Erectile dysfunction (ED) is important to a man's well-being and health, since it not only affects the individual but also causes strain on a couple's lifestyle and relationship. There are multiple ...non-invasive treatments that exist for ED including lifestyle changes, oral medications (phosphodiesterase type 5 inhibitors), vacuum-assisted erectile devices, and intraurethral suppositories. While lifestyle changes and oral medications are typically first-line treatments for ED, more-invasive treatments including intracavernosal injections and surgically implanted prosthetic devices may be required for the management of complex cases. Additionally, novel therapies are currently being developed, and future treatment options may include shock-wave therapy, external prosthetic devices, and injection of stem cells or platelet-rich plasma. The current manuscript seeks to highlight advances in management and may eventually alter the treatment paradigm to allow more-inclusive care pathways.
We demonstrate the tunable enhancement of the zero phonon line of a single nitrogen-vacancy colour centre in diamond at cryogenic temperature. An open cavity fabricated using focused ion beam milling ...provides mode volumes as small as 1.24 m3 (4.7 ) and quality factor In situ tuning of the cavity resonance is achieved with piezoelectric actuators. At optimal coupling to a TEM00 cavity mode, the signal from individual zero phonon line transitions is enhanced by a factor of 6.25 and the overall emission rate of the NV− centre is increased by 40% compared with that measured from the same centre in the absence of cavity field confinement. This result represents a step forward in the realisation of efficient spin-photon interfaces and scalable quantum computing using optically addressable solid state spin qubits.
The most effective timing for renal-replacement therapy in critically ill patients is unclear. In this randomized trial, patients with acute kidney injury who were assigned to an accelerated strategy ...did not have a lower risk of death at 90 days than those assigned to a standard strategy.
Background. Reston ebolavirus was recently detected in pigs in the Philippines. Specific antibodies were found in pig farmers, indicating exposure to the virus. This important observation raises the ...possibility that pigs may be susceptible to Ebola virus infection, including from other species, such as Zaire ebolavirus (ZEBOV), and can transmit to other susceptible hosts. Methods. This study investigated whether ZEBOV, a species commonly reemerging in central Africa, can replicate and induce disease in pigs and can be transmitted to naive animals. Domesticated Landrace pigs were challenged through mucosal exposure with a total of 1 X10⁶ plaque-forming units of ZEBOV and monitored for virus replication, shedding, and pathogenesis. Using similar conditions, virus transmission from infected to naive animals was evaluated in a second set of pigs. Results. Following mucosal exposure, pigs replicated ZEBOV to high titers (reaching 10⁷ median tissue culture infective doses/mL), mainly in the respiratory tract, and developed severe lung pathology. Shedding from the oronasal mucosa was detected for up to 14 days after infection, and transmission was confirmed in all naive pigs cohabiting with inoculated animals. Conclusions. These results shed light on the susceptibility of pigs to ZEBOV infection and identify an unexpected site of virus amplification and shedding linked to transmission of infectious virus.
Many bacterial histidine kinases work in two-component systems that combine into larger multi-kinase networks. NahK is one of the kinases in the GacS Multi-Kinase Network (MKN), which is the MKN that ...controls biofilm regulation in the opportunistic pathogen
. This network has also been associated with regulating many virulence factors
secretes to cause disease. However, the individual role of each kinase is unknown. In this study, we identify NahK as a novel regulator of the phenazine pyocyanin (PYO). Deletion of
leads to a fourfold increase in PYO production, almost exclusively through upregulation of phenazine operon two (
). We determined that this upregulation is due to mis-regulation of all
quorum-sensing (QS) systems, with a large upregulation of the
quinolone signal system and a decrease in production of the acyl-homoserine lactone-producing system,
. In addition, we see differences in expression of quorum-sensing inhibitor proteins that align with these changes. Together, these data contribute to understanding how the GacS MKN modulates QS and virulence and suggest a mechanism for cell density-independent regulation of quorum sensing. IMPORTANCE
is a Gram-negative bacterium that establishes biofilms as part of its pathogenicity.
infections are associated with nosocomial infections. As the prevalence of multi-drug-resistant
increases, it is essential to understand underlying virulence molecular mechanisms. Histidine kinase NahK is one of several kinases in
implicated in biofilm formation and dispersal. Previous work has shown that the nitric oxide sensor, NosP, triggers biofilm dispersal by inhibiting NahK. The data presented here demonstrate that NahK plays additional important roles in the
lifestyle, including regulating bacterial communication mechanisms such as quorum sensing. These effects have larger implications in infection as they affect toxin production and virulence.
The genetic, biologic, and clinical heterogeneity of sarcomas poses a challenge for the identification of therapeutic targets, clinical research, and advancing patient care. Because there are > 100 ...sarcoma subtypes, in-depth genetic studies have focused on one or a few subtypes. Herein, we report a comparative genetic analysis of 2,138 sarcomas representing 45 pathological entities. This cohort is prospectively analyzed using targeted sequencing to characterize subtype-specific somatic alterations in targetable pathways, rates of whole genome doubling, mutational signatures, and subtype-agnostic genomic clusters. The most common alterations are in cell cycle control and TP53, receptor tyrosine kinases/PI3K/RAS, and epigenetic regulators. Subtype-specific associations include TERT amplification in intimal sarcoma and SWI/SNF alterations in uterine adenosarcoma. Tumor mutational burden, while low compared to other cancers, varies between and within subtypes. This resource will improve sarcoma models, motivate studies of subtype-specific alterations, and inform investigations of genetic factors and their correlations with treatment response.
Numerous insect species undertake regular seasonal migrations in order to exploit temporary breeding habitats
1. These migrations are often achieved by high-altitude windborne movement at night
2–6, ...facilitating rapid long-distance transport, but seemingly at the cost of frequent displacement in highly disadvantageous directions (the so-called “pied piper” phenomenon
7). This has lead to uncertainty about the mechanisms migrant insects use to control their migratory directions
8, 9. Here we show that, far from being at the mercy of the wind, nocturnal moths have unexpectedly complex behavioral mechanisms that guide their migratory flight paths in seasonally-favorable directions. Using entomological radar, we demonstrate that free-flying individuals of the migratory noctuid moth
Autographa gamma actively select fast, high-altitude airstreams moving in a direction that is highly beneficial for their autumn migration. They also exhibit common orientation close to the downwind direction, thus maximizing the rectilinear distance traveled. Most unexpectedly, we find that when winds are not closely aligned with the moth's preferred heading (toward the SSW), they compensate for cross-wind drift, thus increasing the probability of reaching their overwintering range. We conclude that nocturnally migrating moths use a compass and an inherited preferred direction to optimize their migratory track.
It has been postulated that the G protein-coupled receptor, GPR55, is a third cannabinoid receptor. Given that the ligands at the CB
1 and CB
2 receptors are effective analgesic and anti-inflammatory ...agents, the role of GPR55 in hyperalgesia associated with inflammatory and neuropathic pain has been investigated. As there are no well-validated GPR55 tool compounds, a GPR55 knockout (GPR55
−/−) mouse line was generated and fully backcrossed onto the C57BL/6 strain. General phenotypic analysis of GPR55
−/− mice revealed no obvious primary differences, compared with wild-type (GPR55
+/+) littermates. GPR55
−/− mice were then tested in the models of adjuvant-induced inflammation and partial nerve ligation. Following intraplantar administration of Freund’s complete adjuvant (FCA), inflammatory mechanical hyperalgesia was completely absent in GPR55
−/− mice up to 14 days post-injection. Cytokine profiling experiments showed that at 14 days post-FCA injection there were increased levels of IL-4, IL-10, IFNγ and GM-CSF in paws from the FCA-injected GPR55
−/− mice when compared with the FCA-injected GPR55
+/+ mice. This suggests that GPR55 signalling can influence the regulation of certain cytokines and this may contribute to the lack of inflammatory mechanical hyperalgesia in the GPR55
−/− mice. In the model of neuropathic hypersensitivity, GPR55
−/− mice also failed to develop mechanical hyperalgesia up to 28 days post-ligation. These data clearly suggest that the manipulation of GPR55 may have therapeutic potential in the treatment of both inflammatory and neuropathic pain.
Sangivamycin (S) is an adenosine (A) nucleoside analog with low nanomolar antiviral activity against SARS-CoV-2 in vitro. Previously, low nanomolar antiviral efficacy was revealed when tested against ...multiple viral variants in several cell types. SARS-CoV-2 RNA isolated from live virus infected cells and the virions released from these cells was analyzed by mass spectrometry (MS) for S incorporation. Dose-dependent incorporation occurred up to 1.8 S per 1,000 nucleotides (49 S per genome) throughout the viral genomes isolated from both infected cells and viral particles, but this incorporation did not change the viral mutation rate. In contrast, host mRNA, affinity purified from the same infected and treated cells, contained little or no S. Sangivamycin triphosphate (STP) was synthesized to evaluate its incorporation into RNA by recombinant SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) under defined in vitro conditions. SARS-CoV-2 RdRp showed that S was not a chain terminator and S containing oligonucleotides templated as A. Though the antiviral mechanism remains to be determined, the data suggests that SARS-CoV-2 RdRp incorporates STP into SARS-CoV-2 RNA, which does not significantly impair viral RNA synthesis or the mutation rate.
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•Sangivamycin is an antiviral nucleoside analog preferentially incorporated into SARS-CoV-2 RNA by the viral polymerase.•Sangivamycin templates as an A and is not a chain terminator or a viral mutator.•Viral genomes containing sangivamycin are packaged into virions.
Despite more than 30 years of searching, the compact object in Supernova (SN) 1987A has not yet been detected. We present new limits on the compact object in SN 1987A using millimeter, near-infrared, ...optical, ultraviolet, and X-ray observations from ALMA, VLT, HST, and Chandra. The limits are approximately 0.1 mJy ( erg s−1 cm−2 Hz−1) at 213 GHz, 1 L ( erg s−1 cm−2 Hz−1) in the optical if our line of sight is free of ejecta dust, and 1036 erg s−1 ( erg s−1 cm−2 Hz−1) in 2-10 keV X-rays. Our X-ray limits are an order of magnitude less constraining than previous limits because we use a more realistic ejecta absorption model based on three-dimensional neutrino-driven SN explosion models. The allowed bolometric luminosity of the compact object is 22 L if our line of sight is free of ejecta dust, or 138 L if dust-obscured. Depending on assumptions, these values limit the effective temperature of a neutron star (NS) to -8 MK and do not exclude models, which typically are in the range 3-4 MK. For the simplest accretion model, the accretion rate for an efficiency is limited to M yr−1, which excludes most predictions. For pulsar activity modeled by a rotating magnetic dipole in vacuum, the limit on the magnetic field strength (B) for a given spin period (P) is G s−2, which firmly excludes pulsars comparable to the Crab. By combining information about radiation reprocessing and geometry, we infer that the compact object is a dust-obscured thermally emitting NS, which may appear as a region of higher-temperature ejecta dust emission.
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