Very-high-energy particle acceleration powered by the jets of the microquasar SS 433.

SS 433 is a binary system containing a supergiant star that is overflowing its Roche lobe with matter accreting onto a compact object (either a black hole or neutron star)1-3. Two jets of ionized matter with a bulk velocity of approximately 0.26c (where c is the speed of light in vacuum) extend from the binary, perpendicular to the line of sight, and terminate inside W50, a supernova remnant that is being distorted by the jets2,4-8. SS 433 differs from other microquasars (small-scale versions of quasars that are present within our own Galaxy) in that the accretion is believed to be super-Eddington9-11, and the luminosity of the system is about 1040 ergs per second2,9,12,13. The lobes of W50 in which the jets terminate, about 40 parsecs from the central source, are expected to accelerate charged particles, and indeed radio and X-ray emission consistent with electron synchrotron emission in a magnetic field have been observed14-16. At higher energies (greater than 100 gigaelectronvolts), the particle fluxes of γ-rays from X-ray hotspots around SS 433 have been reported as flux upper limits6,17-20. In this energy regime, it has been unclear whether the emission is dominated by electrons that are interacting with photons from the cosmic microwave background through inverse-Compton scattering or by protons that are interacting with the ambient gas. Here we report teraelectronvolt γ-ray observations of the SS 433/W50 system that spatially resolve the lobes. The teraelectronvolt emission is localized to structures in the lobes, far from the centre of the system where the jets are formed. We have measured photon energies of at least 25 teraelectronvolts, and these are certainly not Doppler-boosted, because of the viewing geometry. We conclude that the emission-from radio to teraelectronvolt energies-is consistent with a single population of electrons with energies extending to at least hundreds of teraelectronvolts in a magnetic field of about 16 microgauss.

Publisher Correction: Very-high-energy particle acceleration powered by the jets of the microquasar SS 433.

In this Letter, owing to a production error, the penultimate version of the PDF was published. The HTML version was always correct. The PDF has been corrected online.

Discovery of Gamma Rays from the Quiescent Sun with HAWC.

We report the first detection of a TeV γ-ray flux from the solar disk (6.3σ), based on 6.1 years of data from the High Altitude Water Cherenkov (HAWC) observatory. The 0.5-2.6 TeV spectrum is well fit by a power law, dN/dE=A(E/1 TeV)^{-γ}, with A=(1.6±0.3)×10^{-12} TeV^{-1} cm^{-2} s^{-1} and γ=3.62±0.14. The flux shows a strong indication of anticorrelation with solar activity. These results extend the bright, hard GeV emission from the disk observed with Fermi-LAT, seemingly due to hadronic Galactic cosmic rays showering on nuclei in the solar atmosphere. However, current theoretical models are unable to explain the details of how solar magnetic fields shape these interactions. HAWC's TeV detection thus deepens the mysteries of the solar-disk emission.

Influence of higher-order modes on ferroconvection.

Using Fourier representations, an elaborate study of regular cellular-convective and chaotic motions in a ferrofluid is made. Investigation is made on the adequacy or otherwise of the minimal mode in studying such motions. Higher-order modes are also considered by adding modes (vertical/horizontal/combined extension). For higher modes, the extensions yield a dynamical system of order greater than three. The characteristic features of extended ferromagnetic-Lorenz models are analyzed using the largest Lyapunov exponent(LE), second largest LE, bifurcation diagram, and phase-space plots. The effect of additional modes on critical modal-Rayleigh (infinitesimal and finite-amplitude ones) numbers and the Rayleigh number at which transition to chaos occurs are examined to report features of ferroconvection hitherto unseen in previous studies. As both horizontal and vertical modes are increased, our findings infer that the dynamical system displays advanced onset of regular convection and delayed chaotic motion. Vigorous-chaotic motion is seen on adding vertical modes, whereas on adding horizontal modes, intense chaos appears with decreased intensity for large values of the scaled Rayleigh number. Most important finding from the study is that as modes are increased (vertical/horizontal), the transition from regular to chaotic motion is greatly modified and leads the system to a hyper-chaotic state. Conventionally, the chaotic or hyper-chaotic state is intermittent with a periodic/quasi-periodic state but it can be retained in the chaotic or hyper-chaotic state by considering moderate values of the Prandtl number and/or by bringing in the ferromagnetic effect.

Effects of prepartum vaccination timing relative to pen change with an acidogenic diet on serum and colostrum immunoglobulins in Holstein dairy cows.

The objective of the present study was to assess the effects of prepartum vaccination timing relative to pen change with an acidogenic diet at 28 or 21 d before expected parturition (dpp) on colostral and serum IgG concentrations at calving in pregnant Holstein dairy cows. Pregnant multiparous Holstein cows (n = 308) from one large dairy herd were randomly allocated into 1 of 3 treatment groups at 35 ± 3 dpp: (1) vaccination at 28 dpp and pen change at 21 dpp (V28PC21; n = 108), (2) vaccination and pen change at 28 dpp (V28PC28; n = 99), and (3) vaccination and pen change at 21 dpp (V21PC21; n = 101). An acidogenic diet was fed when cows changed pens at 28 or 21 dpp. Blood and colostral samples were collected within 1 h following parturition. The total number of clinical mastitis (CM) cases within the first 150 d in milk (DIM) were recorded. The V28PC21 cows had greater colostral IgG concentrations at calving (160.4 ± 7.0 g/L) compared with V21PC21 cows (134.4 ± 7.0 g/L), and V28PC28 cows were intermediate (148.3 ± 7.2 g/L). At calving, V28PC21 cows had lower serum IgG concentrations (29.1 ± 1.2 g/L) compared with V21PC21 cows (32.2 ± 1.2 g/L) or V28PC28 cows (32.6 ± 1.3 g/L). Overall, 41% of V21PC21 cows received the booster vaccinations with at least 21 d before actual calving compared with V28PC21 or V28PC28 cows (88 and 86% respectively). The shorter the interval from prepartum booster vaccination to calving, the lower the colostral IgG at calving, regardless of treatment groups. Vaccinating at 28 dpp and pen change with an acidogenic diet at 21 dpp tended to reduce the rate of CM within the first 150 DIM compared with V21PC21. These findings provide evidence that vaccinating cows at 28 dpp, followed by pen change with an acidogenic diet at 21 dpp, improved the concentrations of colostral IgG at calving and tended to reduce the rate of CM. The interaction of prepartum vaccination timing relative to feeding an acidogenic diet should be considered when implementing an effective vaccination program to enhance overall herd health.

Effect of timing of prepartum vaccination relative to pen change with an acidogenic diet on lying time and metabolic profile in Holstein dairy cows.

The objective was to assess the effect of prepartum vaccination timing relative to pen change with an acidogenic diet at 28 or 21 d before expected parturition (dpp) on lying time (LT), prepartum serum energy status (glucose, IGF-1, and nonesterified fatty acids), urine pH, and serum Ca at calving in pregnant Holstein dairy cows. Pregnant multiparous Holstein cows (n = 308) from 1 large dairy herd were randomly allocated into 1 of 3 treatment groups at 35 ± 3 dpp as follows: (1) vaccination at 28 dpp and pen change at 21 dpp (V28PC21; n = 108), (2) vaccination and pen change at 28 dpp (V28PC28; n = 99), and (3) vaccination and pen change at 21 dpp (V21PC21; n = 101). When cows changed pens, an acidogenic diet was introduced. Every other week, a group of 43 to 53 animals were enrolled and electronic data loggers (IceQube, IceRobotics) were fitted to the hind leg of individual cows to assess their LT. Blood samples were collected at 28, 26, 21, 19, 14 dpp and at calving. Parity, body condition score, days dry, and gestation length were not different among groups. Overall, V28PC28 cows had 7 additional days in prepartum pens consuming an acidogenic diet compared with V28PC21 or V21PC21 cows. Regardless of treatment group, cows in the far-off pen had 43 min/d less LT (709 vs. 753 min/d) and increased day-to-day coefficient of variation of LT (0.21 vs. 0.10) compared with cows within the prepartum pen. On average, for the 7 d following vaccination alone (28 to 22 dpp period), V28PC21 cows had ~22 min/d less LT compared with V21PC21 cows. Serum concentrations of glucose, nonesterified fatty acids, and IGF-1 were altered following vaccination alone, pen change alone, or vaccination plus pen change with an acidogenic diet before calving. At calving, V28PC21 cows had greater glucose concentrations (6.45 mmol/L) compared with V21PC21 cows (5.76 mmol/L), with V28PC28 cows intermediate (6.11 mmol/L). The assessment of Ca status at calving revealed that V28PC21 cows had greater Ca concentration (2.34 mmol/L) with lower subclinical hypocalcemia (<2.0 mmol/L; 17.3%) compared with V21PC21 cows (2.17 mmol/L and 31.9%), with V28PC28 cows intermediate (2.28 mmol/L and 25.2%). Serum concentrations of IGF-1 at calving were also greater for V28PC21 (3.43 nmol/L) cows compared with V21PC21 (2.69 nmol/L), with V28PC28 cows intermediate (3.07 nmol/L). Overall, V28PC21 cows had greater serum glucose, IGF-1, and ~46% reduction in subclinical hypocalcemia (from 31.9 to 17.3%) compared with V21PC21 cows but did not differ from V28PC28 cows (25.2%). These findings provided evidence that vaccinating cows at 28 dpp, followed 7 d later by pen change with an acidogenic diet at 21 dpp, would be beneficial.

Constraints on Lorentz Invariance Violation from HAWC Observations of Gamma Rays above 100 TeV.

Because of the high energies and long distances to the sources, astrophysical observations provide a unique opportunity to test possible signatures of Lorentz invariance violation (LIV). Superluminal LIV enables the decay of photons at high energy. The high altitude water Cherenkov (HAWC) observatory is among the most sensitive gamma-ray instruments currently operating above 10 TeV. HAWC finds evidence of 100 TeV photon emission from at least four astrophysical sources. These observations exclude, for the strongest of the limits set, the LIV energy scale to 2.2×10^{31} eV, over 1800 times the Planck energy and an improvement of 1 to 2 orders of magnitude over previous limits.

Multiple Galactic Sources with Emission Above 56 TeV Detected by HAWC.

We present the first catalog of gamma-ray sources emitting above 56 and 100 TeV with data from the High Altitude Water Cherenkov Observatory, a wide field-of-view observatory capable of detecting gamma rays up to a few hundred TeV. Nine sources are observed above 56 TeV, all of which are likely galactic in origin. Three sources continue emitting past 100 TeV, making this the highest-energy gamma-ray source catalog to date. We report the integral flux of each of these objects. We also report spectra for three highest-energy sources and discuss the possibility that they are PeVatrons.

Angiotensin II receptor agonist antibodies are associated with microvascular damage in lupus nephritis.

Angiotensin II type 1 receptor agonist antibodies (AT1R-AAs) have been associated with hypertension, atherosclerosis and vascular inflammation in human diseases. The aim of the study was to evaluate the prevalence of AT1R-AAs in active lupus nephritis (LN) patients and their association with vascular damage. One hundred and seven active LN patients underwent a complete clinical examination, measurement of AT1R-AAs, ambulatory blood pressure monitoring, carotid intima-media thickness measurement and morphometric analysis of subintimal fibrosis and medial hyperplasia of the vessels in the kidney tissue. Plasma AT1R-AAs were positive in 58 (54.2%) patients. The Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) score, complement C3 and C4 levels and titers of anti-dsDNA antibodies were higher in the group with positive AT1R-AAs compared with those with negative AT1R-AAs. The AT1R-AA titers correlated with anti-dsDNA antibody titers and with complement C3 and C4 serum levels. In the kidney biopsy, the percentage of subintimal fibrosis and the area of medial hyperplasia were greater in the AT1R-AA-positive patients. No differences in arterial pressure, carotid intima-media thickness and response to therapy were detected. In conclusion, AT1R-AAs are prevalent in active LN patients and are associated with histologic features of microvascular damage.

Incidence and risk factors for reproductive disorders in organic certified dairies.

The objective was to determine the lactational incidence risks of reproductive disorders (RD) including dystocia (DYS), retained fetal membranes (RFM), puerperal metritis (PM), clinical endometritis (CE), pyometra (PYO), late pregnancy loss (LPL), and culling due to reproductive reasons (CRR) in large organic certified dairies with predominant use of Holstein genetics. In addition, potential risk factors for RD, including parity category, milk yield in the previous lactation, season of dry-off, access to grazing at dry-off, length of the dry period (DPL), length of the close-up period (CUPL), calculated gestation length (CGL), season of calving, access to grazing at calving, concurrent health conditions, and total number of artificial inseminations were analyzed. A retrospective study was performed using information from 8 organic certified herds located in northern Colorado and west Texas, ranging from 900 to 6,000 milking cows. Cow information consisted of finalized lactations starting with calvings occurring between January 1, 2016, and December 31, 2018. Data were analyzed using time-to-event analyses and multivariable logistic regression. Clinical endometritis had the greatest lactational incidence risk (incidence risk = 10.1%; 95% CI = 9.8-10.3%), followed by DYS (8.8%; 8.5-9.1%), PM (4.9%; 4.7-5.1%), PYO (4.0%; 3.8-4.1%), LPL (3.6%; 3.4-3.7%), and RFM (2.0%; 1.8-2.1%). The incidence risk of CRR was 7.5% (7.3-8.7%), representing 29.1% (28.4-30.0%) of all culling reasons. Median time from calving to diagnosis of PM, CE, PYO, and LPL were 6, 23, 111, and 228 d, respectively. Median time for CRR was 391 d. The main risk factors for RD were DPL, CGL, and CUPL. Season of dry-off was a risk factor for RFM, PM, CE, LPL, and PYO. Short DPL (<30 d) was associated with increased odds (95% CI) of RFM [2.1 (1.6-2.7)], PM [1.4 (1.2-1.7)], and LPL [2.5 (1.5-4.2)]. Shortened CGL (<270 d) increased the odds of DYS [1.5 (1.3-1.8)], RFM [3.2 (2.4-4.1)], and PM [2.4 (1.7-3.3)], whereas extended CGL (>285 d) increased the odds of DYS [1.5 (1.4-1.7)], PM [1.5 (1.2-2.0)], CE [1.5 (1.1-2.0)], and CRR [1.2 (1.10-1.4)]. Shortened CUPL was associated with increased odds of all the RD. Cows spending less than 7 d in the close-up groups had greater odds of DYS [1.4 (1.1-1.8)], RFM [2.1 (1.8-2.4)], PM [1.9 (1.6-2.1)], PYO [1.5 (1.2-1.8)], LPL [2 (1.7-2.3)], and CRR [1.4 (1.04-1.8)] compared with cows spending more than 14 d in the close-up group. Season of calving was associated with the odds of PM [summer = 1.13 (1.01-1.2)], PYO [summer = 1.7 (1.1-2.5)], and LPL ([fall = 0.8 (0.6-0.96)] compared with winter calving. Other risk factors affecting RD were parity number, total number of artificial inseminations, and concurrent health conditions. Overall, lactational incidence risks of reproductive diseases were comparable with those reported in conventional herds. The identified risk factors for RD open opportunities for interventions, especially focused in precalving management, estimation of due dates, and closer monitoring of pregnancies from natural services in large organic certified dairy herds.

Administration of acetylsalicylic acid after parturition in lactating dairy cows under certified organic management: Part I. Milk yield, milk components, activity patterns, fertility, and health.

Parturition is a natural process that gradually progresses from one stage to the next. However, around 5% of dairy cows will experience dystocia, which is considered to be a painful and stressful event. Studies have reported positive effects on cow performance and welfare after treatment with nonsteroidal anti-inflammatory drugs during the first postpartum days. The objectives were to assess the effects of acetylsalicylic acid administration after calving on (1) milk yield and components, (2) daily activity patterns, (3) reproductive performance, and (4) health in lactating dairy cows under certified organic management. Cows from 3 organic herds were enrolled. Within 12 h after parturition, cows were blocked by parity and calving ease and randomly assigned to 2 treatments: (1) aspirin (ASP; n = 278), in which cows received 4 consecutive treatments every 12 h with acetylsalicylic acid (100 mg/kg; 2 boluses) or (2) placebo (PLC, n = 285), in which cows received 4 treatments every 12 h with gelatin capsules (2 capsules) filled with water. Daily milk yield for the first 30 d in milk (DIM) and monthly milk yield, fat, protein, and somatic cell count (SCC) data from the first 5 Dairy Herd Improvement Association tests were collected. Activity patterns were measured using activity data loggers in the first 7 DIM. Clinical disease events (60 DIM) and fertility data were collected from on-farm computer records. Statistical analysis was performed using the MIXED (milk yield, components, and activity), LIFETEST (fertility), and GLIMMIX (health) procedures of SAS (SAS Institute Inc., Cary, NC). Overall, ASP cows produced 1.82 kg/d more milk than PLC cows during the first 30 DIM. Interestingly, cows that experienced dystocia and received ASP produced 4.48 kg/d more milk compared with cows in the PLC group that experienced dystocia. Cows treated with ASP had lower somatic cell count during the first 5 Dairy Herd Improvement Association tests. There were no differences in daily lying time, lying bouts, and lying bout duration between the ASP and PLC groups. However, cows in the ASP group had 587,64 steps/d more compared with PLC cows. In addition, ASP cows tended to require fewer days (ASP = 113.76 ± 4.99 d; PLC = 125.36 ± 4.74 d) and needed fewer services (ASP = 1.86 ± 0.21 services; PLC = 2.19 ± 0.24 services) to become pregnant compared with PLC cows. There were no differences in clinical disease events between treatments. Results from this study suggest that treating cows with ASP after calving may help improve milk yields and udder health, increase activity, and enhance fertility in dairy cattle under certified organic management.

Administration of acetylsalicylic acid after parturition in lactating dairy cows under certified organic management: Part II. Biomarkers of nociception, inflammation, and stress.

The objective was to assess the effect of oral administration of acetylsalicylic acid after calving on the concentrations of substance P (SP), haptoglobin (HP), and cortisol in lactating dairy cows. Holstein dairy cows (n = 152) from 3 organic herds were included. At parturition, cows were blocked by parity [multiparous (MULT) and primiparous (PRIM)] and calving ease [eutocia (EUT) and dystocia (DYS)] and were randomly assigned to 1 of 2 treatment groups: aspirin (ASP; n = 76), in which within 12 h after parturition cows received 4 treatments with acetylsalicylic acid (100 mg/kg; 2 boluses) at 12-h intervals, or placebo (PLC; n = 76), in which within 12 h after parturition cows received 4 consecutive treatments with gelatin capsules (2 capsules) containing water 12 h apart. Blood samples were collected immediately before treatment and at 12, 24, 36, 48, and 168 h (7 DIM) for assessment of circulating concentration of SP, HP, and cortisol. Based on farm records, cows were classified in the following clinical disease categories: no clinical disease event (NO-EVT), a single clinical disease event (SI-EVT), and more than 1 clinical disease event (MU-EVT). The study data were analyzed as a randomized complete block design using mixed multiple linear and logistic regression models. With regard to HP, there was a tendency for an interaction between treatment and parity, where MULT cows treated with ASP had lower concentration of HP compared with MULT cows treated with PLC (ASP = 124.33 ± 6.83 µg/mL; PLC = 143.9 ± 7.24 µg/mL). Analysis by calving ease showed that cows with DYS had higher concentrations of HP (DYS = 159.17 ± 5.97 µg/mL; EUT = 138.72 ± 6.22 µg/mL) and SP (only at 168 h; DYS = 64.99 pg/mL, 95% confidence interval, CI: 2.68-2.81; EUT = 60.33 pg/mL, 95% CI: 2.91-3.06) after calving compared with EUT cows. Regardless of treatment, PRIM cows had higher concentrations of SP (MULT = 55.11 pg/mL, 95% CI: 1.27-1.30; PRIM = 57.62 pg/mL, 95% CI: 1.99-2.06), HP (MULT = 134.14 ± 4.96 µg/mL; PRIM = 163.75 ± 7.76 µg/mL), and cortisol (MULT = 18.65 µg/mL, 95% CI: 1.02-1.05; PRIM = 21.92 µg/mL, 95% CI: 1.67-1.74) compared with MULT cows. In addition, cows that experienced SI-EVT or MU-EVT had higher concentrations of HP (NO-EVT = 134.13 ± 5.95 µg/mL; SI-EVT = 142.68 ± 7.32 µg/mL; MU-EVT = 170.03 ± 9.42 µg/mL) and cortisol (NO-EVT = 17.86 µg/mL, 95% CI: 1.20-1.24; SI-EVT = 21.01 µg/mL, 95% CI: 1.61-1.67; MU-EVT = 22.01 µg/mL, 95% CI: 2.08-2.18) compared with cows with NO-EVT recorded. Results from this study suggest that a short-duration anti-inflammatory therapy after calving reduced HP in MULT cows but may not have effects on SP and cortisol concentrations. Calving ease and parity affected the concentrations of markers of inflammation, nociception, and stress regardless of treatment. Further research is warranted to assess anti-inflammatory strategies aimed at decreasing inflammation and stress in DYS and PRIM cows and therefore improve welfare and performance of these high-priority groups.

Chaotic convection in an Oldroyd viscoelastic fluid in saturated porous medium with feedback control.

The control effects on the convection dynamics in a viscoelastic fluid-saturated porous medium heated from below and cooled from above are studied. A truncated Galerkin expansion was applied to balance equations to obtain a four-dimensional generalized Lorenz system. The dynamical behavior is mainly characterized by the Lyapunov exponents, bifurcation, and isospike diagrams. The results show that within a range of moderate and high Rayleigh numbers, proportional controller gain is found to enhance the stabilization and destabilization effects on the thermal convection. Furthermore, due to the effect of viscoelasticity, the system exhibits remarkable topological structures of regular regions embedded in chaotic domains.

Periodicity characterization of the nonlinear magnetization dynamics.

In this work, we study numerically the periodicity of regular regions embedded in chaotic states for the case of an anisotropic magnetic particle. The particle is in the monodomain regime and subject to an applied magnetic field that depends on time. The dissipative Landau-Lifshitz-Gilbert equation models the particle. To perform the characterization, we compute several two-dimensional phase diagrams in the parameter space for the Lyapunov exponents and the isospikes. We observe multiple transitions among periodic states, revealing complex topological structures in the parameter space typical of dynamic systems. To show the finer details of the regular structures, iterative zooms are performed. In particular, we find islands of synchronization for the magnetization and the driven field and several shrimp structures with different periods.

The PHF21B gene is associated with major depression and modulates the stress response.

Major depressive disorder (MDD) affects around 350 million people worldwide; however, the underlying genetic basis remains largely unknown. In this study, we took into account that MDD is a gene-environment disorder, in which stress is a critical component, and used whole-genome screening of functional variants to investigate the 'missing heritability' in MDD. Genome-wide association studies (GWAS) using single- and multi-locus linear mixed-effect models were performed in a Los Angeles Mexican-American cohort (196 controls, 203 MDD) and in a replication European-ancestry cohort (499 controls, 473 MDD). Our analyses took into consideration the stress levels in the control populations. The Mexican-American controls, comprised primarily of recent immigrants, had high levels of stress due to acculturation issues and the European-ancestry controls with high stress levels were given higher weights in our analysis. We identified 44 common and rare functional variants associated with mild to moderate MDD in the Mexican-American cohort (genome-wide false discovery rate, FDR, <0.05), and their pathway analysis revealed that the three top overrepresented Gene Ontology (GO) processes were innate immune response, glutamate receptor signaling and detection of chemical stimulus in smell sensory perception. Rare variant analysis replicated the association of the PHF21B gene in the ethnically unrelated European-ancestry cohort. The TRPM2 gene, previously implicated in mood disorders, may also be considered replicated by our analyses. Whole-genome sequencing analyses of a subset of the cohorts revealed that European-ancestry individuals have a significantly reduced (50%) number of single nucleotide variants compared with Mexican-American individuals, and for this reason the role of rare variants may vary across populations. PHF21b variants contribute significantly to differences in the levels of expression of this gene in several brain areas, including the hippocampus. Furthermore, using an animal model of stress, we found that Phf21b hippocampal gene expression is significantly decreased in animals resilient to chronic restraint stress when compared with non-chronically stressed animals. Together, our results reveal that including stress level data enables the identification of novel rare functional variants associated with MDD.

Linkage and association analysis of ADHD endophenotypes in extended and multigenerational pedigrees from a genetic isolate.

Attention-deficit/hyperactivity disorder (ADHD) is a heritable, chronic, neurodevelopmental disorder with serious long-term repercussions. Despite being one of the most common cognitive disorders, the clinical diagnosis of ADHD is based on subjective assessments of perceived behaviors. Endophenotypes (neurobiological markers that cosegregate and are associated with an illness) are thought to provide a more powerful and objective framework for revealing the underlying neurobiology than syndromic psychiatric classification. Here, we present the results of applying genetic linkage and association analyses to neuropsychological endophenotypes using microsatellite and single nucleotide polymorphisms. We found several new genetic regions linked and/or associated with these endophenotypes, and others previously associated to ADHD, for example, loci harbored in the LPHN3, FGF1, POLR2A, CHRNA4 and ANKFY1 genes. These findings, when compared with those linked and/or associated to ADHD, suggest that these endophenotypes lie on shared pathways. The genetic information provided by this study offers a novel and complementary method of assessing the genetic causes underpinning the susceptibility to behavioral conditions and may offer new insights on the neurobiology of the disorder.

APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer's disease.

Alzheimer's disease (AD) age of onset (ADAOO) varies greatly between individuals, with unique causal mutations suggesting the role of modifying genetic and environmental interactions. We analyzed ~50 000 common and rare functional genomic variants from 71 individuals of the 'Paisa' pedigree, the world's largest pedigree segregating a severe form of early-onset AD, who were affected carriers of the fully penetrant E280A mutation in the presenilin-1 (PSEN1) gene. Affected carriers with ages at the extremes of the ADAOO distribution (30s-70s age range), and linear mixed-effects models were used to build single-locus regression models outlining the ADAOO. We identified the rs7412 (APOE*E2 allele) as a whole exome-wide ADAOO modifier that delays ADAOO by ~12 years (ß=11.74, 95% confidence interval (CI): 8.07-15.41, P=6.31 × 10(-8), PFDR=2.48 × 10(-3)). Subsequently, to evaluate comprehensively the APOE (apolipoprotein E) haplotype variants (E1/E2/E3/E4), the markers rs7412 and rs429358 were genotyped in 93 AD affected carriers of the E280A mutation. We found that the APOE*E2 allele, and not APOE*E4, modifies ADAOO in carriers of the E280A mutation (ß=8.24, 95% CI: 4.45-12.01, P=3.84 × 10(-5)). Exploratory linear mixed-effects multilocus analysis suggested that other functional variants harbored in genes involved in cell proliferation, protein degradation, apoptotic and immune dysregulation processes (i.e., GPR20, TRIM22, FCRL5, AOAH, PINLYP, IFI16, RC3H1 and DFNA5) might interact with the APOE*E2 allele. Interestingly, suggestive evidence as an ADAOO modifier was found for one of these variants (GPR20) in a set of patients with sporadic AD from the Paisa genetic isolate. This is the first study demonstrating that the APOE*E2 allele modifies the natural history of AD typified by the age of onset in E280A mutation carriers. To the best of our knowledge, this is the largest analyzed sample of patients with a unique mutation sharing uniform environment. Formal replication of our results in other populations and in other forms of AD will be crucial for prediction, follow-up and presumably developing new therapeutic strategies for patients either at risk or affected by AD.

Patients with a new variant of endemic pemphigus foliaceus have autoantibodies against arrector pili muscle, colocalizing with MYZAP, p0071, desmoplakins 1 and 2 and ARVCF.

BACKGROUND: We identified a new variant of endemic pemphigus foliaceus in El Bagre, Colombia, South America, which we term El Bagre-EPF, and observed reactivity to arrector pili muscle (APM), thus we tested for autoimmunity to APM. METHODS: We took skin biopsies from 30 patients with El Bagre-EPF and 30 healthy controls (HCs) matched by age, sex and occupation, who were all from the endemic area, and tested these using direct immunofluorescence (DIF), confocal microscopy, immunohistochemistry and immunoblotting (IB). RESULTS: Of the 30 patients with El Bagre-EPF, 27 had autoantibodies to APM that colocalized with commercial antibodies to myocardium-enriched zonula occludens-1-associated protein (MYZAP), desmoplakin (DP)1 and DP2, plakophilin 4, and Armadillo repeat gene deleted in velo-cardio-facial syndrome (ARVCF) (P < 0.001, Fisher exact test). The positive staining also colocalized with Junctional Adhesion Molecule 1 (JAM-A), a control antibody for gap cell junctions. No HC samples were positive. In 27 of the 30 patients, serum that was APM-positive also displayed IB colocalization of their autoantibody molecular weights with the Progen antibodies (P < 0.001, Fisher exact test). CONCLUSIONS: Patients affected by El Bagre-EPF have autoantibodies to APM, colocalizing with the antibodies MYZAP, ARVCF, p0071, DP1 and DP2, suggesting that these molecules are El Bagre-EPF antigens. Further, all of these antigens represent components of cell junctions, indicating that the immune response is directed, at least partially, against cell junctions. The immune response in patients affected by El Bagre-EPF is polyclonal, and it includes B and T lymphocytes, mast cells, IgG, IgA, IgM, IgD, IgE, fibrinogen, albumin, complement/C1q, C3c and C4.

Effect of serum calcium status at calving on survival, health, and performance of postpartum Holstein cows and calves under certified organic management.

The study objective was to assess the effect of hypocalcemia (HYPO; ≤2.0 mmol/L) of the dam at calving on survival, health, and performance of lactating dairy cows and their calves under certified organic management. Prepartum dairy cows (primiparous, n = 445; multiparous, n = 328) from 1 dairy herd were monitored (prepartum pen) for imminent signs of parturition (appearance of amniotic sac outside the vulva) until birth. All calves were subject to the same newborn care, colostrum management, and failure of passive transfer assessment (serum total protein ≤5.5 mg/dL). Serum total calcium of cows was determined in samples taken within 2 h after calving. To define HYPO cows after calving, a cut-point of total serum Ca concentration with optimal sensitivity and specificity to predict metritis or calf diarrhea was established by using the receiver operator characteristic. The effect of HYPO on survival (died or culled within 60 DIM), health status, and pregnancy per artificial insemination (PAI) for first services of lactating cows were analyzed using the GLIMMIX procedure of SAS. Additionally, the effect of HYPO at calving on days in milk (DIM) at first service (DIMFS), milk yield (kg), milk components (percent fat and protein), and somatic cell count were analyzed for the first 3 Dairy Herd Improvement Association (DHIA) tests using the MIXED procedure of SAS (SAS Institute Inc., Cary, NC). The effect of parity (primiparous and multiparous), body condition score at calving, and manure hygiene score at calving were also included in the statistical models. The effect of HYPO at calving on calf survival, serum total protein, and diarrhea within 10 d of age were assessed using GLIMMIX procedure of SAS. The overall prevalence of HYPO was 14.6% (2.7% for primiparous and 30.8% for multiparous cows). Cows experiencing HYPO at calving had greater proportion of metritis (25.1 vs. 14.7%) and culling within 60 DIM (15.9 vs. 6.8%) compared with non-HYPO cows, respectively. For the first 3 DHIA tests, milk yield and components did not differ between HYPO and non-HYPO cows. The DIMFS as well as proportion of cows with dystocia, births of twins, mastitis, and PAI at first service were not different between HYPO and non-HYPO cows. The proportion of stillbirth, weaned calves, and serum total protein did not differ between calves born from HYPO or non-HYPO cows. However, calves born from HYPO cows had greater incidence of diarrhea (49%) than calves born (33.3%) from non-HYPO cows. Findings from the present study showed that HYPO at calving had significant health implications for both dams and calves under certified organic management.