Liger is a next-generation near-infrared (0.81 - 2.45 mu m) integral field spectrograph (IFS) and imaging camera for the W. M. Keck Observatory (WMKO) adaptive optics (AO) system. The instrument concept originated by coupling designs from WMKO AO instruments and the future Thirty Meter Telescope IRIS spectrograph. Liger is designed for the Keck I telescope to operate behind the upcoming Keck All-sky Precision Adaptive optics (KAPA) system. The imaging camera sequentially feeds an IFS that makes use of slicer assembly for the coarsest sampling (75 mas and 150 mas per spaxel) and lenslet array (14 mas and 31 mas per spaxel) for diffraction-limited sampling. The imaging camera makes use of off-axis parabolas and a Hawaii-2RG detector to achieve a 14 mas/pixel plate scale and 20.5 '' x20.5 '' field of view. The IFS offers a range of spectral resolving power of R=4,000 10,000 and yields large fields of view for an AO-fed IFS. Liger will enable new science by providing enhanced capabilities, including higher spectral resolving power, access to shorter wavelengths, and larger fields of view than any current or planned ground- or space-based IFS system. Liger will be able to unlock previously inaccessible science across a wide range of the cosmos, such as dark matter substructure, supermassive black holes, the Galactic Center, exoplanet atmospheres, and the time-variable Solar System. We present the overall design of the Liger subsystems and review unique science drivers.

Liger is an adaptive optics (AO) fed imager and integral field spectrograph (IFS) designed to take advantage of the Keck All-sky Precision Adaptive-optics (KAPA) upgrade to the Keck I telescope. Liger adapts the design of the InfraRed Imaging Spectrograph (IRIS) for the Thirty Meter Telescope (TMT) to Keck by implementing a new imager and re-imaging optics. The performance of the imager is critical as it sequentially feeds the spectrograph and contains essential components such as the pupil wheel, filter wheel, and pupil viewing camera. We present the design and structural analysis of the Liger imager optical assembly including static, modal, and thermal simulations. We present the fabrication as well as the full assembly and characterization plan. The imager will be assembled bench-top in a clean room utilizing a coordinate-measuring machine (CMM) for warm alignment. To ensure optimal performance, the imager will be characterized in a test cryostat before integration with the full Liger instrument. This comprehensive approach to characterization ensures the precision and reliability of the imager, enhancing the observational capabilities of Liger and W.M. Keck Observatory.

Measurements of oxygen abundance throughout galaxies provide insight to the formation histories and ongoing processes. Here we present a study of the gas-phase oxygen abundance in the H ii regions and diffuse gas of the nearby starburst dwarf galaxy, IC 10. Using the Keck Cosmic Web Imager at W. M. Keck Observatory, we map the central region of IC 10 from 3500 to 5500 & Aring;. The auroral [O III] 4363 & Aring; line is detected with a high signal-to-noise ratio in 12 of 46 H II regions observed, allowing for direct measurement of the oxygen abundance, yielding a median and standard deviation of 12+log(O/H)=8.37 +/- 0.25 . We investigate trends between these directly measured oxygen abundances and other H II region properties, finding weak negative correlations with the radius, velocity dispersion, and luminosity. We also find weak negative correlations between the oxygen abundance and the derived quantities of turbulent pressure and ionized gas mass, and a moderate correlation with the derived dynamical mass. Strong line, R 23 abundance estimates are used in the remainder of the H II regions and on a resolved spaxel-by-spaxel basis. There is a large offset between the abundances measured with R 23 and the auroral line method. We find that the R 23 method is unable to capture the large range of abundances observed via the auroral line measurements. The extent of this variation in the measured abundances further indicates a poorly mixed interstellar medium in IC 10, which is not typical of dwarf galaxies and may be partly due to the ongoing starburst, accretion of pristine gas, or a late stage merger.

Liger is an adaptive optics (AO)-fed imager and integral field spectrograph (IFS) designed for W.M. Keck Observatory. Liger will be coupled with the Keck All-sky Precision Adaptive-optics (KAPA) upgrade which will allow both systems to fully utilize their capabilities to maximize scientific return for the broader community. Liger features a custom-designed imaging camera that sequentially feeds the pristine AO image to two select-able integral field spectrograph (IFS) modes: an image slicer for coarse spatial sampling and a lenslet array for finer spatial scales. Both IFS modes utilize a final "camera" three-mirror anastigmat (TMA) and a Hawaii 4RG detector for data collection. This paper will discuss the assembly, integration, and testing (AIT) of the Liger instrument sub-assemblies. The project is currently in the first of two-fabrication phases where we are manufacturing, assembling, and testing the complete imager system, the IFS camera TMA, grating turret mechanism, and the IFS re-imaging optics mechanisms. The second fabrication phase will include the final fabrication and assembly of the IFS and science cryostat. An integration phase will follow where the full instrument is assembled and integrated into the science cryostat. Once complete the Liger instrument will be shipped to Hawaii for final assembly, integration, and verification at W.M. Keck Observatory.

We present results from the ``Quasar hosts Unveiled by high Angular Resolution Techniques" (QUART) survey studying the Circumgalactic Medium (CGM) by observing rest-frame UV emission lines Ly$\alpha$, C IV and He II around two radio-loud quasars, 3C 9 (z=2.02) and 4C 05.84 (z=2.32), using Keck Cosmic Web Imager (KCWI). We detect large-scale Ly$\alpha$ nebulae around both quasars with projected diameters $\sim$ 100 kpc, with spatially resolved, embedded 15-30 kpc He II and C IV nebulae around both quasars as well as kinematically distinct He II and C IV nebulae at a physical separation of $\sim$ 15 kpc from both quasars. Observations of H$\alpha$, H$\beta$, and [O III] emission using Keck MOSFIRE spectroscopically confirm that the Ly$\alpha$ nebulae extend to companion galaxies and that these quasars are in a protogroup/protocluster environment. We confirm that the He II and C IV emission is kinematically and spatially coincident with the companion galaxies. We estimate the virial masses of the companion galaxies, their metallicities, and star formation rates, and investigate the sources of ionization. We measure the dynamical mass of the host dark matter halos and estimate that the dark matter halos of these systems will grow to a mass of 2 $\times 10^{14}$ M$_{\odot}$ (3C 9) and 2 $\times 10^{13}$ M$_{\odot}$ (4C 05.84) by z=0. The combined CGM and companion galaxies observations indicate Ly$\alpha$ substructure can indicate the presence of companion galaxies in the CGM.

The Panoramic Search for Extraterrestrial Intelligence (PANOSETI) experiment is designed to detect pulsed optical signals on nanosecond timescales. PANOSETI is therefore sensitive to Cherenkov radiation generated by extensive air showers, and can be used for gamma-ray astronomy. Each PANOSETI telescope uses a 0.5 m Fresnel lens to focus light onto a 1024 pixel silicon photomultiplier camera that images a 9.9$^\circ\times$9.9$^\circ$ square field of view. Recent detections of PeV gamma-rays from extended sources in the Galactic Plane motivate constructing an array with effective area and angular resolution surpassing current observatories. The PANOSETI telescopes are much smaller and far more affordable than traditional imaging atmospheric Cherenkov telescopes (IACT), making them ideal instruments to construct such an array. We present the results of coincident observations between two PANOSETI telescopes and the gamma-ray observatory VERITAS, along with simulations characterizing the performance of a PANOSETI IACT array.

Abstract Background: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques in the brain, leading to neuroinflammation, synaptic dysfunction and cognitive decline. Developing therapeutic strategies that enhance Aβ clearance is an active area of research. Methods: In this study, we investigated glatiramer acetate (GA) that has demonstrated the ability to promote Aβ phagocytosis by mouse microglia. Through a series of experiments, we aimed to understand the underlying mechanisms and their implications for AD pathogenesis. First, the interaction between GA and Aβ was investigated using circular dichroism and microscale thermophoresis. Second, the reduction of Aβ-mediated toxicity and attenuation of neuroinflammation were investigated using MTT assay, membrane fluidity assay and long-term potentiation (LTP). Third, the long-term therapeutic effect was investigated by directly delivering GA into lateral cerebral ventricles of 22-month-old APP/PS1 mice and evaluating with behavioural tests, LTP, ELISA and IHC. Finally, biosafety and pharmacokinetics were investigated in sheep. Results: Our findings suggest that the binding between GA and Aβ contributes to the reduction of Aβ-mediated toxicity. Additionally, by enhancing Aβ clearance and attenuating microglial activation, GA creates an environment more conducive to synaptic plasticity and the restoration of long-term potentiation (LTP), contributing to the improvement of cognitive function and behavioural deficits observed in mouse model of AD. Conclusions: Overall, these results highlight the potential of the phagocytosis-promoting drugs to enhance Aβ clearance and its therapeutic implications for AD.

Altered innate immunity has been long associated with late-onset Alzheimer’s disease (AD) and its associated blood-based biomarkers are important for AD diagnosis and prognosis. We collected 38 participants from the AIBL study, including 22 cognitive normal (CN) individuals with negative amyloid burden (Centiloid [CL] < 15), 5 CN individuals with positive amyloid burden (CL > 15), and 11 mild cognitive impairment (MCI) and AD cases. A total of 17 leukocyte surface antigens were examined by flow cytometry immunophenotyping and compared between healthy controls (CN Ab -ve), pre-clinical patients (CN Ab +ve), and clinical cases (MCI & AD), including CD36, MerTK, Clec7a, RAGE, Tyro3, CR1 (CD35), CX3CR1, CCR2, Axl, LILRB2, LILRB3, LILRB4, PILRA, and P2×7. We identified leukocyte surface markers differentially expressed between HC, pre-clinical patients, and clinical cases. Mean fluorescence intensities of CD85d and CD85k were significantly reduced in pre-clinical patients and cases compared with HC, implicating CD85d and CD85k downregulation in AD pathogenesis. Significant upregulation of RAGE, Tyro3, CCR2, CD85a, and PILRA was also noted in cases compared with HC. Leukocyte surface expressions of RAGE, CCR2, PILRA, and CD85k were significantly associated with the Preclinical Alzheimer’s Cognitive Composite (PACC), which is one of the most accurate estimates of cognition in AD diagnosis. Our preliminary investigations into these leukocyte markers demonstrated their dysregulations in pre-clinical stage of AD, implicating early deficits in innate immunity, as supported by genomic studies of AD. This project will continue collecting more AIBL participants up to 200 to evaluate leukocyte surface markers more comprehensively, which would benefit AD screening and diagnosis.

Liger is a next-generation near-infrared (810 - 2450 nm) integral field spectrograph (IFS) and imaging camera for the Keck Observatory adaptive optics (AO) system. Liger will enable new science by providing enhanced capabilities, including higher spectral resolving power (R=4,000 – 10,000), access to shorter wavelengths (< 1000 nm), and larger fields of view (13 arcsec x 7 arcsec) than any current or planned ground- or space-based IFS system. The imaging camera sequentially feeds an IFS that makes use of slicer assembly unit and lenslet array. We will present the overall design of the Liger subsystems and review the key science drivers.

Alzheimer’s disease (AD) is characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, reactive astrogliosis, and microgliosis. Aberrant Aβ accumulation starts 20–30 years before clinical onset, so biomarker test is essential to diagnose people living with early AD. PET imaging and CSF measurements allow the diagnosis of preclinical and prodromal AD in research and clinical trials, but their invasiveness and costliness might limit their application in hospital setting. Therefore, developing non-invasive population screening tests is necessary for the early diagnosis of AD. Recent genetic findings strongly implicate the role of innate and adaptive immunity in AD and suggest that a systemic failure of cell-mediated Aβ clearance contributes to AD onset and progression. Our research question was to develop an immune-related blood-based biomarker test to facilitate the diagnosis and prognosis of AD. It was hypothesized that the pattern of immune-related receptors and molecules expressed on peripheral leukocytes could differentiate people living with AD from healthy population. We recruited 180 and 200 participants from AIBL in two discovery phases and validated our findings by an independent cohort of 112 participants from AIBL. A total of 34 innate and adaptive immunity-related leukocyte antigens on peripheral lymphocytes, monocytes, and neutrophils were examined by flow cytometry immunophenotyping. Data was analysed by logistic regression and ROC analyses. We identified upregulated CD35, CD59, CD91, RAGE, and Scara-1 expressions and downregulated CD11c, CD18, CD36, CD163, MerTK, and P2X7 expressions on leukocytes of MCI/AD patients. Significant correlation between them and Aβ burden, episodic memory, and PACC score was observed, such as CD59 and CD91. Pathway analysis revealed upregulation of complement inhibition and downregulation of cargo receptor activity and Aβ clearance in AD. We proposed a marker panel including CD11c, CD59, CD91 and CD163 and this panel predicted patients’ PET Aβ status with AUC of 0.93 (0.88 to 0.97), which was repeated in validation cohort. Regarding adaptive immunity, we did not see significant results. Our study suggested deficits in innate immunity in AD, which is consistent with genomic studies. Our proposed leukocyte-based biomarker panel might be sensitive and practical for AD screening and diagnosis.

We have shown deficits in monocyte phagocytosis from patients with age-related macular degeneration (AMD). Cell membrane fluidity is known to affect phagocytic capacity and leucocyte functionality more generally. Therefore, we examined membrane fluidity of peripheral blood leucocytes in human patients with AMD and in the P2X7 null mouse model of AMD using flow cytometry with a fluorescent probe for fluidity, TMA-DPH. The results showed that membrane fluidity was decreased in all leucocyte types of late AMD relative to healthy controls (HC) including monocytes, neutrophils and lymphocytes but this was not apparent in earlier stages of AMD. Further analysis of factors contributing to membrane fluidity indicated that pre-treatment of monocytes and lymphocytes with ATP greatly increased membrane fluidity in humans and mice. Evidence from P2X7 null mice and P2X7 antagonists confirmed that these ATP-driven increases in membrane fluidity were mediated by P2X7 but were not associated with the classic P2X7 functions of pore formation or phagocytosis. Analysis of P2X7 expression indicated that receptor levels were elevated in classic monocytes of late AMD patients, further suggesting the P2X7 may contribute to altered plasma membrane properties. Our findings identified a novel biological function of P2X7 in modulating membrane fluidity of leucocytes and demonstrated reduced membrane fluidity in cellular changes associated with the late stage of AMD.

Optical SETI (Search for Extraterrestrial Intelligence) instruments that can explore the very fast time domain, especially with large sky coverage, offer an opportunity for new discoveries that can complement multimessenger and time domain astrophysics. The Panoramic SETI experiment (PANOSETI) aims to observe optical transients with nanosecond to second duration over a wide field-of-view (∼2,500 sq.deg.) by using two assemblies of tens of telescopes to reject spurious signals by coincidence detection. Three PANOSETI telescopes, connected to a White Rabbit timing network used to synchronize clocks at the nanosecond level, have been deployed at Lick Observatory on two sites separated by a distance of 677 meters to distinguish nearby light sources (such as Cherenkov light from particle showers in the Earth’s atmosphere) from astrophysical sources at large distances. In parallel to this deployment, we present results obtained during four nights of simultaneous observations with the four 12-meter VERITAS gamma-ray telescopes and two PANOSETI telescopes at the Fred Lawrence Whipple Observatory. We report PANOSETI’s first detection of astrophysical gamma rays, comprising three events with energies in the range between ∼15 TeV and ∼50 TeV. These were emitted by the Crab Nebula, and identified as gamma rays using joint VERITAS observations.

Liger is an adaptive optics (AO) fed imager and integral field spectrograph (IFS) designed to take advantage of the Keck All-sky Precision Adaptive-optics (KAPA) upgrade for the W.M. Keck Observatory. We present the design and analysis of the imager optical assembly including the spectrograph Re-Imaging Optics (RIO) which transfers the beam path from the imager focal plane to the IFS slicer module and lenslet array. Each imager component and the first two RIO mechanisms are assembled and individually aligned on the same optical plate. Baffling suppresses background radiation and scattered light, and a pupil viewing camera allows the imager detector to focus on an image of the telescope pupil. The optical plate mounts on an adapter frame for alignment of the overall system. The imager and RIO will be characterized in a cryogenic test chamber before installation in the final science cryostat.

Introduction Blood-based diagnostics and prognostics in sporadic Alzheimer's disease (AD) are important for identifying at-risk individuals for therapeutic interventions. Methods In three stages, a total of 34 leukocyte antigens were examined by flow cytometry immunophenotyping. Data were analyzed by logistic regression and receiver operating characteristic (ROC) analyses. Results We identified leukocyte markers differentially expressed in the patients with AD. Pathway analysis revealed a complex network involving upregulation of complement inhibition and downregulation of cargo receptor activity and A beta clearance. A proposed panel including four leukocyte markers - CD11c, CD59, CD91, and CD163 - predicts patients' PET A beta status with an area under the curve (AUC) of 0.93 (0.88 to 0.97). CD163 was the top performer in preclinical models. These findings have been validated in two independent cohorts. Conclusion Our finding of changes on peripheral leukocyte surface antigens in AD implicates the deficit in innate immunity. Leukocyte-based biomarkers prove to be both sensitive and practical for AD screening and diagnosis.

Abstract Background: We and others have reported that glatiramer acetate promotes innate phagocytosis. Methods: In this study, we investigated the interaction between glatiramer acetate and amyloid-β (Aβ) by using circular dichroism and microscale thermophoresis. Glatiramer acetate was delivered intracerebroventricularly to 22-month-old APP/PS1 mice by using mini-osmotic pumps. Mice underwent behavioural testing for two consecutive weeks after three-weeks treatment. Five weeks after implantation, animals were sacrificed and brain samples were collected for electrophysiology, immunochemistry and histopathology studies. Intracerebroventricular delivery of glatiramer acetate to sheep was also examined. Results: Glatiramer acetate binds to amyloid-β within high affinity and antagonize its toxicity. Glatiramer acetate treatment significantly improved cognitive function, restored long-term potentiation, reduced soluble amyloid-β and amyloid-β plaques in aged APP/PS1 mice, and promoted energy metabolism in sheep. Conclusions: Our results suggest a novel treatment strategy that targets both innate phagocytosis and amyloid-β, which may prove useful for treatment of all stages of Alzheimer’s disease.

We present a survey of the central region of the nearest starburst galaxy, IC 10, using the W. M. Keck Observatory Keck Cosmic Web Imager (KCWI) at high spectral and spatial resolution. We map the central starburst of IC 10 to sample the kinematic and ionization properties of the individual star-forming regions. Using the low spectral resolution mode of KCWI, we map the oxygen abundance, and with the high spectral resolution mode, we identify 46 individual H II regions. These H II regions have an average radius of 4.0 pc, star formation rate similar to 1.3 x 10(-4) M-circle dot yr(-1), and velocity dispersion similar to 16 km s(-1). None of the H II regions appear to be virialized (alpha(vir) >> 1), and on average, they show evidence of ongoing expansion. IC 10's H II regions are offset from the star-forming-region size-luminosity scaling relationships, as well as Larson's Law that relates size and velocity dispersion. We investigate the balance of inward and outward pressure, P-in and P-out, finding P-out > P-in in 89% of H II regions, indicating feedback-driven expansion even in these low-mass H II regions. We find warm gas pressure (P-gas) provides the dominant contribution to the outward pressure (P-out). This counteracts the inward pressure, which is dominated by turbulence in the surrounding gas rather than self-gravity. Five H II regions show evidence of outflows that are most likely supported by either stellar winds (two regions) or champagne flows (three regions). These observations provide new insights into the state of the star-forming regions in IC 10 and negative feedback from low-mass clusters.

Platelets express P2X1 receptors and our data also show the expression of P2X7 receptors. We studied the role of both receptors in platelet apoptosis by incubation of PRP with P2X agonists, then centrifuged to remove viable platelets, and analyzed the supernatant by flow cytometry to identify a sparse platelet-derived population that stained with MitoTracker dyes and CD41. BzATP, a potent agonist of P2X receptors, and ABT737, an activator of intrinsic apoptosis, produced altered platelets that stained moderately for annexin V and corresponded to an early stage apoptotic platelet (ESAP). Over a range of BzATP concentrations, we observed a dose-dependent formation of ESAPs between 5 and 500 uM BzATP, together with a variable formation of ESAPs at nanomolar ATP or BzATP (50-200 nM). Production of ESAPs occurred with alpha beta-meATP, while responses with either BzATP or alpha beta-meATP showed desensitization at a higher agonist concentration. Formation of ESAPs by either 100 nM or 0.5 mM BzATP was inhibited by preincubation of platelets with latrunculin A, an inhibitor of the actin cytoskeleton that prevents apoptosis. ESAP production was totally inhibited by preincubation of platelets with methyl-beta-cyclodextrin, which removes cholesterol from lipid rafts. Our data show that both P2X1 and P2X7 receptors are localized in platelet lipid rafts where P2X-agonists act to produce early stage apoptotic platelets.

Alzheimer’s disease (AD) has shown altered immune responses in the periphery. We studied P2X7 (a proinflammatory receptor and a scavenger receptor) and two integrins, CD11b and CD11c, on the surface of circulating leukocytes and analysed their associations with Aβ-PET, brain atrophy, neuropsychological assessments, and cerebrospinal fluid (CSF) biomarkers. Total 287 age-matched, sex-balanced participants were recruited in a discovery cohort and two validation cohorts through the AIBL study and studied using tri-colour flow cytometry. Our results demonstrated reduced expressions of P2X7, CD11b, and CD11c on leukocytes, particularly monocytes, in Aβ +ve cases compared with Aβ −ve controls. P2X7 and integrin downregulation was observed at pre-clinical stage of AD and stayed low throughout disease course. We further constructed a polygenic risk score (PRS) model based on 12 P2RX7 risk alleles to assess the genetic impact on P2X7 function in AIBL and ADNI cohorts. No significant association was identified between the P2RX7 gene and AD, indicating that P2X7 downregulation in AD is likely caused by environmental changes rather than genetic factors. In conclusion, the downregulation of P2X7 and integrins at pre-clinical stage of AD indicates altered pro-inflammatory responses, phagocytic functions, and migrating capabilities of circulating monocytes in early AD pathogenesis. Our study not only improves our understanding of peripheral immune involvement in early stage of AD but also provides more insights into novel biomarker development, diagnosis, and prognosis of AD.

Alzheimer's disease (AD) is a chronic neurodegenerative disease characterised by cognitive impairment, behavioural alteration, and functional decline. Over 130 AD-associated susceptibility loci have been identified by genome-wide association studies (GWAS), while whole genome sequencing (WGS) and whole exome sequencing (WES) studies have identified AD-associated rare variants. These variants are enriched in APOE, TREM2, CR1, CD33, CLU, BIN1, CD2AP, PILRA, SCIMP, PICALM, SORL1, SPI1, RIN3, and more genes. Given that aging is the single largest risk factor for late-onset AD (LOAD), the accumulation of somatic mutations in the brain and blood of AD patients have also been explored. Collectively, these genetic findings implicate the role of innate and adaptive immunity in LOAD pathogenesis and suggest that a systemic failure of cell-mediated amyloid-β (Aβ) clearance contributes to AD onset and progression. AD-associated variants are particularly enriched in myeloid-specific regulatory regions, implying that AD risk variants are likely to perturbate the expression of myeloid-specific AD-associated genes to interfere Aβ clearance. Defective phagocytosis, endocytosis, and autophagy may drive Aβ accumulation, which may be related to naturally-occurring antibodies to Aβ (Nabs-Aβ) produced by adaptive responses. Passive immunisation is providing efficiency in clearing Aβ and slowing cognitive decline, such as aducanumab, donanemab, and lecanemab (ban2401). Causation of AD by impairment of the innate immunity and treatment using the tools of adaptive immunity is emerging as a new paradigm for AD, but immunotherapy that boosts the innate immune functions of myeloid cells is highly expected to modulate disease progression at asymptomatic stage.