Neurosyphilis: Old Disease, New Implications for Emergency Physicians

Recent epidemiologic data demonstrate increasing rates of neurosyphilis, particularly among those in the community of men who have sex with men and those coinfected with the human immunodeficiency virus (HIV). Here we discuss a case of early neurosyphilis and new HIV diagnosis in a 27-year-old previously-healthy trans woman presenting for the second time with progressive, ascending weakness and cranial nerve VI palsy. Emergency physicians should consider this rare but highly morbid diagnosis, given the rising prevalence of neurosyphilis among at-risk patients and those with new neurologic deficits

Male differentiation patterns in two polyphenic sister species of the genus Onthophagus Latreille, 1802 (Coleoptera: Scarabaeidae): a geometric morphometric approach

This paper focuses on morphological (both shape and size) differences that quite similar polyphenic sister species evolve during divergence processes. Traits were analysed using a geometrical morphometric approach, which has the ability to evidence also very subtle differences in shape. As a case study, we considered males of the dung beetle sister species pair Onthophagus taurus and Onthophagus illyricus (Coleoptera, Scarabaeidae); these species represent a typical example of polyphenic trait expression concerning the facultative development of horns and considerable body size differences. External shape morphology failed to discriminate O. taurus from O. illyricus, whereas the reproductive system shape showed significant interspecific discrimination power. However, the head of O. taurus was significantly larger than that of O. illyricus and the reverse was true for the elytra. The two species also showed different allometric values of the head with respect to body size. This complex pattern of interspecific morphological divergence is discussed in the light of the differential trait divergence rate hypothesis. In both species, differences between major and minor forms concern the overall shape of head and pronotum: we suggest that such different forms, which likely reflect morphological readjustment to accommodate horns of considerable bulk and disproportionate length, may be nevertheless advantageously used by the two male morphs in their alternative reproductive tactics. Male genitalia sizes were virtually constant with respect to body size; however, the ratio between phallotheca and body size was significantly higher in minor males, in keeping with the hypothesis of a higher investment in genitalia borne by this morph. Resume Cet article porte sur les differences morphologiques (au niveau de la forme et de la taille) que deux especes voisines polypheniques ont evolue au cours des processus de divergence. L'etude utilise les methodes de la morphometrie geometrique, ayant la capacite de mettre en evidence des differences subtiles entre les formes. Comme modele d'etude nous avons considere les males de deux especes voisines de coleopteres, Onthophagus taurus et Onthophagus illyricus (Coleoptera, Scarabaeidae), qui representent un exemple typique d'expression polyphenique des traits morphologiques concernant des differences importantes de la taille du corps et le developpement facultatif des cornes. L'analyse a mis en evidence que la forme des traits de la morphologie externe ne permette pas de distinguer O. taurus par rapport aO. illyricus, alors que la forme des structures genitales masculines montre un signifiant pouvoir de discrimination interspecifique. Cependant, la tete de O. taurus a une taille plus grande par rapport aO. illyricus, et l'inverse est vrai pour la taille des elytres. Les deux especes montrent aussi une difference au niveau des valeurs allometriques de la taille de la tete respect a la taille du corps. Ce complexe pattern de differences morphologiques interspecifiques est discute sous l'hypothese d'un taux de divergence et d'evolution differentiele entre traits morphologiques differentes. Dans chaque espece, les differences entre les males minor et major concernent la forme generale de la tete et du pronotum: on suggere que ces differences de forme, qui refletent probablement des changements morphologiques necessaires a accommoder des cornes d'un poids considerable et d'une longueur disproportionnee, sont, peut-etre, cependant avantageuses dans les differentes strategies reproductives utilisees par le deux morphes. La taille de la phallotheca est resultee virtuellement constant respect a la taille du corps; cependant, les resultats de la standardisation entre la taille de la phallotheca et la taille du corps sont significativement plus hauts dans les mâles minor, en accord avec l'hypothese d'un plus important investissement dans le systeme reproductif soutenu par cette morphe

Seeded x-ray free-electron laser generating radiation with laser statistical properties

The invention of optical lasers led to a revolution in the field of optics and even to the creation of completely new fields of research such as quantum optics. The reason was their unique statistical and coherence properties. The newly emerging, short-wavelength free-electron lasers (FELs) are sources of very bright coherent extreme-ultraviolet (XUV) and x-ray radiation with pulse durations on the order of femtoseconds, and are presently considered to be laser sources at these energies. Most existing FELs are highly spatially coherent but in spite of their name, they behave statistically as chaotic sources. Here, we demonstrate experimentally, by combining Hanbury Brown and Twiss (HBT) interferometry with spectral measurements that the seeded XUV FERMI FEL-2 source does indeed behave statistically as a laser. The first steps have been taken towards exploiting the first-order coherence of FELs, and the present work opens the way to quantum optics experiments that strongly rely on high-order statistical properties of the radiation.Comment: 24 pages, 10 figures, 37 reference

Novel Pyridine-Based Hydroxamates and 2'-Aminoanilides as Histone Deacetylase Inhibitors: Biochemical Profile and Anticancer Activity

Starting from the N-hydroxy-3-(4-(2-phenylbutanoyl)amino)phenyl)acrylamide 5b previously described by us as HDAC inhibitor, we prepared four aza-analogues of 5b (6-8, 9b) as regioisomers containing the pyridine nucleus. A preliminary screening against mHDAC1 highlighted the N-hydroxy-5-(2-(2-phenylbutanoyl)amino)pyridyl)acrylamide 9b as the most potent inhibitor. Thus, we further developed both pyridylacrylic- and nicotinic-based hydroxamates (9a, 9c-f, and 11a-f) and 2'-aminoanilides (10a-f and 12a-f), related to 9b, to be tested against HDACs. Among them, the nicotinic hydroxamate 11d displayed subnanomolar potency (IC50: 0.5 nM) and selectivity up to 34000-fold over HDAC4 and from 100- to 1300-fold over all the other tested HDAC isoforms. The 2'-aminoanilides were class I-selective HDAC inhibitors, generally more potent against HDAC3, with the nicotinic anilide 12d being the most effective (IC50HDAC3 = 0.113 μM). When tested in U937 leukemia cells, the hydroxamates 9e, 11c, and 11d blocked over 80% cells in G2/M phase, whereas the anilides did not alter the cell cycle progress. In the same cell line, the hydroxamate 11c and the anilide 10b induced about 30% apoptosis, and the anilide 12c displayed about 40% cytodifferentiation. Finally, the most potent compounds in leukemia cells 9b, 11c, 10b, 10e, and 12c were also tested in K562, HCT116, and A549 cancer cells, displaying antiproliferative IC50 values at single-digit to sub-micromolar level

Kinome-Wide Functional Genomics Screen Reveals a Novel Mechanism of TNFα-Induced Nuclear Accumulation of the HIF-1α Transcription Factor in Cancer Cells

Hypoxia-inducible factor-1 (HIF-1) and its most important subunit, HIF-1α, plays a central role in tumor progression by regulating genes involved in cancer cell survival, proliferation and metastasis. HIF-1α activity is associated with nuclear accumulation of the transcription factor and regulated by several mechanisms including modulation of protein stability and degradation. Among recent advances are the discoveries that inflammation-induced cytokines and growth factors affect protein accumulation of HIF-1α under normoxia conditions. TNFα, a major pro-inflammatory cytokine that promotes tumorigenesis is known as a stimulator of HIF-1α activity. To improve our understanding of TNFα-mediated regulation of HIF-1α nuclear accumulation we screened a kinase-specific siRNA library using a cell imaging–based HIF-1α-eGFP chimera reporter assay. Interestingly, this systematic analysis determined that depletion of kinases involved in conventional TNFα signaling (IKK/NFκB and JNK pathways) has no detrimental effect on HIF-1α accumulation. On the other hand, depletion of PRKAR2B, ADCK2, TRPM7, and TRIB2 significantly decreases the effect of TNFα on HIF-1α stability in osteosarcoma and prostate cancer cell lines. These newly discovered regulators conveyed their activity through a non-conventional RELB-depended NFκB signaling pathway and regulation of superoxide activity. Taken together our data allow us to conclude that TNFα uses a distinct and complex signaling mechanism to induce accumulation of HIF-1α in cancer cells. In summary, our results illuminate a novel mechanism through which cancer initiation and progression may be promoted by inflammatory cytokines, highlighting new potential avenues for fighting this disease

New Indole Tubulin Assembly Inhibitors Cause Stable Arrest of Mitotic Progression, Enhanced Stimulation of Natural Killer Cell Cytotoxic Activity, and Repression of Hedgehog-Dependent Cancer

We designed 39 new 2-phenylindole derivatives as potential anticancer agents bearing the 3,4,5-trimethoxyphenyl moiety with a sulfur, ketone, or methylene bridging group at position 3 of the indole and with halogen or methoxy substituent(s) at positions 4-7. Compounds 33 and 44 strongly inhibited the growth of the P-glycoprotein-overexpressing multi-drug-resistant cell lines NCI/ADR-RES and Messa/Dx5. At 10 nM, 33 and 44 stimulated the cytotoxic activity of NK cells. At 20-50 nM, 33 and 44 arrested >80% of HeLa cells in the G2/M phase of the cell cycle, with stable arrest of mitotic progression. Cell cycle arrest was followed by cell death. Indoles 33, 44, and 81 showed strong inhibition of the SAG-induced Hedgehog signaling activation in NIH3T3 Shh-Light II cells with IC50 values of 19, 72, and 38 nM, respectively. Compounds of this class potently inhibited tubulin polymerization and cancer cell growth, including stimulation of natural killer cell cytotoxic activity and repression of Hedgehog-dependent cancer

Toward highly potent cancer agents by modulating the c-2 group of the arylthioindole class of tubulin polymerization inhibitors

New arylthioindole derivatives having different cyclic substituents at position 2 of the indole were synthesized as anticancer agents. Several compounds inhibited tubulin polymerization at submicromolar concentration and inhibited cell growth at low nanomolar concentrations. Compounds 18 and 57 were superior to the previously synthesized 5. Compound 18 was exceptionally potent as an inhibitor of cell growth: it showed IC50 = 1.0 nM in MCF-7 cells, and it was uniformly active in the whole panel of cancer cells and superior to colchicine and combretastatin A-4. Compounds 18, 20, 55, and 57 were notably more potent than vinorelbine, vinblastine, and paclitaxel in the NCI/ADR-RES and Messa/Dx5 cell lines, which overexpress P-glycoprotein. Compounds 18 and 57 showed initial vascular disrupting effects in a tumor model of liver rhabdomyosarcomas at 15 mg/kg intravenous dosage. Derivative 18 showed water solubility and higher metabolic stability than 5 in human liver microsomes

The wide-field, multiplexed, spectroscopic facility WEAVE : survey design, overview, and simulated implementation

Funding for the WEAVE facility has been provided by UKRI STFC, the University of Oxford, NOVA, NWO, Instituto de Astrofísica de Canarias (IAC), the Isaac Newton Group partners (STFC, NWO, and Spain, led by the IAC), INAF, CNRS-INSU, the Observatoire de Paris, Région Île-de-France, CONCYT through INAOE, Konkoly Observatory (CSFK), Max-Planck-Institut für Astronomie (MPIA Heidelberg), Lund University, the Leibniz Institute for Astrophysics Potsdam (AIP), the Swedish Research Council, the European Commission, and the University of Pennsylvania.WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, will see first light in late 2022. WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366-959 nm at R ∼ 5000, or two shorter ranges at R ∼ 20,000. After summarising the design and implementation of WEAVE and its data systems, we present the organisation, science drivers and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for ∼ 3 million stars and detailed abundances for ∼ 1.5 million brighter field and open-cluster stars; (ii) survey ∼ 0.4 million Galactic-plane OBA stars, young stellar objects and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey  ∼ 400 neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionised gas in z 1 million spectra of LOFAR-selected radio sources; (viii) trace structures using intergalactic/circumgalactic gas at z > 2. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator.PostprintPeer reviewe

The wide-field, multiplexed, spectroscopic facility WEAVE: Survey design, overview, and simulated implementation

WEAVE, the new wide-field, massively multiplexed spectroscopic survey facility for the William Herschel Telescope, will see first light in late 2022. WEAVE comprises a new 2-degree field-of-view prime-focus corrector system, a nearly 1000-multiplex fibre positioner, 20 individually deployable 'mini' integral field units (IFUs), and a single large IFU. These fibre systems feed a dual-beam spectrograph covering the wavelength range 366$-$959\,nm at $R\sim5000$, or two shorter ranges at $R\sim20\,000$. After summarising the design and implementation of WEAVE and its data systems, we present the organisation, science drivers and design of a five- to seven-year programme of eight individual surveys to: (i) study our Galaxy's origins by completing Gaia's phase-space information, providing metallicities to its limiting magnitude for $\sim$3 million stars and detailed abundances for $\sim1.5$ million brighter field and open-cluster stars; (ii) survey $\sim0.4$ million Galactic-plane OBA stars, young stellar objects and nearby gas to understand the evolution of young stars and their environments; (iii) perform an extensive spectral survey of white dwarfs; (iv) survey $\sim400$ neutral-hydrogen-selected galaxies with the IFUs; (v) study properties and kinematics of stellar populations and ionised gas in $z<0.5$ cluster galaxies; (vi) survey stellar populations and kinematics in $\sim25\,000$ field galaxies at $0.3\lesssim z \lesssim 0.7$; (vii) study the cosmic evolution of accretion and star formation using $>1$ million spectra of LOFAR-selected radio sources; (viii) trace structures using intergalactic/circumgalactic gas at $z>2$. Finally, we describe the WEAVE Operational Rehearsals using the WEAVE Simulator.Comment: 41 pages, 27 figures, accepted for publication by MNRA