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A continuous-wave (CW), high-power, quasi-three-level Nd:YAG laser operating at 946 nm is reported. The beam quality of the laser is greatly improved. The laser consists of a composite Nd:YAG rod end pumped by a fiber-coupled diode laser inside a simple concave-plane cavity. At an incident pump power of 31 W, a maximum CW output of 9.98 W was obtained at 946 nm, with a beam quality factor of M2~5. The corresponding optical-to-optical efficiency was 32.2% with respect to the incident pump power. To the best of our knowledge, this is the highest output power at 946 nm with such a beam quality ever generated by diode-pumped Nd:YAG laser with bulk crystals.

Wind farm optimization is pivotal in maximizing energy output, reducing costs, and minimizing environmental impact. This study comprehensively explores wind farm behavior under varying wind conditions and yaw angles to achieve these objectives. The primary motivation is to optimize wind farm performance and efficiency through proper yaw adjustment in response to wind speed changes. A computational investigation using a three-by-three wind turbine array was conducted, employing large eddy simulation (LES) to evaluate wind farm performance. Nine LES cases were considered, incorporating three wind speeds (7.3 ms−1, 10.4 ms−1, and 4.3 ms−1) and three yaw angles (30°, 20°, and 0°), with nearly constant turbulence intensity (TI) at 12.0%. The impact of wind speed and yaw angles on wake characteristics and power outputs were analyzed. The findings reveal that wind speed has limited influence on wake characteristics and power outputs, except for lower wind speeds at a yaw angle of 20 degrees. These results contribute to understanding wind farm performance optimization, aiding in developing strategies to enhance energy extraction while minimizing costs and environmental implications.

A continuous-wave (CW), high-power, quasi-three-level Nd:YAG laser operating at 946 nm is reported. The beam quality of the laser is greatly improved. The laser consists of a composite Nd:YAG rod end pumped by a fiber-coupled diode laser inside a simple concave-plane cavity. At an incident pump power of 31 W, a maximum CW output of 9.98 W was obtained at 946 nm, with a beam quality factor of M2~5. The corresponding optical-to-optical efficiency was 32.2% with respect to the incident pump power. To the best of our knowledge, this is the highest output power at 946 nm with such a beam quality ever generated by diode-pumped Nd:YAG laser with bulk crystals. [ABSTRACT FROM AUTHOR]

Wind farm optimization is pivotal in maximizing energy output, reducing costs, and minimizing environmental impact. This study comprehensively explores wind farm behavior under varying wind conditions and yaw angles to achieve these objectives. The primary motivation is to optimize wind farm performance and efficiency through proper yaw adjustment in response to wind speed changes. A computational investigation using a three-by-three wind turbine array was conducted, employing large eddy simulation (LES) to evaluate wind farm performance. Nine LES cases were considered, incorporating three wind speeds (7.3 ms−1, 10.4 ms−1, and 4.3 ms−1) and three yaw angles (30°, 20°, and 0°), with nearly constant turbulence intensity (TI) at 12.0%. The impact of wind speed and yaw angles on wake characteristics and power outputs were analyzed. The findings reveal that wind speed has limited influence on wake characteristics and power outputs, except for lower wind speeds at a yaw angle of 20 degrees. These results contribute to understanding wind farm performance optimization, aiding in developing strategies to enhance energy extraction while minimizing costs and environmental implications. [ABSTRACT FROM AUTHOR]

Synthesis of ultrasmall, citrate functionalized and intrinsically radiolabeled [198Au]Au nanoparticles ([198Au]Au NPs) below 5 nm diameter in a polytetrafluoroethylene (PTFE) microreactor is reported. The radioactive gold precursor along with trisodiumcitrate were premixed and infused into a PTFE microbore tube kept immersed inside a hot oil bath using a syringe pump. The synthesized [198Au]Au NPs were mostly spherical in shape. Systematic studies were conducted to investigate effect of residence time, reaction temperature and citrate to gold ratio on the average particle size of the nanoparticles. The radioactive nanoparticles demonstrated excellent radiochemical stability under both in vitro and in vivo conditions. Biodistribution studies of the ultrasmall [198Au]Au NPs in healthy Wistar rats showed fast clearance of the formulation (>85%ID at 24 h post-injection) predominantly through renal route, with its elimination half-life comparable to that of clinically used small molecule-based radiopharmaceuticals. Overall, this strategy of synthesis of ultrasmall intrinsically radiolabeled nanoparticles in a microreactor will potentially lay down the foundation for further development of renal clearable inorganic radionanomedicines with minimized toxicity for clinical translation.

The entry of no-carrier-added (NCA) 177Lu in the arena of clinical nuclear medicine has revolutionized the practice of targeted radionuclide tumor therapy. In this study, we report the development of an electrochemical separation and purification procedure to obtain NCA 177Lu in a clinically usable form. The overall yield of the process developed was > 70% and it was reproducible in multiple batches. The effective specific activity of NCA 177Lu was 3.32 ± 0.04 TBq/mg and the radioisotope was found suitable for formulation of therapeutically relevant doses of [177Lu]Lu-DOTA-TATE with >98% radiolabeling yield. As a proof of concept, [177Lu]Lu-DOTA-TATE synthesized using electrochemically purified NCA 177Lu was administered in patients with proven neuroendocrine tumor (NET) and satisfactory preliminary clinical outcome was obtained. The feasibility of recovery of enriched (in 176Yb) target in chemical form suitable for reuse in the production of a fresh batch of NCA 177Lu was demonstrated, which makes the process economically viable. Overall, this robust and efficient radiochemical separation and purification technology might aid towards introduction of new 177Lu-based radiopharmaceuticals for use in clinical context in the foreseeable future.

Microfluidics based liquid-liquid extraction is emerging as an enabling and powerful technology in radiochemical separations of medically important radioisotopes. In this study, we report the production of high specific activity 64Cu via 64Zn (n, p) 64Cu reaction in a research reactor. A microfluidic continuous flow liquid-liquid extraction system based on the use of dithizone as extractant was developed for efficient separation of miniscule quantity of 64Cu (in ng level) from bulk irradiated Zn target (in g level). The extraction process is completely selective for 64Cu, which could subsequently be retrieved in the desired medium for preparation of radiopharmaceuticals. The overall yield of 64Cu after the separation process was > 85 % and it was obtained with adequately high radionuclidic, radiochemical and chemical purities. Additionally, the effective specific activity of radio chemically separated 64Cu was determined to be 12.2 ± 0.8 GBq/µg, which is quite close to that reported for cyclotron produced no-carrier-added (NCA) 64Cu available commercially. The final 64Cu formulation could be effectively used for preparation of a variety of radiopharmaceuticals with high radiolabeling yields. The promising results obtained in this study open the pathway to achieve continuous and efficient recovery of reactor produced NCA 64Cu from the irradiated target using an automated microfluidic setup.

Presents several abstracts on neurology. 'Neuroimaging Testing of the Clinical Classification of Ischemic Stroke'; Carotid Angioplasty and Stent Implantation: Acute and Follow-up Results in 100 Consecutive Lesion'; ultrasonography for Asymptomatic Carotid Stenosis in Patients with Peripheral Vascular Disease.'

Competing Interests: These studies were funded by Biogen. CR, TC, and GD are employees and shareholders of Biogen. Medical writing support, under direction of the authors, was provided by Nucleus Global and was funded by Biogen.

Introduction: We assessed the use of cerebrospinal fluid (CSF) biomarkers as an alternative to positron emission tomography (PET) for brain amyloid beta (Aβ) pathology confirmation in the EMERGE and ENGAGE clinical trials., Methods: EMERGE and ENGAGE were randomized, placebo-controlled, Phase 3 trials of aducanumab in participants with early Alzheimer's disease. Concordance between CSF biomarkers (Aβ42, Aβ40, phosphorylated tau 181, and total tau) and amyloid PET status (visual read) at screening was examined., Results: Robust concordance between CSF biomarkers and amyloid PET visual status was observed (for Aβ42/Aβ40, AUC: 0.90; 95% CI: 0.83-0.97; p < 0.0001), confirming CSF biomarkers as a reliable alternative to amyloid PET in these studies. Compared with single CSF biomarkers, CSF biomarker ratios showed better agreement with amyloid PET visual reads, demonstrating high diagnostic accuracy., Discussion: These analyses add to the growing body of evidence supporting CSF biomarkers as reliable alternatives to amyloid PET imaging for brain Aβ pathology confirmation., Highlights: CSF biomarkers and amyloid PET concordance were assessed in Ph3 aducanumab trials. Robust concordance between CSF biomarkers and amyloid PET was observed. CSF biomarker ratios increased diagnostic accuracy over single CSF biomarkers. CSF Aβ42/Aβ40 demonstrated high concordance with amyloid PET. Results support CSF biomarker testing as a reliable alternative to amyloid PET., (© 2023 the Alzheimer's Association.)

Background: There is currently a lack of reliable and easily accessible biomarkers predicting cognitive decline in Alzheimer's disease (AD). Synaptic dysfunction and loss occur early in AD and synaptic loss measured in the brain tissue and by PET are closely linked to cognitive decline, rendering synaptic proteins a promising target for biomarker development., Methods: We used novel Simoa assays to measure cerebrospinal fluid (CSF) levels of two synaptic biomarker candidates, postsynaptic density protein 95 (PSD-95/DLG4), and the presynaptically localized synaptosomal-associated protein 25 (SNAP-25), as well as neurogranin (Ng), an established postsynaptic biomarker. CSF samples from two well-characterized cohorts (n=178 and n=156) were selected from banked samples obtained from diagnostic lumbar punctures containing subjects with amyloid-ß (Aß) positive AD, subjects with non-AD neurodegenerative diseases, subjects with other neurological conditions, and healthy controls (HC)., Results: All subjects had detectable CSF levels of PSD-95, SNAP-25, and Ng. CSF levels of PSD-95, SNAP-25, and Ng were all correlated, with the strongest correlation between the presynaptic SNAP-25 and the postsynaptic neurogranin. AD subjects had on average higher concentrations of all three synaptic markers compared to those with non-AD neurodegenerative diseases, other neurological disorders, and HCs. Increased CSF levels of PSD-95, SNAP-25, and Ng were, however, not specific for AD and were present in sporadic cases with inflammatory or vascular disorders as well. High CSF levels of PSD-95 were also observed in a few subjects with other neurodegenerative disorders., Conclusion: The data establishes PSD-95 as a promising CSF marker for neurodegenerative disease synaptic pathology, while SNAP-25 and Ng appear to be somewhat more specific for AD. Together, these synaptic markers hold promise to identify early AD pathology, to correlate with cognitive decline, and to monitor responses to disease-modifying drugs reducing synaptic degeneration., (© 2022. The Author(s).)

CHIP (carboxyl terminus of heat shock 70-interacting protein) has long been recognized as an active member of the cellular protein quality control system given the ability of CHIP to function as both a co-chaperone and ubiquitin ligase. We discovered a genetic disease, now known as spinocerebellar autosomal recessive 16 (SCAR16), resulting from a coding mutation that caused a loss of CHIP ubiquitin ligase function. The initial mutation describing SCAR16 was a missense mutation in the ubiquitin ligase domain of CHIP (p.T246M). Using multiple biophysical and cellular approaches, we demonstrated that T246M mutation results in structural disorganization and misfolding of the CHIP U-box domain, promoting oligomerization, and increased proteasome-dependent turnover. CHIP-T246M has no ligase activity, but maintains interactions with chaperones and chaperone-related functions. To establish preclinical models of SCAR16, we engineered T246M at the endogenous locus in both mice and rats. Animals homozygous for T246M had both cognitive and motor cerebellar dysfunction distinct from those observed in the CHIP null animal model, as well as deficits in learning and memory, reflective of the cognitive deficits reported in SCAR16 patients. We conclude that the T246M mutation is not equivalent to the total loss of CHIP, supporting the concept that disease-causing CHIP mutations have different biophysical and functional repercussions on CHIP function that may directly correlate to the spectrum of clinical phenotypes observed in SCAR16 patients. Our findings both further expand our basic understanding of CHIP biology and provide meaningful mechanistic insight underlying the molecular drivers of SCAR16 disease pathology, which may be used to inform the development of novel therapeutics for this devastating disease., Competing Interests: The authors have declared that no competing interests exist.

The importance of the kidney distal convoluted tubule (DCT) and cortical collecting duct (CCD) is highlighted by various water and electrolyte disorders that arise when the unique transport properties of these segments are disturbed. Despite this critical role, little is known about which proteins have a regulatory role in these cells and how these cells can be regulated by individual physiologic stimuli. By combining proteomics, bioinformatics, and cell biology approaches, we found that the E3 ubiquitin ligase CHIP is highly expressed throughout the collecting duct; is modulated in abundance by vasopressin; interacts with aquaporin-2 (AQP2), Hsp70, and Hsc70; and can directly ubiquitylate the water channel AQP2 in vitro shRNA knockdown of CHIP in CCD cells increased AQP2 protein t 1/2 and reduced AQP2 ubiquitylation, resulting in greater levels of AQP2 and phosphorylated AQP2. CHIP knockdown increased the plasma membrane abundance of AQP2 in these cells. Compared with wild-type controls, CHIP knockout mice or novel CRISPR/Cas9 mice without CHIP E3 ligase activity had greater AQP2 abundance and altered renal water handling, with decreased water intake and urine volume, alongside higher urine osmolality. We did not observe significant changes in other water- or sodium-transporting proteins in the gene-modified mice. In summary, these results suggest that CHIP regulates AQP2 and subsequently, renal water handling., (Copyright © 2018 by the American Society of Nephrology.)

Objective: Left atrial thrombi are an important cause for embolism-related morbidity and mortality. Transesophageal echocardiography (TEE), the clinical reference, is semiinvasive; thus, we aimed to assess the value of contrast-enhanced cardiovascular MRI for the detection of thrombus in the left atrial appendage., Conclusion: The image quality was good for both 2D perfusion (grade 4 +/- 1) and 3D turbo fast low-angle shot (FLASH) (grade 4 +/- 1, n.s.). Compared with TEE, 2D perfusion, 3D turboFLASH, and the combination of both techniques yielded sensitivities of 47/35/44%, specificities of 50/67/67%, positive predictive values of 73/75/80%, and negative predictive values of 25/27/29%, respectively. The size of the thrombus was overestimated by 2D perfusion (66%) and by 3D turboFLASH (25%) and agreement for location and shape of thrombus was 50% and 75% for 2D perfusion and 75% and 50% for 3D turboFLASH, respectively. The TEE thrombus size was significantly larger in patients with true-positive diagnoses by 2D perfusion (148%) and by 3D turboFLASH (151%) when compared with patients with false-negative diagnoses (p < 0.05 for both). No such difference was found for image quality, time delay between TEE and MRI examination, and location and shape of thrombi. Contrast-enhanced MRI lacks diagnostic accuracy for the detection of thrombi in the left atrial appendage. Future technical improvements are essential to establish this technique as a noninvasive alternative to TEE.

Objective: The aim of this study was to evaluate the feasibility of dynamic contrast-enhanced MRI for detection of patent foramen ovale., Subjects and Methods: Fifteen patients with and five patients without patent foramen ovale underwent transesophageal echocardiography and MRI, which were performed during the Valsalva maneuver. Grading results (grade 0, no patent foramen ovale and grades 1-3, minor to major enhancement due to intracardiac shunt) were assessed visually. Signal-intensity curves in the left atrium and in a pulmonary vein served to underline the diagnosis., Results: The diagnoses of all patients with (15/15) and without patent foramen ovale (5/5) were correct compared with the findings of the reference transesophageal echocardiography. In 12 (60%) of 20 patients, the grading scores were identical, and in four (20%) of 20 patients, the scores differed by more than one grade. Overall, there was a good correlation of grading scores (r = 0.7, p < 0.05). Using signal-intensity curves, we found that the patients with patent foramen ovale showed an additional signal peak in the left atrium before the enhancement of the pulmonary vein because of an intracardiac shunt. In three of 15 patients with patent foramen ovale, an atrial septal aneurysm was correctly diagnosed., Conclusion: This pilot study shows that MRI is a new noninvasive method to detect patent foramen ovale and atrial septal aneurysm. A grading is possible but warrants further investigation regarding its predictive value and impact on treatment strategies.

Shiga toxin type 2 (Stx2) produced by Escherichia coli O:157H7 can cause hemolytic-uremic syndrome in children, a disease for which there is neither a vaccine nor an effective treatment. This toxin consists of an enzymatically active A subunit and a pentameric B subunit responsible for the toxin binding to host cells, and also found to be immunogenic in rabbits. In this study we developed eukaryotic plasmids expressing the B subunit gene of Stx2 (pStx2B) and the B subunit plus the gene coding for the A subunit with an active-site deletion (pStx2 Delta A). Transfection of eukaryotic cells with these plasmids produced proteins of the expected molecular weight which reacted with specific monoclonal antibodies. Newborn and adult BALB/c mice immunized with two intramuscular injections of each plasmid, either alone or together with the same vector expressing the granulocyte and monocyte colony-stimulating factor (pGM-CSF), elicited a specific Th1-biased humoral response. The effect of pGM-CSF as an adjuvant plasmid was particularly notable in newborn mice and in pStx2B-vaccinated adult mice. Stx2-neutralizing activity, evaluated in vitro on VERO cell monolayers, correlated with in vivo protection. This is the first report using plasmids to induce a neutralizing humoral immune response against the Stx2.