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A colony of the rare hydrozoan siphonophore Lilyopsis Chun, 1885, was observed for the first time in shallow water in False Bay, South Africa, swimming amongst kelp. A study of a high-quality image of this individual found it to share some characters with the prayine prayid L. fluoracantha Haddock, Dunn & Pugh, 2005, so far known only from Monterey Bay, California, in the eastern Pacific. No Lilyopsis species has previously been reliably identified from either the South Atlantic or the Indian Ocean, so this record represents an expansion of the known worldwide distribution for this genus.

Supplemental Methods

Supplemental Figure 1. Representative example from one patient showing the rash that was most frequently observed with ensartinib. The white arrow in the top figure points to the rash that is circled in the bottom figure.

The mean concentration of ensartinib in plasma and skin at multiple time points after a single dose of 50 mg/kg is listed in Supplemental Table 2. At 12 hours post-dose, the concentration of ensartinib was 9.0 higher in the skin than in the plasma.

Ensartinib was tested against wild-type ALK and 17 ALK variants in the Reaction Biology panel. Ensartinib potently inhibited all evaluated ALK variants, with in vitro IC50s

The key pharmacokinetic (PK) parameters (Supplemental Table 3) at the recommended phase 2 dose of 225 mg show that food has minimal impact on absorption of ensartinib.

Supplemental Figure 2. Arithmetic mean concentration-time curves for fasted patients receiving 225 mg of ensartinib on Days 1 and 22 of Cycle 1.

Supplemental Figure 3. Best percentage change from baseline in sum of target lesions is presented for the ALK-positive evaluable patients at 200 mg who had received prior crizotinib and as second-generation ALK TKI. Dashed lines indicate RECIST v1.1 cut-offs for partial response and progressive disease. Of the 16 patients, four had partial responses and four had stable disease. The color scheme represents which second-generation ALK TKI that patient received after crizotinib. Of note, the primary lesion of one of the 16 patients was too small, and thus indeterminate, at the post-baseline assessment, therefore a change in tumor size is not available. This patient had received, in order, prior crizotinib, alectinib, and ceritinib, and developed progression on ensartinib in a non-target brain lesion prior to cycle 3. *Denotes those patients with progressive disease as the best response. >Denotes patients still on study at the time of data cutoff.

Purpose: Evaluate safety and determine the recommended phase II dose (RP2D) of ensartinib (X-396), a potent anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI), and evaluate preliminary pharmacokinetics and antitumor activity in a first-in-human, phase I/II clinical trial primarily in patients with non–small cell lung cancer (NSCLC).Patients and Methods: In dose escalation, ensartinib was administered at doses of 25 to 250 mg once daily in patients with advanced solid tumors; in dose expansion, patients with advanced ALK-positive NSCLC were administered 225 mg once daily. Patients who had received prior ALK TKI(s) and patients with brain metastases were eligible.Results: Thirty-seven patients enrolled in dose escalation, and 60 enrolled in dose expansion. The most common treatment-related toxicities were rash (56%), nausea (36%), pruritus (28%), vomiting (26%), and fatigue (22%); 23% of patients experienced a treatment-related grade 3 to 4 toxicity (primarily rash and pruritus). The maximum tolerated dose was not reached, but the RP2D was chosen as 225 mg based on the frequency of rash observed at 250 mg without improvement in activity. Among the ALK-positive efficacy evaluable patients treated at ≥200 mg, the response rate (RR) was 60%, and median progression-free survival (PFS) was 9.2 months. RR in ALK TKI-naïve patients was 80%, and median PFS was 26.2 months. In patients with prior crizotinib only, the RR was 69% and median PFS was 9.0 months. Responses were also observed in the central nervous system, with an intracranial RR of 64%.Conclusions: Ensartinib was active and generally well tolerated in patients with ALK-positive NSCLC. Clin Cancer Res; 24(12); 2771–9. ©2018 AACR.

5-Chloro-6-[2,6-difluoro-4-[3-(methylamino)propoxy]phenyl]-N-[(1S)-2,2,2-trifluoro-1-methylethyl]-[1,2,4]triazolo[1,5-a]pyrimidin-7-amine butanedioate (TTI-237) is a microtubule-active compound of novel structure and function. Structurally, it is one of a class of compounds, triazolo[1,5a]pyrimidines, previously not known to bind to tubulin. Functionally, TTI-237 inhibited the binding of [3H]vinblastine to tubulin, but it caused a marked increase in turbidity development that more closely resembled the effect observed with docetaxel than that observed with vincristine. The morphologic character of the presumptive polymer is unknown at present. When applied to cultured human tumor cells at concentrations near its IC50 value for cytotoxicity (34 nmol/L), TTI-237 induced multiple spindle poles and multinuclear cells, as did paclitaxel, but not vincristine or colchicine. Flow cytometry experiments revealed that, at low concentrations (20–40 nmol/L), TTI-237 produced sub-G1 nuclei and, at concentrations above 50 nmol/L, it caused a strong G2-M block. The compound was a weak substrate of multidrug resistance 1 (multidrug resistance transporter or P-glycoprotein). In a cell line expressing a high level of P-glycoprotein, the IC50 of TTI-237 increased 25-fold whereas those of paclitaxel and vincristine increased 806-fold and 925-fold, respectively. TTI-237 was not recognized by the MRP or MXR transporters. TTI-237 was active in vivo in several nude mouse xenograft models of human cancer, including LoVo human colon carcinoma and U87-MG human glioblastoma, when dosed i.v. or p.o. Thus, TTI-237 has a set of properties that distinguish it from other classes of microtubule-active compounds. [Cancer Res 2008;68(7):2292–300]

Supplementary Table 1, Figures 1-2 from A New Pharmacologic Action of CCI-779 Involves FKBP12-Independent Inhibition of mTOR Kinase Activity and Profound Repression of Global Protein Synthesis

Supplementary Tables 1-5, Figures 1-5 from TTI-237: A Novel Microtubule-Active Compound with In vivo Antitumor Activity

The mammalian target of rapamycin (mTOR) inhibitor CCI-779 (temsirolimus) is a recently Food and Drug Administration–approved anticancer drug with efficacy in certain solid tumors and hematologic malignancies. In cell culture studies, CCI-779 at the commonly used nanomolar concentrations generally confers a modest and selective antiproliferative activity. Here, we report that, at clinically relevant low micromolar concentrations, CCI-779 completely suppressed proliferation of a broad panel of tumor cells. This “high-dose” drug effect did not require FKBP12 and correlated with an FKBP12-independent suppression of mTOR signaling. An FKBP12-rapamycin binding domain (FRB) binding–deficient rapamycin analogue failed to elicit both the nanomolar and micromolar inhibitions of growth and mTOR signaling, implicating FRB binding in both actions. Biochemical assays indicated that CCI-779 and rapamycin directly inhibited mTOR kinase activity with IC50 values of 1.76 ± 0.15 and 1.74 ± 0.34 μmol/L, respectively. Interestingly, a CCI-779–resistant mTOR mutant (mTOR-SI) displayed an 11-fold resistance to the micromolar CCI-779 in vitro (IC50, 20 ± 3.4 μmol/L) and conferred a partial protection in cells exposed to micromolar CCI-779. Treatment of cancer cells with micromolar but not nanomolar concentrations of CCI-779 caused a marked decline in global protein synthesis and disassembly of polyribosomes. The profound inhibition of protein synthesis was accompanied by rapid increase in the phosphorylation of translation elongation factor eEF2 and the translation initiation factor eIF2α. These findings suggest that high-dose CCI-779 inhibits mTOR signaling through an FKBP12-independent mechanism that leads to profound translational repression. This distinctive high-dose drug effect could be directly related to the antitumor activities of CCI-779 and other rapalogues in human cancer patients. [Cancer Res 2008;68(8):2934–43]

Supplementary Table 1, Figures 1-2 Legends from A New Pharmacologic Action of CCI-779 Involves FKBP12-Independent Inhibition of mTOR Kinase Activity and Profound Repression of Global Protein Synthesis

Supplementary Methods, Figures 1-2, Tables 1-2 from Biochemical, Cellular, and In vivo Activity of Novel ATP-Competitive and Selective Inhibitors of the Mammalian Target of Rapamycin

Purpose The purpose of this study is to demonstrate and characterise a soft-tooled micro-injection moulding process through in-line measurements and surface metrology using a data-intensive approach. Design/methodology/approach A soft tool for a demonstrator product that mimics the main features of miniature components in medical devices and microsystem components has been designed and fabricated using material jetting technique. The soft tool was then integrated into a mould assembly on the micro-injection moulding machine, and mouldings were made. Sensor and data acquisition devices including thermal imaging and injection pressure sensing have been set up to collect data for each of the prototypes. Off-line dimensional characterisation of the parts and the soft tool have also been carried out to quantify the prototype quality and dimensional changes on the soft tool after the manufacturing cycles. Findings The data collection and analysis methods presented here enable the evaluation of the quality of the moulded parts in real-time from in-line measurements. Importantly, it is demonstrated that soft-tool surface temperature difference values can be used as reliable indicators for moulding quality. Reduction in the total volume of the soft-tool moulding cavity was detected and quantified up to 100 cycles. Data collected from in-line monitoring was also used for filling assessment of the soft-tool moulding cavity, providing about 90% accuracy in filling prediction with relatively modest sensors and monitoring technologies. Originality/value This work presents a data-intensive approach for the characterisation of soft-tooled micro-injection moulding processes for the first time. The overall results of this study show that the product-focussed data-rich approach presented here proved to be an essential and useful way of exploiting additive manufacturing technologies for soft-tooled rapid prototyping and new product introduction.

Telomere maintenance is a hallmark of malignant cells and allows cancers to divide indefinitely. In some cancers, this is achieved through the alternative lengthening of telomeres (ALT) pathway. Whilst loss of ATRX is a near universal feature of ALT-cancers, it is insufficient in isolation. As such, other cellular events must be necessary - but the exact nature of the secondary events has remained elusive. Here, we report that trapping of proteins (such as TOP1, TOP2A and PARP1) on DNA leads to ALT induction in cells lacking ATRX. We demonstrate that protein-trapping chemotherapeutic agents, such as etoposide, camptothecin and talazoparib, induce ALT markers specifically in ATRX-null cells. Further, we show that treatment with G4-stabilising drugs cause an increase in trapped TOP2A levels which leads to ALT induction in ATRX-null cells. This process is MUS81-endonuclease and break-induced replication dependent, suggesting that protein trapping leads to replication fork stalling, with these forks being aberrantly processed in the absence of ATRX. Finally, we show ALT-positive cells harbour a higher load of genome-wide trapped proteins, such as TOP1, and knockdown of TOP1 reduced ALT activity. Taken together, these findings suggest that protein trapping is a fundamental driving force behind ALT-biology in ATRX-deficient malignancies.

The permanent seismic stations of the European Arctic maintain a detection threshold of around magnitude 2 for events on and around Novaya Zemlya. Events above magnitude 3 are clearly observed by multiple stations at regional and far-regional distances and, with improved travel-time models, can be located with high accuracy. The monitoring capability for smaller magnitude events is dominated by the small aperture seismic arrays ARCES and SPITS. We review the properties of Novaya Zemlya seismic signals on key stations and discuss how empirical signal processing may enhance detection and interpretation of future events in the region. We present a joint probabilistic location for 21 low-magnitude events between 1986 and 2020 in which the joint probability distribution for all events simultaneously exploits both constraints on earlier events from stations no longer in operation and constraints on newer events from more recently deployed stations. Advances in signal processing, enhanced exploitation of archive data, new permanent stations, and comparative multiple event analysis will all contribute both to a more robust and sensitive detection capability and higher confidence in signal interpretation.

SUMMARY A low-magnitude earthquake was recorded on 2017 January 18, in the Ténéré desert in northern Niger. This intraplate region is exceptionally sparsely covered with seismic stations and the closest open seismic station, G.TAM in Algeria at a distance of approximately 600 km, was unusually and unfortunately not operational at the time of the event. Body-wave magnitude estimates range from mb 4.2 to mb 4.7 and both seismic location and magnitude constraints are dominated by stations at teleseismic distances. The seismic constraints are strengthened considerably by array stations of the International Monitoring System for verifying compliance with the Comprehensive Nuclear Test-Ban-Treaty. This event, with magnitude relevant to low-yield nuclear tests, provides a valuable validation of the detection and location procedure for small land-based seismic disturbances at significant distances. For seismologists not in the CTBT system, the event is problematic as data from many of the key stations are not openly available. We examine the uncertainty in published routinely determined epicentres by performing multiple Bayesloc location estimates with published arrival times considering both all published arrival times and those from open stations only. This location exercise confirms lateral uncertainties in seismologically derived location no smaller than 10 km. Coherence for interferometric synthetic aperture radar in this region is exceptionally high, and allows us to confidently detect a displacement of the order 6 mm in the time frame containing the earthquake, consistent with the seismic location estimates, and with a lateral length scale consistent with an earthquake of this size, allowing location constraint to within one rupture length (≤5 km)—significantly reducing the lateral uncertainty compared with relying on seismological data only. Combining Open Access-only seismological and geodetic data, we precisely constrain the source location, and conclude that this earthquake likely had a shallow source. We then discuss potential ways to continue the integration of geodetic data in the calibration of seismological earthquake location.

A seismic event with mb 4.8 (Mw 4.2) was detected close to the Chinese Lop Nor nuclear test site on 27 February 2022. Waveforms recorded at regional and far regional distances in central Asia indicate greater likeness with previous earthquakes in the region than with historical nuclear tests. We investigate signal-to-noise ratio (SNR) at regional and global stations, and find the best signals in central Asia and Alaska. Lower SNR at stations in China, Europe, and Australia is likely related to the radiation pattern. A joint probabilistic location of the 2022 event and well-constrained historical nuclear tests indicates an epicenter near 41.88° N and 88.10° E, about 25 km northwest of the tunnel portion of the test site. A moment tensor inversion using high-quality regional signals indicates a nearly deviatoric source with a 72% double couple and a reverse fault mechanism. The centroid depth is 20–25 km, consistent with depth phases recorded in Alaska. The observed faulting geometry and source composition for the 2022 Lop Nor event is consistent with previous earthquakes in the region and the spatial alignment of local geomorphological features, indicating tectonic and not anthropogenic origin.

International audience; Despite concern around plastic pollution in subtropical gyres, our understanding of the biological component of the neustonic layer (upper 20 cm of the ocean) in these areas is poor. Here we investigate the neuston (excluding copepods) assemblages across the Southern Indian Subtropical Gyre using triplicate samples collected by manta-trawls from 28 stations along a transect at latitude 20 S during June/July 2015. The vertical structure of the water column at each station was assessed using a CTD. With the exception of siphonophores, all non-copepod neuston were identified to morphospecies. Assemblages were dominated by ostracods, mysids, larval chaetognaths and siphonophores. The majority of collected specimens comprised facultative neuston, which were more common at night than during the day. Neuston assemblages from the east were quite distinct from the balance of samples, and their distribution reflected that of the warm, low salinity water associated with the Indonesian Throughflow. Two anticyclonic eddies had been documented at the time of the survey between 70 and 85° E, and this area was associated with a distinct neuston assemblage of generally low abundance. The key environmental factors that were linked to assemblage structure were associated with longitude - salinity, fluorescence and temperature at 200 m, emphasising the interaction between Indonesian Throughflow Water and the South Equatorial Current, eddy-related process and settlement of meroplankton. The study highlights the value of using morphospecies in studies of plankton assemblages.

The EU Center of Excellence for Exascale in Solid Earth (ChEESE) develops exascale transition capabilities in the domain of Solid Earth, an area of geophysics rich in computational challenges embracing different approaches to exascale (capability, capacity, and urgent computing). The first implementation phase of the project (ChEESE-1P; 2018–2022) addressed scientific and technical computational challenges in seismology, tsunami science, volcanology, and magnetohydrodynamics, in order to understand the phenomena, anticipate the impact of natural disasters, and contribute to risk management. The project initiated the optimisation of 10 community flagship codes for the upcoming exascale systems and implemented 12 Pilot Demonstrators that combine the flagship codes with dedicated workflows in order to address the underlying capability and capacity computational challenges. Pilot Demonstrators reaching more mature Technology Readiness Levels (TRLs) were further enabled in operational service environments on critical aspects of geohazards such as long-term and short-term probabilistic hazard assessment, urgent computing, and early warning and probabilistic forecasting. Partnership and service co-design with members of the project Industry and User Board (IUB) leveraged the uptake of results across multiple research institutions, academia, industry, and public governance bodies (e.g. civil protection agencies). This article summarises the implementation strategy and the results from ChEESE-1P, outlining also the underpinning concepts and the roadmap for the on-going second project implementation phase (ChEESE-2P; 2023–2026)., Future Generation Computer Systems, 146, ISSN:0167-739X, ISSN:1872-7115

CCL20-CCR6 interactions promote colorectal cancer through direct effects on neoplastic epithelial cells and through modulating the tumor microenvironment. The mechanism of these effects on neoplastic epithelial cells is poorly understood. This study demonstrates that CCL20 induces secretion of hepatocyte growth factor (HGF) and phosphorylation of HGF’s cognate receptor c-Met in HT29 and HCT116 colorectal cancer cell lines both in concentration- and time-dependent manners. Similar to CCL20, HGF induces migration, autofeedback CCL20 secretion, and ERK1/2 phosphorylation in the colon cancer cells. CCL20-dependent ERK1/2 phosphorylation is blocked by HGF inhibition, and CCL20-dependent migration and CCL20 secretion are blocked by inhibition of HGF or ERK. Interestingly, unlike CCL20, HGF does not induce proliferation of colon cancer cells, and CCL20-dependent cell proliferation is not blocked by direct HGF inhibition. CCL20-dependent proliferation, however, is blocked by the multi-tyrosine kinase inhibitor crizotinib. Exploring this effect, it was found that CCL20 also induces production of MSP and phosphorylation of MSP’s receptor MSPR by the colorectal cancer cells. CCL20-dependent cell proliferation is inhibited by directly blocking MSP-MSPR interactions. Thus, CCL20-mediated migration and CCL20 secretion are regulated through a pathway involving HGF, c-Met, and ERK, while CCL20-mediated proliferation is instead regulated through MSP and its receptor MSPR.

Psilocybin, a drug most commonly recognized as a recreational psychedelic, is quickly gaining attention as a promising therapy for an expanding range of neurological conditions, including depression, anxiety, and addiction. This growing interest has led to many recent advancements in psilocybin synthesis strategies, including multiple in vivo fermentation-based approaches catalyzed by recombinant microorganisms. In this work, we show that psilocybin can be produced in biologically relevant quantities using a recombinant E. coli strain in a homebrew style environment. In less than 2 days, we successfully produced approximately 300 mg/L of psilocybin under simple conditions with easily sourced equipment and supplies. This finding raises the question of how this new technology should be regulated as to not facilitate clandestine biosynthesis efforts, while still enabling advancements in psilocybin synthesis technology for pharmaceutical applications. Here, we present our homebrew results, and suggestions on how to address the regulatory concerns accompanying this new technology.

Psilocybin and its active metabolite psilocin are hallucinogenic serotonergic agonists with high affinity for several serotonin receptors. In addition to underlying the hallucinogenic effects of these compounds, serotonin receptor activation also has important effects on decision-making and goal-directed behaviors. The impact of psilocybin and psilocin on these cognitive systems, however, remains unclear. This study investigated the effects of psilocybin treatment on decision-making and motivation in healthy male and female rats. We compared probability and delay discounting performance of psilocybin treated (1 mg/kg) to vehicle rats (n = 10/sex/group), and further assessed motivation in each group using a progressive ratio task. We also confirmed drug action by assessing head twitch responses after psilocybin treatment (1 mg/kg). Results from this study demonstrated that exposure to 1 mg/kg psilocybin did not affect decision-making in the probability and delay discounting tasks and did not reduce response rates in the progressive ratio task. However, psilocybin treatment did cause the expected increase in head twitch responses in both male and female rats, demonstrating that the drug was delivered at a pharmacologically relevant dosage. Combined, these results suggest that psilocybin may not impair or improve decision-making and motivation. Considering recent interest in psilocybin as a potential fast-acting therapeutic for a variety of mental health disorders, our findings also suggest the therapeutic effects of this drug may not be mediated by changes to the brain systems underlying reward and decision-making. Finally, these results may have important implications regarding the relative safety of this compound, suggesting that widespread cognitive impairments may not be seen in subjects, even after chronic treatment.

SUMMARY Correlation detectors are now used routinely in seismology to detect occurrences of signals bearing close resemblance to a reference waveform. They facilitate the detection of low-amplitude signals in significant background noise that may elude detection using energy detectors, and they associate a detected signal with a source location. Many seismologists use the fully normalized correlation coefficient C between the template and incoming data to determine a detection. This is in contrast to other fields with a longer tradition for matched filter detection where the theoretically optimal statistic C2 is typical. We perform a systematic comparison between the detection statistics C and C|C|, the latter having the same dynamic range as C2 but differentiating between correlation and anticorrelation. Using a database of short waveform segments, each containing the signal on a 3-component seismometer from one of 51 closely spaced explosions, we attempt to detect P- and S-phase arrivals for all events using short waveform templates from each explosion as reference signals. We present empirical statistics of both C and C|C| traces and demonstrate that C|C| detects confidently a higher proportion of the signals than C without evidently increasing the likelihood of triggering erroneously. We recall from elementary statistics that C2, also called the coefficient of determination, represents the fraction of the variance of one variable which can be explained by another variable. This means that the fraction of a segment of our incoming data that could be explained by our signal template decreases almost linearly with C|C| but diminishes more rapidly as C decreases. In most situations, replacing C with C|C| in operational correlation detectors may improve the detection sensitivity without hurting the performance-gain obtained through network stacking. It may also allow a better comparison between single-template correlation detectors and higher order multiple-template subspace detectors which, by definition, already apply an optimal detection statistic.

Although molecular tools are becoming more important in the delineation of scyphozoan species there is, perforce, a need to substantiate new species definitions using morphological data. Access to type material is often difficult and detailed, raw morphometric data are rarely provided in older type descriptions, which makes comparisons of new with old challenging. Here, we use null models based on simple measures of central tendency to generate morphometric data sets for four species of Aurelia, three species of Chrysaora and two species of Crambionella. The results of PERMANOVA and CAP analyses indicate no significant differences between random and real data within species, but significant differences between congeneric species (null or real), suggesting that this multivariate approach may be a useful tool for defining species when comparative data are scant.