Semi-Quantitative Models for Identifying Potent and Selective Transthyretin Amyloidogenesis Inhibitors

Rate-limiting dissociation of the tetrameric protein transthyretin (TTR), followed by monomer misfolding and misassembly, appears to cause degenerative diseases in humans known as the transthyretin amyloidoses, based on human genetic, biochemical and pharmacologic evidence. Small molecules that bind to the generally unoccupied thyroxine binding pockets in the native TTR tetramer kinetically stabilize the tetramer, slowing subunit dissociation proportional to the extent that the molecules stabilize the native state over the dissociative transition state—thereby inhibiting amyloidogenesis. Herein, we use previously reported structure-activity relationship data to develop two semi-quantitative algorithms for identifying the structures of potent and selective transthyretin kinetic stabilizers/amyloidogenesis inhibitors. The viability of these prediction algorithms, in particular the more robust in silico docking model, is perhaps best validated by the clinical success of tafamidis, the first-in-class drug approved in Europe, Japan, South America, and elsewhere for treating transthyretin aggregation-associated familial amyloid polyneuropathy. Tafamidis is also being evaluated in a fully-enrolled placebo-controlled clinical trial for its efficacy against TTR cardiomyopathy. These prediction algorithms will be useful for identifying second generation TTR kinetic stabilizers, should these be needed to ameliorate the central nervous system or ophthalmologic pathology caused by TTR aggregation in organs not accessed by oral tafamidis administration

Isotopic signature of dissolved iron delivered to the Southern Ocean from hydrothermal vents in the East Scotia Sea

It has recently been demonstrated that hydrothermal vents are an important source of dissolved Fe (dFe) to the Southern Ocean. The isotopic composition (?56Fe) of dFe in vent fluids appears to be distinct from other sources of dFe to the deep ocean, but the evolution of ?56Fe during mixing between vent fluids and seawater is poorly constrained. Here we present the evolution of ?56Fe for dFe in hydrothermal fluids and dispersing plumes from two sites in the East Scotia Sea. We show that ?56Fe values in the buoyant plume are distinctly lower (as low as ?1.19 ‰) than the hydrothermal fluids (?0.29 ‰), attributed to (i) precipitation of Fe-sulfides in the early stages of mixing, and (ii) partial oxidation of Fe(II) to Fe(III), > 55 % of which subsequently precipitates as Fe-oxyhydroxides. By contrast, the ?56Fe signature of stabilized dFe in the neutrally buoyant plume is ?0.3 to ?0.5 ‰. This cannot be explained by continued dilution of the buoyant plume with background seawater; rather, we suggest that isotope fractionation of dFe occurs during plume dilution due to Fe ligand complexation and exchange with labile particulate Fe. The ?56Fe signature of stabilized hydrothermal dFe in the East Scotia Sea is distinct from background seawater and may be used to quantify the hydrothermal dFe input to the ocean interior

One of the earliest refractory inclusions and its implications for solar system history

A ∼175 µm refractory inclusion, A-COR-01 from one of the least altered carbonaceous chondrites, ALHA 77307 (CO3.0), has been found to bear unique characteristics that indicate that it is one of the first solids to have formed at the very birth of the solar system while isotopic reservoirs were still evolving rapidly. Its core is composed mainly of hibonite and corundum, the two phases predicted to condense first from a gas of solar composition, and like many common types of Calcium-, Aluminium-rich Inclusions (CAIs) is surrounded by a rim of diopside. Core minerals in A-COR-01 are very 16O-rich (Δ17OCore = -32.5 ± 3.3 (2SD) ‰) while those in the rim display an O isotopic composition (Δ17ORim = -24.8 ± 0.5 (2SD) ‰) indistinguishable from that found in the vast majority of the least altered CAIs. These observations indicate that this CAI formed in a very 16O-rich reservoir and either recorded the subsequent evolution of this reservoir or the transit to another reservoir. The origin of A-COR-01in a primitive reservoir is consistent with the very low content of excess of radiogenic 26Mg in its core minerals corresponding to the inferred initial 26Al/27Al ratio ((26Al/27Al)0 = (1.67 ± 0.31) × 10-7), supporting a very early formation before injection and/or homogenisation of 26Al in the protoplanetary disk. Possible reservoir evolution and short-lived radionuclide (SLRs) injection scenarios are discussed and it is suggested that the observed isotope composition resulted from mixing of a previously un-observed early reservoir with the rest of the disk

Widespread extrahippocampal NAA/(Cr+Cho) abnormalities in TLE with and without mesial temporal sclerosis

MR spectroscopy has demonstrated extrahippocampal NAA/(Cr+Cho) reductions in medial temporal lobe epilepsy with (TLE-MTS) and without (TLE-no) mesial temporal sclerosis. Because of the limited brain coverage of those previous studies, it was, however, not possible to assess differences in the distribution and extent of these abnormalities between TLE-MTS and TLE-no. This study used a 3D whole brain echoplanar spectroscopic imaging (EPSI) sequence to address the following questions: (1) Do TLE-MTS and TLE-no differ regarding severity and distribution of extrahippocampal NAA/(Cr+Cho) reductions? (2) Do extrahippocampal NAA/(Cr+Cho) reductions provide additional information for focus lateralization? Forty-three subjects (12 TLE-MTS, 13 TLE-no, 18 controls) were studied with 3D EPSI. Statistical parametric mapping (SPM2) was used to identify regions of significantly decreased NAA/(Cr+Cho) in TLE groups and in individual patients. TLE-MTS and TLE-no had widespread extrahippocampal NAA/(Cr+Cho) reductions. NAA/(Cr+Cho) reductions had a bilateral fronto-temporal distribution in TLE-MTS and a more diffuse, less well defined distribution in TLE-no. Extrahippocampal NAA/(Cr+Cho) decreases in the single subject analysis showed a large inter-individual variability and did not provide additional focus lateralizing information. Extrahippocampal NAA/(Cr+Cho) reductions in TLE-MTS and TLE-no are neither focal nor homogeneous. This reduces their value for focus lateralization and suggests a heterogeneous etiology of extrahippocampal spectroscopic metabolic abnormalities in TLE

Clinical trials in amyotrophic lateral sclerosis:a systematic review and perspective

Amyotrophic lateral sclerosis is a progressive and devastating neurodegenerative disease. Despite decades of clinical trials, effective disease modifying drugs remain scarce. To understand the challenges of trial design and delivery, we performed a systematic review of phase II, phase II/III and phase III amyotrophic lateral sclerosis clinical drug trials on trial registries and PubMed between 2008 and 2019. We identified 125 trials, investigating 76 drugs and recruiting more than 15000 people with amyotrophic lateral sclerosis. 90% of trials used traditional fixed designs. The limitations in understanding of disease biology, outcome measures, resources and barriers to trial participation in a rapidly progressive, disabling and heterogenous disease hindered timely and definitive evaluation of drugs in two-arm trials. Innovative trial designs, especially adaptive platform trials may offer significant efficiency gains to this end. We propose a flexible and scalable multi-arm, multi-stage trial platform where opportunities to participate in a clinical trial can become the default for people with amyotrophic lateral sclerosis

Tracking the provenance of Greenland-sourced, Holocene aged, individual sand-sized ice-rafted debris using the Pb-isotope compositions of feldspars and 40Ar/39Ar ages of hornblendes

The provenance of sand-sized ice-rafted debris (IRD) sourced from Greenland is currently difficult to determine. Such knowledge, if it could be ascertained with a high degree of certainty, could be applied to the Greenland-proximal marine records to improve both our understanding of modern-day spatial patterns of iceberg rafting and the past history of the Greenland Ice Sheet (GIS). Recent studies have highlighted the utility of the Pb-isotope composition of individual sand-sized feldspars and the 40Ar/39Ar ages of individual sand-sized hornblendes in this regard. However, before any such provenance toolkit can be applied to the palaeo-record, it is necessary first to determine whether this approach can be used to track the sources of known recent Greenland-proximal IRD deposition. To this end we present new records of the Pb-isotope composition and the 40Ar/39Ar ages of individual sand-sized grains of feldspars and hornblendes, respectively, from modern Greenland glacifluvial and fjord sands and Holocene to modern Greenland-proximal marine sediments. These new data demonstrate that sand-sized feldspars and hornblendes glacially eroded by the GIS exhibit distinct intra- and inter-tectonic terrane differences in their Pb-isotope compositions and ages and that these differences are clearly expressed in the geochemistry and geochronology of sand-sized IRD deposited in marine sediments around Greenland. Although overlap exists between some Greenland-proximal IRD ‘source fields’ defined by these data, our approach has the potential to both better understand spatial patterns of Greenland-derived IRD in the modern day as well as during past episodes of iceberg calving

Vailulu’u Seamount, Samoa: Life and death on an active submarine volcano

Submersible exploration of the Samoan hotspot revealed a new, 300-m-tall, volcanic cone, named Nafanua, in the summit crater of Vailulu’u seamount. Nafanua grew from the 1,000-m-deep crater floor in <4 years and could reach the sea surface within decades. Vents fill Vailulu’u crater with a thick suspension of particulates and apparently toxic fluids that mix with seawater entering from the crater breaches. Low-temperature vents form Fe oxide chimneys in many locations and up to 1-m-thick layers of hydrothermal Fe floc on Nafanua. High-temperature (81°C) hydrothermal vents in the northern moat (945-m water depth) produce acidic fluids (pH 2.7) with rising droplets of (probably) liquid CO₂. The Nafanua summit vent area is inhabited by a thriving population of eels (Dysommina rugosa) that feed on midwater shrimp probably concentrated by anticyclonic currents at the volcano summit and rim. The moat and crater floor around the new volcano are littered with dead metazoans that apparently died from exposure to hydrothermal emissions. Acid-tolerant polychaetes (Polynoidae) live in this environment, apparently feeding on bacteria from decaying fish carcasses. Vailulu’u is an unpredictable and very active underwater volcano presenting a potential long-term volcanic hazard. Although eels thrive in hydrothermal vents at the summit of Nafanua, venting elsewhere in the crater causes mass mortality. Paradoxically, the same anticyclonic currents that deliver food to the eels may also concentrate a wide variety of nektonic animals in a death trap of toxic hydrothermal fluids.KEYWORDS: habitats, hydrothermal, eels, currents, ventsThis is the publisher’s final pdf. The published article is copyrighted by the National Academy of Sciences of the United States of America and can be found at: http://www.pnas.org

The impact of surgical delay on resectability of colorectal cancer: An international prospective cohort study

AIM: The SARS-CoV-2 pandemic has provided a unique opportunity to explore the impact of surgical delays on cancer resectability. This study aimed to compare resectability for colorectal cancer patients undergoing delayed versus non-delayed surgery. METHODS: This was an international prospective cohort study of consecutive colorectal cancer patients with a decision for curative surgery (January-April 2020). Surgical delay was defined as an operation taking place more than 4 weeks after treatment decision, in a patient who did not receive neoadjuvant therapy. A subgroup analysis explored the effects of delay in elective patients only. The impact of longer delays was explored in a sensitivity analysis. The primary outcome was complete resection, defined as curative resection with an R0 margin. RESULTS: Overall, 5453 patients from 304 hospitals in 47 countries were included, of whom 6.6% (358/5453) did not receive their planned operation. Of the 4304 operated patients without neoadjuvant therapy, 40.5% (1744/4304) were delayed beyond 4 weeks. Delayed patients were more likely to be older, men, more comorbid, have higher body mass index and have rectal cancer and early stage disease. Delayed patients had higher unadjusted rates of complete resection (93.7% vs. 91.9%, P = 0.032) and lower rates of emergency surgery (4.5% vs. 22.5%, P < 0.001). After adjustment, delay was not associated with a lower rate of complete resection (OR 1.18, 95% CI 0.90-1.55, P = 0.224), which was consistent in elective patients only (OR 0.94, 95% CI 0.69-1.27, P = 0.672). Longer delays were not associated with poorer outcomes. CONCLUSION: One in 15 colorectal cancer patients did not receive their planned operation during the first wave of COVID-19. Surgical delay did not appear to compromise resectability, raising the hypothesis that any reduction in long-term survival attributable to delays is likely to be due to micro-metastatic disease