First Leptophobic Dark Matter Search from the Coherent-CAPTAIN-Mills Liquid Argon Detector.

We report the first results of a search for leptophobic dark matter (DM) from the Coherent-CAPTAIN-Mills (CCM) liquid argon (LAr) detector. An engineering run with 120 photomultiplier tubes (PMTs) and 17.9×10^{20} protons on target (POT) was performed in fall 2019 to study the characteristics of the CCM detector. The operation of this 10-ton detector was strictly light based with a threshold of 50 keV and used coherent elastic scattering off argon nuclei to detect DM. Despite only 1.5 months of accumulated luminosity, contaminated LAr, and nonoptimized shielding, CCM's first engineering run has already achieved sensitivity to previously unexplored parameter space of light dark matter models with a baryonic vector portal. With an expected background of 115 005 events, we observe 115 005+16.5 events which is compatible with background expectations. For a benchmark mediator-to-DM mass ratio of m_{V_{B}}/m_{χ}=2.1, DM masses within the range 9 MeV≲m_{χ}≲50 MeV are excluded at 90% C. L. in the leptophobic model after applying the Feldman-Cousins test statistic. CCM's upgraded run with 200 PMTs, filtered LAr, improved shielding, and 10 times more POT will be able to exclude the remaining thermal relic density parameter space of this model, as well as probe new parameter space of other leptophobic DM models.

A data resource from concurrent intracranial stimulation and functional MRI of the human brain.

Mapping the causal effects of one brain region on another is a challenging problem in neuroscience that we approached through invasive direct manipulation of brain function together with concurrent whole-brain measurement of the effects produced. Here we establish a unique resource and present data from 26 human patients who underwent electrical stimulation during functional magnetic resonance imaging (es-fMRI). The patients had medically refractory epilepsy requiring surgically implanted intracranial electrodes in cortical and subcortical locations. One or multiple contacts on these electrodes were stimulated while simultaneously recording BOLD-fMRI activity in a block design. Multiple runs exist for patients with different stimulation sites. We describe the resource, data collection process, preprocessing using the fMRIPrep analysis pipeline and management of artifacts, and provide end-user analyses to visualize distal brain activation produced by site-specific electrical stimulation. The data are organized according to the brain imaging data structure (BIDS) specification, and are available for analysis or future dataset contributions on openneuro.org including both raw and preprocessed data.

Venereal transmission of La Crosse (California encephalitis) arbovirus in Aedes triseriatus mosquitoes.

Veneral transmission of La Crosse virus by males of Aedes triseriatus was demonstrated. La Crosse virus was detected in the bursa of females after induced copulation, and disseminated infection was shown to occur occasionally. Since males of Aedes triseriatus have transovarial filial infection rates similar to those of females and can repeatedly mate, veneral transmission may be an important supplement to other natural endemic maintenance mechanisms.

Transovarial transmission of LaCrosse virus (California encephalitis group) in the mosquito, Aedes triseriatus.

LaCrosse virus (California encephalitis group) was recovered from F(1) eggs, larvae, and adults produced by experimentally infected Aedes triseriatus. The F(1) females transmitted the virus by bite to suckling mice and chipmunks. This, plus isolations of LaCrosse virus from larvae collected from their natural habitats in enzootic areas and from males and females reared from them, suggests that transovarial transmission is the overwintering mechanism for this arbovirus in northern United States.

Comparison of the M RNA genome segments of two human isolates of La Crosse virus.

The M genomic RNA segments of La Crosse (LAC) virus isolates from the brains of two children autopsied 18 years apart in Wisconsin were molecularly cloned using a reverse transcriptase-PCR assay and the nucleotide sequences of the cDNAs determined. The M RNA of each virus contains 4526 nucleotides, similar to that reported previously for a New York mosquito isolate of LAC. There were 20 nucleotide differences between the two human isolates, which results in the prediction of 7 amino acid changes in the proteins encoded in the single, long open reading frame of the M segment. One of these predicted differences occurs in the G2 glycoprotein and six in the G1 glycoprotein. The two viruses were identical in terms of predicted amino acid sequence in the region believed to represent a nonstructural protein. These data have been further compared to those available for two other California serogroup isolates.

Evidence that fatal human infections with La Crosse virus may be associated with a narrow range of genotypes.

La Crosse (LAC) virus belongs to the California (CAL) serogroup of the genus Bunyavirus, family Bunyaviridae. It is considered one of the most important mosquito-borne pathogens in North America, especially in the upper Mid-West, where it is associated with encephalitis during the time of year when mosquitoes are active. Infections occur most frequently in children and young adults and, while most cases are resolved after a period of intense illness, a small fraction (< 1%) are fatal. At present there have only been three isolates of LAC virus from humans all made from brain tissue postmortem. The cases yielding viruses are separated chronologically by 33 years and geographically from Minnesota/Wisconsin (1960, 1978) to Missouri (1993). The M RNA sequence of the first two isolates was previously reported. The present study extends the observations to the isolate from the 1993 case and includes several mosquito isolates as well. A comparison of the M RNAs of these viruses shows that for the human isolates both nucleotide sequence and the deduced amino-acid sequence of the encoded proteins are highly conserved, showing a maximum variation of only 0.91% and 0.69%, respectively. This high degree of conservation over time and space leads to the hypothesis that human infections with this particular genotype of LAC virus are those most likely to have a fatal outcome. It is also shown that a virus with this genotype could be found circulating in mosquitoes in an area more or less intermediate between the locations of the first and second fatal cases.

Management of bronchopleural fistula with a variable-resistance valve and a single ventilator.

Independent lung ventilation with two ventilators is sometimes used in the management of bronchopleural fistula (BPF). We describe a patient in whom gas flow through a large BPF was initially reduced, and subsequently eliminated, during differential lung ventilation using a single ventilator and a variable-resistance valve attached to one lumen of a bifurcated endotracheal tube.

Transovarial transmission of LaCrosse virus in Aedes triseriatus.

As part of a continuing investigation on the ecology of LaCrosse virus in Wisconsin, field and laboratory studies were conducted to explore the possibility that the virus is transmitted transovarially in A. triseriatus mosquitoes. In laboratory experiments, A. triseriatus mosquitoes were infected by ingesting LaCrosse virus in defibrinated blood. LaCrosse virus was recovered from F1 eggs, larvae, and adults that originated from the infected parent mosquitoes. In a subsequent field study aimed at determining if transovarial transmission accounted for the survival of LaCrosse virus during the winter season, larvae that originated from overwintering A. triseriatus eggs were collected from a LaCrosse virus enzootic area in southwestern Wisconsin. LaCrosse virus was isolated from these larvae and from adult A. triseriatus that were reared from field-collected larvae. These findings strongly imply that A. triseriatus is the reservoir of LaCrosse virus and that transovarial transmission is the mechanism responsible for the maintenance of the virus during the winter season in the north central region of the United States.

Comparative effects of alpha-receptor stimulation and nitrergic inhibition on bronchovascular tone.

Adrenergic agonists are known to influence bronchial blood flow and bronchovascular resistance. Recently, the nitrergic system has also been implicated in the control of bronchovascular tone. In this study, we compared the effects of the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) and the alpha(1)-receptor agonist phenylephrine on bronchovascular resistance in anesthetized sheep (n = 9). Bronchial blood flow, cardiac output, and systemic and pulmonary arterial pressures were continuously monitored. Phenylephrine (1.2-3.4 microg. kg(-1). min(-1)) was infused intravenously to increase mean systemic arterial pressure above 95 Torr for 10 min and then was discontinued. When hemodynamic parameters returned to baseline, nebulized phenylephrine (10 mg) was given over 10 min. When parameters again normalized, L-NAME (30 mg/kg) was infused intravenously over 1 min. Intravenous phenylephrine increased systemic vascular resistance by 40% at 10 min with no concurrent increase in bronchovascular resistance, but inhaled phenylephrine increased bronchovascular resistance by 66% at 10 min. By comparison, intravenous L-NAME produced a rapid and sustained fivefold increase in bronchovascular resistance at 10 min. We conclude that, although alpha-agonist stimulation has some influence on bronchovascular resistance in sheep, the nitrergic system has predominant control of bronchovascular tone.

Effect of expiratory resistive loading on the noninvasive tension-time index in COPD.

Expiratory resistive loading (ERL) is used by chronic obstructive pulmonary disease (COPD) patients to improve respiratory function. We, therefore, used a noninvasive tension-time index of the inspiratory muscles (TT(mus) = I/PI(max) x TI/TT, where I is mean inspiratory pressure estimated from the mouth occlusion pressure, PI(max) is maximal inspiratory pressure, TI is inspiratory time, and TT is total respiratory cycle time) to better define the effect of ERL on COPD patients. To accomplish this, we measured airway pressures, mouth occlusion pressure, respiratory cycle flow rates, and functional residual capacity (FRC) in 14 COPD patients and 10 normal subjects with and without the application of ERL. TT(mus) was then calculated and found to drop in both COPD and normal subjects (P<0.05). The decline in TT(mus) in both groups resulted solely from a prolongation of expiratory time with ERL (P<0.001 for COPD, P<0.05 for normal subjects). In contrast to the COPD patients, normal subjects had an elevation in I and FRC, thus minimizing the decline in TT(mus). In conclusion, ERL reduces the potential for inspiratory muscle fatigue in COPD by reducing TI/TT without affecting FRC and I.

Effect of aerosolized acetylcholine on bronchial blood flow.

We studied the effects of aerosolized as well as intravenous infusion of acetylcholine on bronchial blood flow in six anesthetized sheep. Intravenous infusion of acetylcholine, at a dose of 2 microg/kg, increased bronchial blood flow from 45 +/- 15 (SE) to 74 +/- 30 ml/min, and vascular conductance increased by 76 +/- 22%. In contrast, aerosolized acetylcholine at doses of 2 and 20 microg/kg decreased bronchial vascular conductance by approximately 10%. At an aerosolized dose of 200 microg/kg, the bronchial vascular conductance increased by approximately 15%, and there was no further increase in conductance when the aerosolized dose was increased to 2,000 microg/kg. Pretreatment of animals with a nitric oxide synthase inhibitor, Nomega-nitro-L-arginine methyl ester hydrochloride, partially blocked the vasodilatory effects of intravenous acetylcholine and completely blocked the vasodilatory effects of high-dose aerosolized acetylcholine. These data suggest that aerosolized acetylcholine does not readily penetrate the vascular wall of bronchial circulatory system and, therefore, has minimal vasodilatory effects on the bronchial vasculature.

Nitric oxide and beta-adrenergic agonist-induced bronchial arterial vasodilation.

In anesthetized sheep, we measured bronchial blood flow (Qbr) by an ultrasonic flow probe to investigate the interaction between inhaled nitric oxide (NO; 100 parts/million) given for 5 min and 5 ml of aerosolized isoetharine (1.49 x 10(-2) M concentration). NO and isoetharine increased Qbr from 26.5 +/- 6.5 to 39.1 (SE) +/- 10.6 and 39.7 +/- 10.7 ml/min, respectively (n = 5). Administration of NO immediately after isoetharine further increased Qbr to 57.3 +/- 15.1 ml/min. NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester hydrochloride (L-NAME; 30 mg/kg, in 20 ml saline given i.v.) decreased Qbr to 14.6 +/- 2.6 ml/min. NO given three times alternately with isoetharine progressively increased Qbr from 14.6 +/- 2.6 to 74.3 +/- 17.0 ml/min, suggesting that NO and isoetharine potentiate vasodilator effects of each other. In three other sheep, after L-NAME three sequential doses of isoetharine increased Qbr from 10.2 +/- 3.4 to 11.5 +/- 5.7, 11.7 +/- 4.7, and 13.3 +/- 5.7 ml/min, respectively, indicating that effects of isoetharine are predominantly mediated through synthesis of NO. When this was followed by three sequential administrations of NO, Qbr increased by 146, 172, and 185%, respectively. Thus in the bronchial circulation, there seems to be a close interaction between adenosine 3',5'-cyclic monophosphate- and guanosine 3',5'-cyclic monophosphate-mediated vasodilation.

Lower rates of oral transmission of La Crosse virus by Aedes triseriatus venereally exposed after engorgement on immune chipmunks.

Transmission rates of La Crosse (LAC) virus observed in Aedes triseriatus females that had engorged on chipmunks with antibody to LAC and had been mated by infected males 5-11 days later (24%, 69/288) were 40% lower than in those fed on chipmunks without antibody (38%, 112/293). Similar results were obtained in three separate trials using males infected 1) by inoculation with prototype LAC virus, 2) transovarially with a field strain, or 3) transovarially with the field strain following passage through a viremic chipmunk. Similar rates were also observed in trials with F2 and F3 progeny of several strains of Ae. triseriatus collected from LAC-endemic and non-endemic areas. Reduction of oral transmission by venereally infected females mated by transovarially infected males following engorgement of antibody in chipmunks or other vertebrates could be important in the natural control of LAC virus, since most adult chipmunks sampled in endemic areas have antibodies neutralizing LAC. Ten-fold higher rates of venereal infection found in females mated by infected males 5 or more days after engorgement on LAC antibody-negative chipmunks than in those mated without prior engorgement extend previous findings of higher rates of transmission after engorgement on laboratory mice to include the natural vertebrate host.

Higher venereal infection and transmission rates with La Crosse virus in Aedes triseriatus engorged before mating.

Infection of colonized female Aedes triseriatus by La Crosse (LAC) virus occurred more frequently when females were inseminated by infected males after the females engorged blood (49% of 39) than when mating took place before engorgement (4% of 554). Salivary transmission of LAC virus to mice also was more frequent in females venerally infected after engorgement on a normal mouse (35% of 34) than in females mated before engorgement (2% of 49). LAC virus was transovarially transmitted by 40% of 10 females mated by infected males, and in 64% of 279 progeny reared from eggs of second or later ovarian cycles.

Quantitation of La Crosse virus in venereally infected Aedes triseriatus.

The replication of two strains of La Crosse (LAC) virus, prototype and an unpassaged field isolate, was followed in intrathoracically inoculated male and venereally infected female Aedes triseriatus mosquitoes. The venereal infection rate following induced mating was 13.6% of 44 females inseminated by males inoculated with prototype virus, and 26.3% of 38 females inseminated by males inoculated with an unpassaged field strain. The males consistently contained concentrations of virus in reproductive tracts equal to or greater than those in salivary glands (SG). In contrast, venereally infected females generally contained the highest concentrations of virus in SG. Prototype LAC virus was demonstrable in nearly all organs of the infected females by 10 days following mating; the unpassaged field strain was detectable in all organ systems tested by day 6. There appeared to be no significant differences in replication between the prototype and field isolate viruses.

Delineation of La Crosse virus in developmental stages of transovarially infected Aedes triseriatus.

The tropisms and development of La Crosse (LAC) virus in stages of transovarially infected Aedes triseriatus were studied with fluorescent antibody (FA) stained dissected organs and titrations of individual arthropods in suckling mice. Viral antigen was detected by FA in 95 of 387 dissected larvae, pupae, and adults. In larvae highest levels of fluorescence were detected in the alimentary tract, followed by ganglia, malpighian tubule, muscle, and other tissues. No specific organs or germ layer-derived tissues appeared to be the sole source of viral replication. Most tissues and organs of A. triseriatus are capable of maintaining LAC virus. Antigen was detected in the identifiable organs immediately upon emergence from the egg. In pupae and adults antigen was detected at high levels in foregut, gonadal and associated tissues, and in salivary glands, which would indicate females could be infective upon emergence. Virus was isolated from all arthropod stages, in 32 of 130 individuals inoculated into suckling mice. Titrations ranged from less than 1.0 log10 SMICLD50 per 0.02 ml for eggs and 1st instar larvae to 3.0 log10 SMICLD50 for 4th instar larvae. Adults and pupae averaged between 2.0 and 3.0 log10 SMICLD50. Increases in titer during maturation were mainly related to increases in size of the organism rather than in titer per unit volume.

Emergence of La Crosse virus from endemic foci. Fluorescent antibody studies of overwintered Aedes triseriatus.

The frequency and distribution of La Crosse (LAC) virus overwintering in Aedes triseriatus diapause eggs were studied during 1974 by following 64 tree-hole oviposition sites in four enzootic hardwood forest areas. A direct fluorescent antibody technique, adapted for detection of LAC virus in individual mosquitoes, proved to be a rapid, reliable and economical tool for ascertaining true field infection rates. Virus was found in larvae from each of the four study areas before the seasonal emergence of adults and detected in 10 (0.6%) of 1,698 individually processed adults reared from collected larvae. In one of these study areas, all 12 located tree-holes were enclosed with screen before the seasonal emergence of adults, to ensure that all collected from these sites originated from overwintered eggs. Of 1,280 Aedes triseriatus processed from this area throughout the season, 16 (1.2%) contained virus. Isolates were found in overwintered Aedes triseriatus throughout the summer months, demonstrating the role of these tree-hole sites as foci for both overwintering and continuing summer season source of LAC virus in these forested areas.

Venereal transmission of La Crosse virus from male to female Aedes triseriatus.

Horizontal transmission of La Crosse (LAC) arbovirus in colonized Aedes triseriatus was first observed in mating cages. LAC antigen was visualized by fluorescent antibody technique in multiple organs of 5 (2.5% of 198 females dissected after contact in mating cages with males, with a transovarial infection rate of 31%. Venereal transmission of LAC virus was demonstrated by limited contact induced mating. Antigen was detected in bursal contents of 35 (53%) of 66 females dissected within 24 h after induced mating by males previously infected by intrathoracic inoculation. Antigen was observed in ovaries, heart, gut, salivary glands, or other organs in 13 (3.4%) of 379 females dissected 1 to 14 days post-mating. LAC virus was isolated from infected males, from contents of the bursa copulatrix of females following mating, and from dissection remnants of 6 of the 13 females in which disseminated antigen had been observed. Venereally infected females were shown to be capable of transmission of LAC virus by bite to mice and to eggs.

Observations on a natural cycle of La Crosse virus (California group) in Southwestern Wisconsin.

Ecological studies were conducted to document the role of the eastern chipmunk (Tramias striatus) as a vertebrate host for La Crosse (LAC) virus in nature during late summer when Aedes triseriatus mosquitoes are most abundant. Movement, home range and density of chipmunk populations were determined by trap mark and recapture techniques on grid study areas. The temporal distribution of A. triseriatus was estimated by use of oviposition traps. Passive antibodies were found in spring-born juveniles captured prior to mid-July and in summer-born juveniles in September. Active antibodies neutralizing LAC virus were first detected in susceptible chipmunks in mid-July and 68 free-living and 4 sentinel animals developed antibodies during the study. Virus transmission continued at a high rate through August but was not detected in September. Chipmunk habitat was ranked for quality and populations of chipmunks. A. triseriatus were more abundant in study areas with most suitable chipmunk habitat. Populations of A. triseriatus were temporally associated with the elaboration of antibodies in chipmunks. In one study area, antibody prevalence rates in adult and spring-born juveniles reached 100% by September. Findings implicate A. triseriatus as the vector and establish chipmunks as important amplifying hosts in discontinuous foci of virus transmission.

A comparison of La Crosse virus isolated obtained from different ecological niches and an analysis of the structural components of California encephalitis serogroup viruses and other bunyaviruses.

Analyses of the oligonucleotide fingerprints of the three genome ribonucleic acid (RNA) species of 11 isolates of La Crosse (LAC) virus, obtained from various ecological niches in the northern United States and compared to those of prototype LAC virus, showed that in each place from which these isolates were obtained LAC variants and varieties were present with related, but distinguishable, nucleotide sequences for their large, medium, or small RNA species. The RNA genomes of prototypes trivittatus (TVT), snowshoe hare (SSH), Tahyna (TAH), and Lumbo (a variety of TAH) viruses of the California encephalitis (CE) serogroup, and Guaroa of the Bunyamwera serogroup also consist of three RNA species, each with unique and distinguishable nucleotide sequences which bear little resemblance to those of the LAC virus isolates. The virions of CE group viruses (CE, Jamestown Canyon, Keystone, LAC, Melao, SSH, TVT, TAH viruses and South River, an unregistered virus) have three major viral polypeptides, designated G1, G2, and N.