The lasing action of organically modified silica gel (ORMOSIL) host media doped with laser dyes, rhodamine 6G, and rhodamine B is described. The laser is a monolithic design pumped transversely by a ...pulsed Nd:YAG laser. Conversion efficiencies as high as 39% were observed with usable lifetimes exceeding 50000 pulses. With a 500- mu J pump source, typical output energies of 200 mu J were produced. The values obtained for the lifetime go well beyond the photostability behavior reported in prior studies. Moreover, this work shows that a simple monolithic solid-state laser pumped by a pulsed Nd:YAG is capable of producing broadband spectral output of 100-kW peak power. More detailed investigations are currently underway with different dyes and pump cavity configurations.< >
The technologies and practices that have enabled the recent boom in shale gas production have also brought attention to the environmental impacts of its use. It has been debated whether the fugitive ...methane emissions during natural gas production and transmission outweigh the lower carbon dioxide emissions during combustion when compared to coal and petroleum. Using the current state of knowledge of methane emissions from shale gas, conventional natural gas, coal, and petroleum, we estimated up-to-date life-cycle greenhouse gas emissions. In addition, we developed distribution functions for key parameters in each pathway to examine uncertainty and identify data gaps such as methane emissions from shale gas well completions and conventional natural gas liquid unloadings that need to be further addressed. Our base case results show that shale gas life-cycle emissions are 6% lower than conventional natural gas, 23% lower than gasoline, and 33% lower than coal. However, the range in values for shale and conventional gas overlap, so there is a statistical uncertainty whether shale gas emissions are indeed lower than conventional gas. Moreover, this life-cycle analysis, among other work in this area, provides insight on critical stages that the natural gas industry and government agencies can work together on to reduce the greenhouse gas footprint of natural gas.
The SARS-CoV-2 virus is primarily transmitted through virus-laden fluid particles ejected from the mouth of infected people. Face covers can mitigate the risk of virus transmission but their outward ...effectiveness is not fully ascertained. Objective: by using a background oriented schlieren technique, we aim to investigate the air flow ejected by a person while quietly and heavily breathing, while coughing, and with different face covers. Results: we found that all face covers without an outlet valve reduce the front flow through by at least 63% and perhaps as high as 86% if the unfiltered cough jet distance was resolved to the anticipated maximum distance of 2-3 m. However, surgical and handmade masks, and face shields, generate significant leakage jets that may present major hazards. Conclusions: the effectiveness of the masks should mostly be considered based on the generation of secondary jets rather than on the ability to mitigate the front throughflow.
Neurosurgeons are familiar with the challenges presented by craniopagus twins, but other types of conjoined twins may also have neurosurgical implications. We report our experience in the management ...of ischiopagus and pygopagus conjoined twins.
This is a retrospective review of the management of conjoined twins at Red Cross Children's Hospital in Cape Town, South Africa.
Twenty-three pairs of symmetrical conjoined twins were managed over a 40-year period (1964-2003), of which 16 (70%) were separated. Of these cases, 6 are the focus of this study, namely 4 pairs of ischiopagus twins and 2 pairs of pygopagus twins seen between 1993 and 2003. In 2 cases, there was direct involvement of the nervous system at the site of union, with 1 pair of ischiopagi manifesting end-to-end union of their spinal cords, while a pair of pygopagi had back-to-back fusion of the conus. Another pair of ischiopagi had a fused dural sac without joined neural elements, but one of these children developed syringomyelia 2 years after separation. Neuroimaging was invaluable in detecting these abnormalities. The one pair of ischiopagi who died before separation were HIV positive and had severe brain atrophy and cystic encephalmalacia at autopsy. Nine of the 12 children (75%) had bony abnormalities of the spine remote from the area of conjunction. The most common finding was the presence of hemivertebrae, usually in the thoracic spine. Six children manifested scoliosis, which has already progressed in the oldest two. Technical aspects such as timing and sequence of separation, the division of neural tissues and reconstruction are discussed, as are the long-term complications of their spinal abnormalities.
Ischiopagus and pygopagus conjoined twins manifest an interesting array of spinal abnormalities, which present challenges, not only at the time of separation, but also in their long-term management.
Recent X-ray and optical observations of the Perseus cluster indicate that a combination of weak shocks at small radii (≳20 kpc) and viscous and conductive dissipation of sound waves at larger radii ...is responsible for heating the intracluster medium and can balance radiative cooling of cluster cores. We discuss this mechanism more generally and show how the specific heating and cooling rates vary with temperature and radius. It appears that this heating mechanism is most effective above 107 K, which allows for radiative cooling to proceed within normal galaxy formation but stifles the growth of very massive galaxies. The scaling of the wavelength of sound waves with cluster temperature and feedback in the system are investigated.
No systemic therapies have been approved for the treatment of advanced cutaneous squamous-cell carcinoma. This cancer may be responsive to immune therapy, because the mutation burden of the tumor is ...high and the disease risk is strongly associated with immunosuppression. In the dose-escalation portion of the phase 1 study of cemiplimab, a deep and durable response was observed in a patient with metastatic cutaneous squamous-cell carcinoma.
We report the results of the phase 1 study of cemiplimab for expansion cohorts of patients with locally advanced or metastatic cutaneous squamous-cell carcinoma, as well as the results of the pivotal phase 2 study for a cohort of patients with metastatic disease (metastatic-disease cohort). In both studies, the patients received an intravenous dose of cemiplimab (3 mg per kilogram of body weight) every 2 weeks and were assessed for a response every 8 weeks. In the phase 2 study, the primary end point was the response rate, as assessed by independent central review.
In the expansion cohorts of the phase 1 study, a response to cemiplimab was observed in 13 of 26 patients (50%; 95% confidence interval CI, 30 to 70). In the metastatic-disease cohort of the phase 2 study, a response was observed in 28 of 59 patients (47%; 95% CI, 34 to 61). The median follow-up was 7.9 months in the metastatic-disease cohort of the phase 2 study. Among the 28 patients who had a response, the duration of response exceeded 6 months in 57%, and 82% continued to have a response and to receive cemiplimab at the time of data cutoff. Adverse events that occurred in at least 15% of the patients in the metastatic-disease cohort of the phase 2 study were diarrhea, fatigue, nausea, constipation, and rash; 7% of the patients discontinued treatment because of an adverse event.
Among patients with advanced cutaneous squamous-cell carcinoma, cemiplimab induced a response in approximately half the patients and was associated with adverse events that usually occur with immune checkpoint inhibitors. (Funded by Regeneron Pharmaceuticals and Sanofi; ClinicalTrials.gov numbers, NCT02383212 and NCT02760498 .).
Depression is a common source of human disability for which etiologic insights remain limited. Although abnormalities of monoamine neurotransmission, including dopamine, are theorized to contribute ...to the pathophysiology of depression, evidence linking dopamine-related genes to depression has been mixed. The current study sought to address this knowledge-gap by examining whether the combined effect of dopamine polymorphisms was associated with depressive symptomatology in both healthy individuals and individuals with depression.
Data were drawn from three independent samples: (1) a discovery sample of healthy adult participants (n = 273); (2) a replication sample of adults with depression (n = 1,267); and (3) a replication sample of healthy adult participants (n = 382). A genetic risk score was created by combining functional polymorphisms from five genes involved in synaptic dopamine availability (COMT and DAT) and dopamine receptor binding (DRD1, DRD2, DRD3).
In the discovery sample, the genetic risk score was associated with depressive symptomatology (β = -0.80, p = 0.003), with lower dopamine genetic risk scores (indicating lower dopaminergic neurotransmission) predicting higher levels of depression. This result was replicated with a similar genetic risk score based on imputed genetic data from adults with depression (β = -0.51, p = 0.04). Results were of similar magnitude and in the expected direction in a cohort of healthy adult participants (β = -0.86, p = 0.15).
Sequence variation in multiple genes regulating dopamine neurotransmission may influence depressive symptoms, in a manner that appears to be additive. Further studies are required to confirm the role of genetic variation in dopamine metabolism and depression.
Babesia microti and Borrelia burgdorferi, the respective causative agents of human babesiosis and Lyme disease, are maintained in their enzootic cycles by the blacklegged tick (Ixodes scapularis) and ...use the white-footed mouse (Peromyscus leucopus) as primary reservoir host. The geographic range of both pathogens has expanded in the United States, but the spread of babesiosis has lagged behind that of Lyme disease. Several studies have estimated the basic reproduction number (R0) for B. microti to be below the threshold for persistence (<1), a finding that is inconsistent with the persistence and geographic expansion of this pathogen. We tested the hypothesis that host coinfection with B. burgdorferi increases the likelihood of B. microti transmission and establishment in new areas. We fed I. scapularis larva on P. leucopus mice that had been infected in the laboratory with B. microti and/or B. burgdorferi. We observed that coinfection in mice increases the frequency of B. microti infected ticks. To identify the ecological variables that would increase the probability of B. microti establishment in the field, we integrated our laboratory data with field data on tick burden and feeding activity in an R0 model. Our model predicts that high prevalence of B. burgdorferi infected mice lowers the ecological threshold for B. microti establishment, especially at sites where larval burden on P. leucopus is lower and where larvae feed simultaneously or soon after nymphs infect mice, when most of the transmission enhancement due to coinfection occurs. Our studies suggest that B. burgdorferi contributes to the emergence and expansion of B. microti and provides a model to predict the ecological factors that are sufficient for emergence of B. microti in the wild.
Significance The spliceosome—the molecular particle responsible for removing interrupting sequences from eukaryotic messenger RNA—is one of the most complex cellular machines. Consisting of five ...snRNAs and over 200 proteins in humans, its numerous changes in composition and shape during splicing have made it difficult to study. We have characterized an algal spliceosome that is much smaller, with only 43 identifiable core proteins, the majority of which are essential for viability in other organisms. We propose that this highly reduced spliceosome has retained only the most critical splicing factors. Cyanidioschyzon merolae therefore provides a powerful system to examine the spliceosome’s catalytic core, enabling future advances in understanding the splicing mechanism and spliceosomal organization that are challenging in more complex systems.
The human spliceosome is a large ribonucleoprotein complex that catalyzes pre-mRNA splicing. It consists of five snRNAs and more than 200 proteins. Because of this complexity, much work has focused on the Saccharomyces cerevisiae spliceosome, viewed as a highly simplified system with fewer than half as many splicing factors as humans. Nevertheless, it has been difficult to ascribe a mechanistic function to individual splicing factors or even to discern which are critical for catalyzing the splicing reaction. We have identified and characterized the splicing machinery from the red alga Cyanidioschyzon merolae , which has been reported to harbor only 26 intron-containing genes. The U2, U4, U5, and U6 snRNAs contain expected conserved sequences and have the ability to adopt secondary structures and form intermolecular base-pairing interactions, as in other organisms. C . merolae has a highly reduced set of 43 identifiable core splicing proteins, compared with ∼90 in budding yeast and ∼140 in humans. Strikingly, we have been unable to find a U1 snRNA candidate or any predicted U1-associated proteins, suggesting that splicing in C . merolae may occur without the U1 small nuclear ribonucleoprotein particle. In addition, based on mapping the identified proteins onto the known splicing cycle, we propose that there is far less compositional variability during splicing in C . merolae than in other organisms. The observed reduction in splicing factors is consistent with the elimination of spliceosomal components that play a peripheral or modulatory role in splicing, presumably retaining those with a more central role in organization and catalysis.
PDF
