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Brookhaven National Laboratory (BNL) and Thomas Jefferson National Accelerator Facility are collaborating on the design and construction of the next Electron Ion Collider (EIC) to be built at BNL. The EIC is a unique high-energy, high-luminosity, polarized electron-proton/ion collider. The EIC accelerator complex needs about 10 new rf and SRF systems with frequencies spanning 24 MHz to 1773 MHz, requiring more than 60 new high-power fundamental power couplers (FPCs). These couplers will operate in either pulsed mode or continuous wave mode with peak traveling wave power ranging from 10 s to 380 kW. Here we present our design for a 1-MW broadband rf window suitable for EIC rf and SRF systems with operating frequencies up to 591 MHz. This design takes advantage of the numerous synergies between the various rf and SRF systems to make it broadly applicable. The rf window design criteria are based on the requirement for the 591-MHz electron storage ring (ESR) SRF cavities, as it will operate at both the highest traveling wave power and the highest peak power over the EIC rf/SRF complex. The results presented will detail the FPC power requirement, rf window choices, design criteria, and multiphysics performance in the most critical application, the ESR SRF cavity, and how the rf window design applies to other EIC rf/SRF systems.

The Beam Energy Scan phase II (BES-II), performed in the Relativistic Heavy Ion Collider (RHIC) from 2019 to 2021, explored the phase transition between quark-gluon plasma and hadronic gas. BES-II exceeded the goal of a fourfold increase in the average luminosity over that achieved during Beam Energy Scan phase I (BES-I), at five gold beam energies: 9.8, 7.3, 5.75, 4.59, and 3.85 GeV/nucleon. This was accomplished by addressing several beam dynamics effects, including intrabeam scattering, beam-beam, space charge, beam instability, and field errors induced by superconducting magnet persistent currents. Some of these effects are especially detrimental at low energies. BES-II achievements are presented, and the measures taken to improve RHIC performance are described. These measures span the whole RHIC complex, including ion beam sources, injectors, beam lifetime improvements in RHIC, and operation with the world’s first bunched beam Low Energy RHIC electron Cooler (LEReC).

A high-current high-brightness electron accelerator for low-energy RHIC electron cooling (LEReC) was successfully commissioned at Brookhaven National Laboratory. The LEReC accelerator includes a dc photoemission gun, a laser system, a photocathode delivery system, magnets, beam diagnostics, a superconducting rf booster cavity, and a set of normal conducting rf cavities to provide enough flexibility to tune the beam in the longitudinal phase space. Cooling with nonmagnetized rf accelerated electron beams requires longitudinal corrections to obtain a small momentum spread while preserving the transverse emittances. Electron beams with kinetic energies of 1.6 and 2.0 MeV with a beam quality suitable for cooling were successfully propagated through 100 m of beam lines, including dispersion sections, maintained through both cooling sections in RHIC and used for cooling ions in both RHIC rings simultaneously. The beam quality suitable for cooling RHIC beams was achieved in 2018, which led to the first experimental demonstration of bunched beam electron cooling of hadron beams in 2019.

The Low Energy RHIC electron Cooling (LEReC) project at Brookhaven National Laboratory recently demonstrated for the first time cooling of hadron bunches with radio-frequency (rf) accelerated electron bunches. LEReC uses a high-voltage photoemission electron gun with stringent requirements for beam current, beam quality, and stability. The electron gun has a photocathode with a high-power fiber laser, and a novel cathode production, transport, and exchange system. It has been demonstrated that the high-voltage photoemission gun can continually produce a high-current electron beam with a beam quality suitable for electron cooling. We describe the operational experience with the LEReC dc photoemission gun in RHIC and discuss the important aspects needed to achieve the required beam current, beam quality, and stability.

To improve RHIC luminosity for heavy ion beam energies below 10 GeV/nucleon, the Low Energy RHIC electron Cooler (LEReC) is currently under commissioning at BNL. The linac of LEReC is designed to deliver a 1.6–2.6 MeV electron beam, with rms dp/p less than 5×10^{−4}. A 704 MHz superconducting radio frequency booster cavity in this linac provides up to 2.2 MeV accelerating voltage. With such a low energy and very demanding energy spread requirement, control of higher order modes (HOMs) in the cavities becomes critical and needs to be carefully evaluated to ensure minimum impact on the beam. In this paper, we report the multiphysics design of the HOM damper for this cavity to meet the energy spread requirement, as well as experimental results of the cavity with and without the HOM damper.

The low energy RHIC electron cooler (LEReC) is currently under commissioning at BNL to improve RHIC luminosity for heavy ion beam energies below 10 GeV/nucleon. The linac of LEReC consists of a dc photoemission gun, one 704 MHz superconducting radio frequency booster cavity, and three normal conducting cavities. It is designed to deliver a 1.6–2.6 MeV electron beam, with peak-to-peak momentum spread dp/p of less than ±7×10^{-4}. Two of the three normal conducting cavities will be used in LEReC for energy spread correction: a single-cell 704 MHz cavity for energy dechirping and a three-cell 2.1 GHz third harmonic cavity for rf curvature correction. In this paper, we present the designs and rf test results of these two cavities.

Abstract Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide, particularly among individuals under the age of 45. It is a complex, and heterogeneous disease with a multifaceted pathophysiology that remains to be elucidated. Metabolomics has the potential to identify metabolic pathways and unique biochemical profiles associated with TBI. Herein, we employed a longitudinal metabolomics approach to study TBI in a weight drop mouse model to reveal metabolic changes associated with TBI pathogenesis, severity, and secondary injury. Using proton nuclear magnetic resonance (1H NMR) spectroscopy, we biochemically profiled post-mortem brain from mice that suffered mild TBI (N = 25; 13 male and 12 female), severe TBI (N = 24; 11 male and 13 female) and sham controls (N = 16; 11 male and 5 female) at baseline, day 1 and day 7 following the injury. 1H NMR-based metabolomics, in combination with bioinformatic analyses, highlights a few significant metabolites associated with TBI severity and perturbed metabolism related to the injury. We report that the concentrations of taurine, creatinine, adenine, dimethylamine, histidine, N-Acetyl aspartate, and glucose 1-phosphate are all associated with TBI severity. Longitudinal metabolic observation of brain tissue revealed that mild TBI and severe TBI lead distinct metabolic profile changes. A multi-class model was able to classify the severity of injury as well as time after TBI with estimated 86% accuracy. Further, we identified a high degree of correlation between respective hemisphere metabolic profiles (r > 0.84, p

Abstract Background Pharmacological treatment of CNS diseases is limited due to the presence of the blood-brain barrier (BBB). Recent years showed significant advancement in the field of CNS drug delivery enablers, with technologies such as MR-guided focused ultrasound reaching clinical trials. This have inspired researchers in the field to invent novel brain barriers opening (BBo) technologies that are required to be simple, fast, safe and efficient. One such technology, recently developed by us, is BDF (Barrier Disrupting Fields), based on low pulsed electric fields (L-PEFs) for opening the BBB in a controlled, safe, reversible and non-invasive manner. Here, we conducted an in vivo study to show that BDF is a feasible technology for delivering Doxorubicin (Doxo) into mice brain. Means for depicting BBBo levels were developed and applied for monitoring the treatment and predicting response. Overall, the goals of the presented study were to demonstrate the feasibility for delivering therapeutic Doxo doses into naïve and tumor-bearing mice brains and applying delayed–contrast MRI (DCM) for monitoring the levels of BBBo. Methods L-PEFs were applied using plate electrodes placed on the intact skull of naïve mice. L-PEFs/Sham mice were scanned immediately after the procedure by DCM (“MRI experiment”), or injected with Doxo and Trypan blue followed by delayed (4 h) perfusion and brain extraction (“Doxo experiment”). Doxo concentrations were measured in brain samples using confocal microscopy and compared to IC50 of Doxo in glioma cell lines in vitro. In order to map BBBo extent throughout the brain, pixel by pixel MR image analysis was performed using the DCM data. Finally, the efficacy of L-PEFs in combination with Doxo was tested in nude mice bearing intracranial human glioma tumors. Results Significant amount of Doxo was found in cortical regions of all L-PEFs-treated mice brains (0.50 ± 0.06 µg Doxo/gr brain) while in Sham brains, Doxo concentrations were below or on the verge of detection limit (0.03 ± 0.02 µg Doxo/gr brain). This concentration was x97 higher than IC50 of Doxo calculated in gl261 mouse glioma cells and x8 higher than IC50 of Doxo calculated in U87 human glioma cells. DCM analysis revealed significant BBBo levels in the cortical regions of L-PEFs-treated mice; the average volume of BBBo in the L-PEFs-treated mice was x29 higher than in the Sham group. The calculated BBBo levels dropped exponentially as a function of BBBo threshold, similarly to the electric fields distribution in the brain. Finally, combining non-invasive L-PEFs with Doxo significantly decreased brain tumors growth rates in nude mice. Conclusions Our results demonstrate significant BBBo levels induced by extra-cranial L-PEFs, enabling efficient delivery of therapeutic Doxo doses into the brain and reducing tumor growth. As BBBo was undetectable by standard contrast-enhanced MRI, DCM was applied to generate maps depicting the BBBo levels throughout the brain. These findings suggest that BDF is a promising technology for efficient drug delivery into the brain with important implications for future treatment of brain cancer and additional CNS diseases.

A half-cell superconducting rf electron gun is designed to provide 0.5 A, 2 MeV beam for the Brookhaven National Laboratory R&D Energy Recovery Linac. Total rf power of 1 MW must be delivered to beam to meet the beam current and energy specifications, resulting in very strong coupling. Two opposing fundamental power couplers (FPCs) are employed to minimize the transverse kick to beam traversing the structure and to halve the power through the coupler. A single-window coaxial coupler has been designed to meet the average power and rf coupling requirements. The coupler features a planar beryllia rf window for better handling high thermal stresses and a “pringle”-shaped tip of the antenna for enhancing rf coupling. Two FPCs have been fabricated and tested in preparation for the gun cryomodule assembly. A room-temperature test stand was used for conditioning couplers in full reflection regime with variable phase of the reflecting wave. The couplers were tested up to 250 kW in pulse mode and 125 kW in cw mode at different settings of the reflecting wave phase to expose all rf surfaces along the couplers to high fields. Several multipacting barriers were encountered and successfully processed away. The rf power levels, at which multipacting was found, match well those found in computer simulations.

Gene Ontology analyses of autism spectrum disorders (ASD) risk genes have repeatedly highlighted synaptic function and transcriptional regulation as key points of convergence. However, these analyses rely on incomplete knowledge of gene function across brain development. Here we leverage Xenopus tropicalis to study in vivo ten genes with the strongest statistical evidence for association with ASD. All genes are expressed in developing telencephalon at time points mapping to human mid-prenatal development, and mutations lead to an increase in the ratio of neural progenitor cells to maturing neurons, supporting previous in silico systems biological findings implicating cortical neurons in ASD vulnerability, but expanding the range of convergent functions to include neurogenesis. Systematic chemical screening identifies that estrogen, via Sonic hedgehog signaling, rescues this convergent phenotype in Xenopus and human models of brain development, suggesting a resilience factor that may mitigate a range of ASD genetic risks.

We tested a newly described molecular memory system, CCR5 signaling, for its role in recovery after stroke and traumatic brain injury (TBI). CCR5 is uniquely expressed in cortical neurons after stroke. Post-stroke neuronal knockdown of CCR5 in pre-motor cortex leads to early recovery of motor control. Recovery is associated with preservation of dendritic spines, new patterns of cortical projections to contralateral pre-motor cortex, and upregulation of CREB and DLK signaling. Administration of a clinically utilized FDA-approved CCR5 antagonist, devised for HIV treatment, produces similar effects on motor recovery post stroke and cognitive decline post TBI. Finally, in a large clinical cohort of stroke patients, carriers for a naturally occurring loss-of-function mutation in CCR5 (CCR5-Δ32) exhibited greater recovery of neurological impairments and cognitive function. In summary, CCR5 is a translational target for neural repair in stroke and TBI and the first reported gene associated with enhanced recovery in human stroke.

Biofilm formation on prostheses and implanted devices can lead to serious complications and increased healthcare expenditures. Once formed, biofilm management is difficult and may involve a long course of antibiotics, additional surgery, and, occasionally, implant removal. This study evaluated the antibacterial properties of medical-grade silicone samples integrated with novel, non-leaching, antibacterial, quaternary ammonium silica (QASi) particles. Our collaborators (Nobio, Israel) prepared silicone sheets integrated with antibacterial QASi nanoparticles. Samples containing 0.5%, 0.75%, and 1%, QASi particles were evaluated for antibacterial properties against S. epidermidis, S. aureus, methicillin-resistant S. aureus (MRSA), E. faecalis, and P. aeruginosa using the direct contact test. The tested silicone samples integrated with QASi particles showed no bacterial growth, while growth was observed in control silicone samples without QASi. In addition, the agar diffusion test, used to evaluate the leaching of antibacterial components, exhibited no inhibition zone around the samples indicating that the QASi particles do not leach into surrounding milieu. The QASi nanoparticles exhibited very potent antibacterial surface properties, killing all viable bacteria placed on their surface. Incorporating QASi nanoparticle technology into medical products during production has the potential to create an antimicrobial surface that prevents microbial colonization and biofilm formation. [ABSTRACT FROM AUTHOR]

Chemical analysis of hazardous surface contaminations, such as hazardous substances, explosives or illicit drugs, is an essential task in security, environmental and safety applications. This task is mostly based on the collection of particles with swabs, followed by thermal desorption into a vapor analyzer, usually a detector based on ion mobility spectrometry (IMS). While this methodology is well established for several civil applications, such as border control, it is still not efficient enough for various conditions, as in sampling rough and porous surfaces. Additionally, the process of thermal desorption is energetically inefficient, requires bulky hardware and introduces device contamination memory effects. Low-temperature plasma (LTP) has been demonstrated as an ionization and desorption source for sample preparation-free analysis, mostly at the inlet of a mass spectrometer analyzer, and in rare cases in conjunction with an ion mobility spectrometer. Herein, we demonstrate, for the first time, the operation of a simple, low cost, home-built LTP apparatus for desorbing non-volatile analytes from various porous surfaces into the inlet of a handheld IMS vapor analyzer. We show ion mobility spectra that originate from operating the LTP jet on porous surfaces such as asphalt and shoes, contaminated with model amine-containing organic compounds. The spectra are in good correlation with spectra measured for thermally desorbed species. We verify through LC-MS analysis of the collected vapors that the sampled species are not fragmented, and can thus be identified by commercial IMS detectors.

Most sensory information destined for the neocortex is relayed through the thalamus, where considerable transformation occurs.sup.1,2. One means of transformation involves interactions between excitatory thalamocortical neurons that carry data to the cortex and inhibitory neurons of the thalamic reticular nucleus (TRN) that regulate the flow of those data.sup.3-6. Although the importance of the TRN has long been recognised.sup.7-9, understanding of its cell types, their organization and their functional properties has lagged behind that of the thalamocortical systems they control. Here we address this by investigating the somatosensory and visual circuits of the TRN in mice. In the somatosensory TRN we observed two groups of genetically defined neurons that are topographically segregated and physiologically distinct, and that connect reciprocally with independent thalamocortical nuclei through dynamically divergent synapses. Calbindin-expressing cells--located in the central core--connect with the ventral posterior nucleus, the primary somatosensory thalamocortical relay. By contrast, somatostatin-expressing cells--which reside along the surrounding edges of the TRN--synapse with the posterior medial thalamic nucleus, a higher-order structure that carries both top-down and bottom-up information.sup.10-12. The two TRN cell groups process their inputs in pathway-specific ways. Synapses from the ventral posterior nucleus to central TRN cells transmit rapid excitatory currents that depress deeply during repetitive activity, driving phasic spike output. Synapses from the posterior medial thalamic nucleus to edge TRN cells evoke slower, less depressing excitatory currents that drive more persistent spiking. Differences in the intrinsic physiology of TRN cell types, including state-dependent bursting, contribute to these output dynamics. The processing specializations of these two somatosensory TRN subcircuits therefore appear to be tuned to the signals they carry--a primary central subcircuit tuned to discrete sensory events, and a higher-order edge subcircuit tuned to temporally distributed signals integrated from multiple sources. The structure and function of visual TRN subcircuits closely resemble those of the somatosensory TRN. These results provide insights into how subnetworks of TRN neurons may differentially process distinct classes of thalamic information. In the thalamic reticular nucleus there are two neuron types that are segregated into central and edge zones and receive inputs from different thalamocortical nuclei, creating subcircuits with distinct dynamics., Author(s): Rosa I. Martinez-Garcia [sup.1] [sup.2] [sup.3] , Bettina Voelcker [sup.1] [sup.6] , Julia B. Zaltsman [sup.1] [sup.3] , Saundra L. Patrick [sup.1] [sup.3] , Tanya R. Stevens [sup.1] [sup.3] [...]

In the mid-nineties, the New York City Schools Chancellor created a citywide improvement zone to take over a significant proportion of the city's lowest performing schools whose local community school districts had failed to improve them. This "Chancellor's District" defined centralized management, rather than local control, as the critical variable necessary to initiate, enforce and ensure the implementation of school improvement. This large-scale intervention involved both a governance change and a set of capacity-building interventions presumably unavailable under local sub-district control. Our study retrospectively examined the origins, structure and components of the Chancellor's District, and analyzed the characteristics and outcomes of the elementary schools mandated to receive these interventions. Our longitudinal analysis compared Chancellor's District schools to New York City's other state-identified low performing schools, based on a school-level panel of performance, demographic, human resource, and expenditure data collected from district Annual School Report Cards and School Based Expenditure Reports from 1998-99 through 2001-02. The results suggest that the Chancellor's District intervention improved these schools' instructional capacity and academic outcomes, both relative to where these schools would have been and relative to comparable schools. (Contains 6 footnotes and 11 tables.)

The blood–brain barrier (BBB) is composed of brain microvasculature that provides selective transport of solutes from the systemic circulation into the central nervous system to protect the brain and spinal microenvironment. Damage to the BBB in the acute phase after traumatic brain injury (TBI) is recognized as a major underlying mechanism leading to secondary long-term damage. Because of the lack of technological ability to detect subtle BBB disruption (BBBd) in the chronic phase, however, the presence of chronic BBBd is disputable. Thus, the dynamics and course of long-term BBBd post-TBI remains elusive. Thirty C57BL/6 male mice subjected to TBI using our weight drop closed head injury model and 19 naïve controls were scanned by magnetic resonance imaging (MRI) up to 540 days after injury. The BBB maps were calculated from delayed contrast extravasation MRI (DCM) with high spatial resolution and high sensitivity to subtle BBBd, enabling depiction and quantification of BBB permeability. At each time point, 2–6 animals were sacrificed and their brains were extracted, sectioned, and stained for BBB biomarkers including: blood microvessel coverage by astrocyte using GFAP, AQP4, ZO-1 gaps, and IgG leakage. We found that DCM provided depiction of subtle yet significant BBBd up to 1.5 years after TBI, with significantly higher sensitivity than standard contrast-enhanced T1-weighted and T2-weighted MRI (BBBd volumes main effect DCM/T1/T2 p < 0.0001 F(2,70) = 107.3, time point p < 0.0001 F(2,133, 18.66) = 23.53). In 33% of the cases, both in the acute and chronic stages, there was no detectable enhancement on standard T1-MRI, nor detectable hyperintensities on T2-MRI, whereas DCM showed significant BBBd volumes. The BBBd values of TBI mice at the chronic stage were found significantly higher compared with age matched naïve animals at 30, 60, and 540 days. The calculated BBB maps were histologically validated by determining significant correlation between the calculated levels of disruption and a diverse set of histopathological parameters obtained from different brain regions, presenting different components of the BBB. Cumulative evidence from recent years points to BBBd as a central component of the pathophysiology of TBI. Therefore, it is expected that routine use of highly sensitive non-invasive techniques to measure BBBd, such as DCM with advanced analysis methods, may enhance our understanding of the changes in BBB function after TBI. Application of the DCM technology to other CNS disorders, as well as to normal aging, may shed light on the involvement of chronic subtle BBBd in these conditions. [ABSTRACT FROM AUTHOR]

The objective of this study was to investigate the molecular response to damage at the blood-brain barrier (BBB) and to elucidate critical pathways that might lead to effective treatment in central nervous system (CNS) pathologies in which the BBB is compromised. We have used a human, stem-cell derived in-vitro BBB injury model to gain a better understanding of the mechanisms controlling BBB integrity. Chemical injury induced by exposure to an organophosphate resulted in rapid lipid peroxidation, initiating a ferroptosis-like process. Additionally, mitochondrial ROS formation (MRF) and increase in mitochondrial membrane permeability were induced, leading to apoptotic cell death. Yet, these processes did not directly result in damage to barrier functionality, since blocking them did not reverse the increased permeability. We found that the iron chelator, Desferal© significantly decreased MRF and apoptosis subsequent to barrier insult, while also rescuing barrier integrity by inhibiting the labile iron pool increase, inducing HIF2α expression and preventing the degradation of Ve-cadherin specifically on the endothelial cell surface. Moreover, the novel nitroxide JP4-039 significantly rescued both injury-induced endothelium cell toxicity and barrier functionality. Elucidating a regulatory pathway that maintains BBB integrity illuminates a potential therapeutic approach to protect the BBB degradation that is evident in many neurological diseases.

The blood–brain barrier (BBB) is a major hurdle for the treatment of central nervous system disorders, limiting passage of both small and large therapeutic agents from the blood stream into the brain. Thus, means for inducing BBB disruption (BBBd) are urgently needed. Here, we studied the application of low pulsed electrical fields (PEFs) for inducing BBBd in mice. Mice were treated by low PEFs using electrodes pressed against both sides of the skull (100–400 square 50 µs pulses at 4 Hz with different voltages). BBBd as a function of treatment parameters was evaluated using MRI-based treatment response assessment maps (TRAMs) and Evans blue extravasation. A 3D numerical model of the mouse brain and electrodes was constructed using finite element software, simulating the electric fields distribution in the brain and ensuring no significant temperature elevation. BBBd was demonstrated immediately after treatment and significant linear regressions were found between treatment parameters and the extent of BBBd. The maximal induced electric field in the mice brains, calculated by the numerical model, ranged between 62.4 and 187.2 V/cm for the minimal and maximal applied voltages. These results demonstrate the feasibility of inducing significant BBBd using non-invasive low PEFs, well below the threshold for electroporation.

Aim. To evaluate influence of long-term monotherapy with nebivolol on blood pressure (BP) (office BP; self-monitoring BP, pre-trip BP monitoring, ambulatory BP monitoring (ABPM)) and metabolic blood profile in locomotive crew staff with newly diagnosed arterial hypertension (HT).Material and methods. Locomotive crew engineers and their assistants (n=50; age 20-55 y.o.) with newly diagnosed HT 1-2 degree with moderate-to-high cardiovascular risk were included into the open prospective uncontrolled study. The study duration was 12 months. The office BP level, heart rate were evaluated initially, in 12 weeks and 12 months of treatment; pre-trip BP level – one time per month; ABPM and blood biochemical tests (glucose and lipid profile) - initially and in 12 months of therapy. Data of BP self-monitoring, nebivolol treatment compliance and safety was also evaluated.Results. Long-term monotherapy with nebivolol allowed reaching the target level of office BP, self-monitoring BP, ABPM. Nebivolol provided BP control both in working days and in week end. Efficacy of nebivolol monotherapy was 88%. Nebivolol therapy improved basic ABPM indicators (load pressure, variability, daily rhythm), pulse BP, heart rate. Nebivolol had no significant negative metabolic effects, 78% of patients demonstrated sufficient compliance with nebivolol treatment. Adverse reaction (bradycardia) was observed in 2 (4%) patients.Conclusion. Nebivolol has high antihypertensive efficacy, metabolic neutrality and good safety profile in the locomotive crew staff with newly diagnosed HT.