypersensitivity reaction (ABC HSR). HLA-B*57:01 allele prevalence varies in different populations, but HLA-B*57:01 testing with immunological confirmation has had a negative predictive value for ABC HSR between 97 and 100%. METHODS: In the ASSURE study (EPZ113734), the HLA-B*57:01 prevalence in virologically suppressed, antiretroviral treatment-experienced, HIV-infected subjects from the United States, including Puerto Rico, was assessed. RESULTS: Three hundred eighty-five subjects were screened; 13 were HLA-B*57:01 positive and 372 were negative. Only HLA-B*57:01-negative, abacavir-naive subjects were eligible to enroll into the ASSURE trial. Eleven of the 13 subjects who possessed the HLA-B*57:01 allele were white, the other 2 were African-American. There was no geographic clustering of HLA-B*57:01-positive subjects, and the incidence correlated roughly with those states with the greatest numbers of subjects screened. Similarly, there was no statistically significant correlation between subjects who possessed or lacked the allele and age, gender, ethnicity or CD4+ T-cell numbers. The incidence of ABC HSR following abacavir initiation was also evaluated. Only 1 of 199 HLA-B*57:01-negative subjects (an African-American male) randomized to receive abacavir-containing treatment developed symptoms consistent with suspected ABC HSR; ABC HSR was not immunologically confirmed. CONCLUSIONS: These findings confirm the utility of HLA-B*57:01 allele testing to reduce the frequency of ABC HSR. The prevalence of HLA-B*57:01 positivity was higher in white than in African-American subjects. In HLA-B*57:01-negative subjects, suspected ABC HSR is very rare, but should lead to discontinuation of abacavir when ABC HSR cannot be definitively excluded from the differential diagnosis. TRIAL REGISTRATION: The ASSURE (EPZ113734) study was registered on ClinicalTrials.gov registration on April 8th 2010 and the registration number is NCT01102972

Expanding Ethical Standards of HMR: Necessary Evils and the Multiple Dimensions of Impact

Ethical challenges abound in HRM. Each day, in the course of executing and communicating HR decisions, managers have the potential to change, shape, redirect, and fundamentally alter the course of other people\u27s lives. Managers make hiring decisions that reward selected applicants with salaries, benefits, knowledge, and skills, but leave the remaining applicants bereft of these opportunities and advantages. Managers make promotion decisions that reward selected employees with raises, status, and responsibility, leaving other employees wondering about their future and their potential. Managers make firing and lay-off decisions in order to improve corporate performance, all the while harming the targeted individuals and even undermining the commitment and energy of survivors. Even when managers complete performance appraisals and deliver performance feedback, they may inspire one employee and devastate another. For each HR practice, there are winners and there are losers: Those who get the job, or receive a portfolio of benefits, and those who do not

Afferent activity to necklace glomeruli is dependent on external stimuli

<p>Abstract</p> <p>Background</p> <p>The main olfactory epithelium (MOE) is a complex organ containing several functionally distinct subpopulations of sensory neurons. One such subpopulation is distinguished by its expression of the guanylyl cyclase GC-D. The axons of GC-D-expressing (GC-D+) neurons innervate 9–15 "necklace" glomeruli encircling the caudal main olfactory bulb (MOB). Chemosensory stimuli for GC-D+ neurons include two natriuretic peptides, uroguanylin and guanylin, and CO₂. However, the biologically-relevant source of these chemostimuli is unclear: uroguanylin is both excreted in urine, a rich source of olfactory stimuli for rodents, and expressed in human nasal epithelium; CO₂is present in both inspired and expired air.</p> <p>Findings</p> <p>To determine whether the principal source of chemostimuli for GC-D+ neurons is external or internal to the nose, we assessed the consequences of removing external chemostimuli for afferent activity to the necklace glomeruli. To do so, we performed unilateral naris occlusions in <it>Gucy2d-Mapt-lacZ </it>^+/-mice [which express a β-galactosidase (β-gal) reporter specifically in GC-D+ neurons] followed by immunohistochemistry for β-gal and a glomerular marker of afferent activity, tyrosine hydroxylase (TH). We observed a dramatic decrease in TH immunostaining, consistent with reduced or absent afferent activity, in both necklace and non-necklace glomeruli ipsilateral to the occluded naris.</p> <p>Conclusion</p> <p>Like other MOB glomeruli, necklace glomeruli exhibit a large decrease in afferent activity upon removal of external stimuli. Thus, we conclude that activity in GC-D+ neurons, which specifically innervate necklace glomeruli, is not dependent on internal stimuli. Instead, GC-D+ neurons, like other OSNs in the MOE, primarily sense the external world.</p

Final Cultural Resources Report For The Salt Creek Midstream, LLC Proposed Waha II Pipeline Project On State Of Texas Lands In Reeves County, Texas

Enercon Services, Inc. (ENERCON), in support of Salt Creek Midstream, LLC, conducted an intensive archeological survey for the proposed Waha II Pipeline Project. The proposed pipeline is approximately 27.33 miles in length, located near Pecos, Texas in Reeves County. This report encompasses only the two State of Texas Lands, administered by the Texas General Land Office (TGLO), segments of the proposed Waha II Pipeline Project which is approximately 0.69-miles (3,666 feet) in length in Reeves County. The State of Texas Lands portion of the project area is mapped on the United States Geological Survey (USGS) Toyah Lake, Tex. (1963), and Old X Ranch, Tex. (1963, Photorevised 1981), 7.5 Minute Quadrangles. The construction corridor consists of a 50-foot-wide permanent pipeline right-of-way (ROW) and a 50-footwide temporary workspace corridor. The cultural resources survey corridor was 100 feet wide for the entire 0.69-mile length of the pipeline segment through the State of Texas Lands. The total area inspected during the cultural resources survey of the State of Texas Lands was 8.43 acres (3.41 hectares). The survey of the State of Texas property was completed under Texas Antiquities Permit No. 9017. The cultural resources field investigation on State of Texas Lands occurred on August 2 and 3, 2018 by J. Matthew Oliver and Gary D. Edington and consisted of an intensive pedestrian survey utilizing transects not spaced greater than 15 meters apart with shovel tests. The field investigation was conducted in accordance with the Texas Historical Commission (THC) Archeological Survey Standards for Texas. The entire project was supervised by Gary D. Edington, an ENERCON archeologist who meets the U.S. Secretary of the Interior’s Professional Qualification Standards for archeology as set forth in 36 CFR 61. The cultural resources survey resulted in the observation of two isolated finds (IF). IF#8 is a single lithic flake of brown chert observed on the surface in the east tract of State of Texas Lands. IF#9 is a small bulldozer push-pile of old wooden fence posts and barbed wire observed adjacent to the east fence line of the east tract of Texas State lands. IF#8 and IF#9 lack information potential and are not eligible for the National Register of Historic Places (NRHP) or State Antiquities Landmarks (SAL). The cultural resources survey did not result in finding any additional historic or prehistoric artifacts, features, cultural lenses, or sites over 50 years of age on State of Texas Lands. No archeological sites were encountered, and no artifacts were collected. Therefore, it is recommended that the project will have no effect on any cultural resources that may qualify for inclusion to the NRHP on State of Texas Lands. No further cultural resources investigations are recommended prior to construction of the proposed Waha II Pipeline project on State of Texas Lands. If cultural material, including sites, features, or artifacts that are 50 years old or older are encountered within the ROW during construction of this project, work in the area must cease and the regional THC Archeologist must be immediately be notified

Cultural Resources Report For The Salt Creek Midstream, LLC Proposed Halcon Pipeline On Texas General Land Office Lands In Reeves County, Texas

Enercon Services, Inc. (ENERCON), in support of Salt Creek Midstream, LLC, conducted an intensive cultural resources survey for the proposed Halcon Pipeline. The proposed pipeline is approximately 43.3 miles (69.7 km) in length and located near Pecos, Texas in Ward and Reeves counties. This report encompasses only the portion of the proposed Halcon Pipeline located on two tracts of Permanent School Fund land in Reeves County, Texas. The Permanent School Fund is administered by the Texas General Land Office (TGLO), a political subdivision of the State of Texas. The portion of the Halcon Pipeline on TGLO lands is approximately 1.8 miles (2.8 km) in length and depicted on the United States Geological Survey (USGS) Quito Draw, Tex. (1963, Photorevised 1981), Old X Ranch, Tex. (1963, Photorevised 1981), Toyah Lake, Tex. (1963) 7.5 Minute Quadrangle maps. The construction corridor consists of a 50 feet (15 m) wide permanent pipeline right-of-way (ROW) and an additional 50 feet (15 m) wide temporary workspace corridor. The cultural resources survey area of potential effect (APE) consists of the 1.8 mile (2.8 km) by 100 feet (30 m) corridor, totaling 21.3 acres (8.6 hectares). The cultural resources investigation is intended to assist in adhering to the 1969 Antiquities Code of Texas and the cultural resources survey on TGLO lands was completed under Texas Antiquities Permit No. 8275. The entire project was supervised by Michael M. Margolis, an ENERCON archeologist who meets the U.S. Secretary of the Interior’s Professional Qualification Standards for archeology as set forth in 36 CFR 61. Prior to the survey, a search of the Texas Archeological Sites Atlas (the Atlas) was conducted by Michael M. Margolis to locate previously recorded archeological sites, archeological surveys, National Register of Historic Places (NRHP) properties, and State Antiquities Landmarks (SALs). Based on the Atlas, one site, 41RV60, has been previously recorded within 1-mile of the APE on TGLO lands. Site 41RV60 is an Early Archaic lithic scatter recorded by URS Corporation in March 2014 and was determined ineligible for listing on the NRHP by the State Historic Preservation Officer (SHPO) on April 8, 2014. Site 41RV60 is located approximately 4,500 feet (1,372 m) from the APE and will not be impacted by construction of the proposed Halcon Pipeline. Two archeological surveys or studies are mapped within 1-mile of the APE on TGLO lands. The cultural resources survey of the Halcon Pipeline APE on TGLO lands was conducted December 1-2, 2017 by Julie Wasinger and Gary D. Edington, ENERCON archeologists who meet the U.S. Secretary of the Interior’s Professional Qualification Standards for archeology as set forth in 36 CFR 61. Salt Creek Midstream, LLC procedures dictate that all standing structures be avoided during construction. Fieldwork was conducted in accordance with the Texas Historical Commission (THC) Archeological Survey Standards for Texas. The cultural resources survey of the Halcon Pipeline APE did not result in finding any historic or prehistoric artifacts, features, cultural lenses, or sites and no artifacts were collected on TGLO lands. Therefore, it is recommended that construction of the proposed Halcon Pipeline on TGLO lands will have no effect on any historic property that may qualify for inclusion on the NRHP or SAL listings. No further cultural resources investigations are recommended prior to construction of the proposed Halcon Pipeline on TGLO lands. If cultural material, including sites, features, or artifacts that are 50 years old or older are encountered within the APE during construction of the Halcon Pipeline on TGLO lands, work in the area must cease and the regional THC Archeologist (512-463-6096) must be notified immediately

Reliability in the Identification of Midbrain Dopamine Neurons

Brain regions typically contain intermixed subpopulations of neurons with different connectivity and neurotransmitters. This complicates identification of neuronal phenotypes in electrophysiological experiments without using direct detection of unique molecular markers. A prime example of this difficulty is the identification of dopamine (DA) neurons in the midbrain ventral tegmental area (VTA). Although immunocytochemistry (ICC) against tyrosine hydroxylase (TH) is widely used to identify DA neurons, a high false negative rate for TH ICC following ex vivo electrophysiology experiments was recently reported, calling into question the validity of comparing DA and non-DA VTA neurons based on post-hoc ICC. However, in whole cell recordings from randomly selected rat VTA neurons we have found that TH labeling is consistently detected in ∼55% of neurons even after long recording durations (range: 2.5–150 min). This is consistent with our prior anatomical finding that 55% of VTA neurons are TH(+). To directly estimate a false negative rate for our ICC method we recorded VTA neurons from mice in which EGFP production is driven by the TH promoter. All 12 EGFP(+) neurons recorded with a K-gluconate internal solution (as used in our rat recordings) were strongly labeled by TH ICC (recording duration 16.6±1.8 min). However, using recording electrodes with an internal solution with high Cl− concentration reduced the intensity of TH co-labeling, in some cases to background (recording duration 16.7±0.9 min; n = 10). Thus TH is a highly reliable molecular marker for DA neurons in VTA patch clamp recordings provided compatible microelectrode solutions are used

Arrest of mammalian fibroblasts in G1 in response to actin inhibition is dependent on retinoblastoma pocket proteins but not on p53

p53 and the retinoblastoma (RB) pocket proteins are central to the control of progression through the G1 phase of the cell cycle. The RB pocket protein family is downstream of p53 and controls S-phase entry. Disruption of actin assembly arrests nontransformed mammalian fibroblasts in G1. We show that this arrest requires intact RB pocket protein function, but surprisingly does not require p53. Thus, mammalian fibroblasts with normal pocket protein function reversibly arrest in G1 on exposure to actin inhibitors regardless of their p53 status. By contrast, pocket protein triple knockout mouse embryo fibroblasts and T antigen–transformed rat embryo fibroblasts lacking both p53 and RB pocket protein function do not arrest in G1. Fibroblasts are very sensitive to actin inhibition in G1 and arrest at drug concentrations that do not affect cell adhesion or cell cleavage. Interestingly, G1 arrest is accompanied by inhibition of surface ruffling and by induction of NF2/merlin. The combination of failure of G1 control and of tetraploid checkpoint control can cause RB pocket protein–suppressed cells to rapidly become aneuploid and die after exposure to actin inhibitors, whereas pocket protein–competent cells are spared. Our results thus establish that RB pocket proteins can be uniquely targeted for tumor chemotherapy

Envelope-specific antibodies and antibody-derived molecules for treating and curing HIV infection

HIV-1 is a retrovirus that integrates into host chromatin and can remain transcriptionally quiescent in a pool of immune cells. This characteristic enables HIV-1 to evade both host immune responses and antiretroviral drugs, leading to persistent infection. Upon reactivation of proviral gene expression, HIV-1 envelope (HIV-1 Env) glycoproteins are expressed on the cell surface, transforming latently infected cells into targets for HIV-1 Env-specific monoclonal antibodies (mAbs), which can engage immune effector cells to kill productively infected CD4+ T cells and thus limit the spread of progeny virus. Recent innovations in antibody engineering have resulted in novel immunotherapeutics such as bispecific dual-affinity re-targeting (DART) molecules and other bi- and trispecific antibody designs that can recognize HIV-1 Env and recruit cytotoxic effector cells to kill CD4+ T cells latently infected with HIV‑1. Here, we review these immunotherapies, which are designed with the goal of curing HIV-1 infection