Views from the Ohio manufacturing index

An introduction to the experimental Ohio Manufacturing Index and a brief examination of the recent patterns of manufacturing growth occurring in the state.Manufactures - Ohio ; Ohio ; Economic indicators - Ohio

Report of the Advisory Committee in Seismology

The Advisory Committee in Seismology has pleasure in reporting the continued progress of its study of California earth movements during the year 1924-1925 without essential change of plan. A considerable amount of geologic work in the study of fault zones has been done during the year in the Mojave Desert and in Death Valley, the system of primary triangulation for the detection and measurement of horizontal displacements has progressed rapidly and effectively, and the development of suitable instruments for determining the two horizontal components of local earth movements has progressed to completion. Ground for a new laboratory has been purchased by the California Institute of Technology and the construction of the central station laboratory building upon it has been begun. The laboratory is expected to be occupied by Mr. H. O. Wood, Research Associate in Seismology, and his associates, about January 1, 1926. It is hoped that additional stations will also be occupied before the close of the present calendar year (1925), and that actual work in what has been happily termed the seismologic triangulation of California will be successfully inaugurated

Terrain trapped airflows and precipitation variability during an atmospheric river event

We examine thermodynamic and kinematic structures of terrain trapped airflows (TTAs) during an atmospheric river (AR) event impacting Northern California 10–11 March 2016 using Alpha Jet Atmospheric eXperiment (AJAX) aircraft data, in situ observations, and Weather and Research Forecasting (WRF) Model simulations. TTAs are identified by locally intensified low-level winds flowing parallel to the coastal ranges and having maxima over the near-coastal waters. Multiple mechanisms can produce TTAs, including terrain blocking and gap flows. The changes in winds can significantly alter the distribution, timing, and intensity of precipitation. We show here how different mechanisms producing TTAs evolve during this event and influence local precipitation variations. Three different periods are identified from the time-varying wind fields. During period 1 (P1), a TTA develops during synoptic-scale onshore flow that backs to southerly flow near the coast. This TTA occurs when the Froude number (Fr) is less than 1, suggesting low-level terrain blocking is the primary mechanism. During period 2 (P2), a Petaluma offshore gap flow develops, with flows turning parallel to the coast offshore and with Fr \u3e 1. Periods P1 and P2 are associated with slightly more coastal than mountain precipitation. In period 3 (P3), the gap flow initiated during P2 merges with a pre-cold-frontal low-level jet (LLJ) and enhanced precipitation shifts to higher mountain regions. Dynamical mixing also becomes more important as the TTA becomes confluent with the approaching LLJ. The different mechanisms producing TTAs and their effects on precipitation pose challenges to observational and modeling systems needed to improve forecasts and early warnings of AR events

"A few good men": Public sector audit in the Swan River Colony, 1828-1835

The appointment of the Auditor General to undertake public sector audit is the primary instrument used to safeguard public finances in most contemporary Westminster-based democracies. It is axiomatic that the independence of the Auditor General from executive government is a critical element in ensuring the effectiveness of the role, yet this separation is a relatively recent phenomenon. Those responsible for nineteenth century public sector audit in the Australian colonies operated in what would today be considered an unacceptable environment, with little, if any, independence from the executive arm of government. Yet, while several other Australian colonies suffered from the mismanagement of government finances, there is nothing to show that the Swan River Colony experienced much more than clerical errors and minor administrative oversights. In this article, we explore the extent to which satisfactory public financial management in the Swan River Colony occurred as a result of both good financial management systems (in the context of the era) and the appointment of competent and ethical administrators – “a few good men”

In Vivo Carbon-13 Dynamic MRS and MRSI of Normal and Fasted Rat Liver with Hyperpolarized 13C-Pyruvate

BACKGROUND: The use of in vivo (13)C nuclear magnetic resonance spectroscopy in probing metabolic pathways to study normal metabolism and characterize disease physiology has been limited by its low sensitivity. However, recent technological advances have enabled greater than 50,000-fold enhancement of liquid-state polarization of metabolically active (13)C substrates, allowing for rapid assessment of (13)C metabolism in vivo. The present study applied hyperpolarized (13)C magnetic resonance spectroscopy to the investigation of liver metabolism, demonstrating for the first time the feasibility of applying this technology to detect differences in liver metabolic states. PROCEDURES: [1-(13)C]pyruvate was hyperpolarized with a dynamic nuclear polarization instrument and injected into normal and fasted rats. The uptake of pyruvate and its conversion to the metabolic products lactate and alanine were observed with slice-localized dynamic magnetic resonance spectroscopy and 3D magnetic resonance spectroscopic imaging (3D-MRSI). RESULTS: Significant differences in lactate to alanine ratio (P < 0.01) between normal and fasted rat liver slice dynamic spectra were observed. 3D-MRSI localized to the fasted livers demonstrated significantly decreased (13)C-alanine levels (P < 0.01) compared to normal. CONCLUSIONS: This study presents the initial demonstration of characterizing metabolic state differences in the liver with hyperpolarized (13)C spectroscopy and shows the ability to detect physiological perturbations in alanine aminotransferase activity, which is an encouraging result for future liver disease investigations with hyperpolarized magnetic resonance technology

Patterns and implications of neurological examination findings in autosomal dominant Alzheimer disease

Introduction: As knowledge about neurological examination findings in autosomal dominant Alzheimer disease (ADAD) is incomplete, we aimed to determine the frequency and significance of neurological examination findings in ADAD. Methods: Frequencies of neurological examination findings were compared between symptomatic mutation carriers and non mutation carriers from the Dominantly Inherited Alzheimer Network (DIAN) to define AD neurological examination findings. AD neurological examination findings were analyzed regarding frequency, association with and predictive value regarding cognitive decline, and association with brain atrophy in symptomatic mutation carriers. Results: AD neurological examination findings included abnormal deep tendon reflexes, gait disturbance, pathological cranial nerve examination findings, tremor, abnormal finger to nose and heel to shin testing, and compromised motor strength. The frequency of AD neurological examination findings was 65.1 %. Cross-sectionally, mutation carriers with AD neurological examination findings showed a more than two-fold faster cognitive decline and had greater parieto-temporal atrophy, including hippocampal atrophy. Longitudinally, AD neurological examination findings predicted a significantly greater decline over time. Discussion: ADAD features a distinct pattern of neurological examination findings that is useful to estimate prognosis and may inform clinical care and therapeutic trial designs

Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer\u27s disease: Associations with Aβ-PET, neurodegeneration, and cognition

Background: Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer\u27s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. Methods: We evaluated plasma, serum, and cerebrospinal fluid (CSF) GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Results: Plasma GFAP elevations appear a decade before expected symptom onset, after amyloid beta (A ) accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished A -positive from A -negative ADAD participants and showed a stronger relationship with A load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Conclusion: Our findings support a role for plasma GFAP as a clinical biomarker of A -related astrocyte reactivity that is associated with cognitive decline and neurodegeneration. Highlights: Plasma glial fibrillary acidic protein (GFAP) elevations appear a decade before expected symptom onset in autosomal dominant Alzheimer\u27s disease (ADAD). Plasma GFAP was associated to amyloid positivity in asymptomatic ADAD. Plasma GFAP increased with clinical severity and predicted disease progression. Plasma and serum GFAP carried similar information in ADAD, while cerebrospinal fluid GFAP did not

De novo design of potent and resilient hACE2 decoys to neutralize SARS-CoV-2

We developed a de novo protein design strategy to swiftly engineer decoys for neutralizing pathogens that exploit extracellular host proteins to infect the cell. Our pipeline allowed the design, validation, and optimization of de novo hACE2 decoys to neutralize SARS-CoV-2. The best decoy, CTC-445.2, binds with low nanomolar affinity and high specificity to the RBD of the spike protein. Cryo-EM shows that the design is accurate and can simultaneously bind to all three RBDs of a single spike protein. Because the decoy replicates the spike protein target interface in hACE2, it is intrinsically resilient to viral mutational escape. A bivalent decoy, CTC-445.2d, shows ~10-fold improvement in binding. CTC-445.2d potently neutralizes SARS-CoV-2 infection of cells in vitro and a single intranasal prophylactic dose of decoy protected Syrian hamsters from a subsequent lethal SARS-CoV-2 challenge

Phase 1, open-label, dose-escalation study on the safety, pharmacokinetics, and preliminary efficacy of intravenous Coxsackievirus A21 (V937), with or without pembrolizumab, in patients with advanced solid tumors

Background Oncolytic virus V937 showed activity and safety with intratumoral administration. This phase 1 study evaluated intravenous V937±pembrolizumab in patients with advanced solid tumors. Methods Patients had advanced non-small cell lung cancer (NSCLC), urothelial cancer, metastatic castration-resistant prostate cancer, or melanoma in part A (V937 monotherapy), and metastatic NSCLC or urothelial cancer in part B (V937+pembrolizumab). Prior immunotherapy was permitted >28 days before study treatment. Patients received intravenous V937 on days 1, 3, and 5 (also on day 8 in part B) of the first 21-day cycle and on day 1 of subsequent cycles for eight cycles. Three ascending dose-escalation cohorts were studied. Dose-escalation proceeded if no dose-limiting toxicities (DLTs) occurred in cycle 1 of the previous cohort. In part B, patients also received pembrolizumab 200 mg every 3 weeks from day 8 for 2 years; dose-expansion occurred at the highest-dose cohort. Serial biopsies were performed. Results No DLTs occurred in parts A (n=18) or B (n=85). Grade 3–5 treatment-related adverse events (AEs) were not observed in part A and were experienced by 10 (12%) patients in part B. The most frequent treatment-related AEs (any grade) in part B were fatigue (36%), pruritus (18%), myalgia (14%), diarrhea (13%), pyrexia (13%), influenza-like illness (12%), and nausea (12%). At the highest tested dose, median intratumoral V937 concentrations were 117,631 copies/mL on day 8, cycle 1 in part A (n=6) and below the detection limit for most patients (86% (19/22)) on day 15, cycle 1 in part B. Objective response rates were 6% (part A), 9% in the NSCLC dose-expansion cohort (n=43), and 20% in the urothelial cancer dose-expansion cohort (n=35). Conclusions Intravenous V937+pembrolizumab had a manageable safety profile. Although V937 was detected in tumor tissue, in NSCLC and urothelial cancer, efficacy was not greater than that observed in previous studies with pembrolizumab monotherapy. Trial registration number NCT02043665

Cerebrospinal fluid proteomics define the natural history of autosomal dominant Alzheimer’s disease

Alzheimer’s disease (AD) pathology develops many years before the onset of cognitive symptoms. Two pathological processes—aggregation of the amyloid- (A ) peptide into plaques and the microtubule protein tau into neurofibrillary tangles (NFTs)—are hallmarks of the disease. However, other pathological brain processes are thought to be key disease mediators of A plaque and NFT pathology. How these additional pathologies evolve over the course of the disease is currently unknown. Here we show that proteomic measurements in autosomal dominant AD cerebrospinal fluid (CSF) linked to brain protein coexpression can be used to characterize the evolution of AD pathology over a timescale spanning six decades. SMOC1 and SPON1 proteins associated with A plaques were elevated in AD CSF nearly 30 years before the onset of symptoms, followed by changes in synaptic proteins, metabolic proteins, axonal proteins, inflammatory proteins and finally decreases in neurosecretory proteins. The proteome discriminated mutation carriers from noncarriers before symptom onset as well or better than A and tau measures. Our results highlight the multifaceted landscape of AD pathophysiology and its temporal evolution. Such knowledge will be critical for developing precision therapeutic interventions and biomarkers for AD beyond those associated with A and tau