Broadly Applicable Methodology for the Rapid and Dosable Small Molecule-Mediated Regulation of Transcription Factors in Human Cells

Direct and selective small molecule control of transcription factor activity is an appealing avenue for elucidating the cell biology mediated by transcriptional programs. However, pharmacologic tools to modulate transcription factor activity are scarce because transcription factors are not readily amenable to small molecule-mediated regulation. Moreover, existing genetic approaches to regulate transcription factors often lead to high nonphysiologic levels of transcriptional activation that significantly impair our ability to understand the functional implications of transcription factor activity. Herein, we demonstrate that small molecule-mediated conformational control of protein degradation is a generally applicable, chemical biological methodology to obtain small molecule-regulated transcription factors that modulate transcriptional responses at physiologic levels in human cells. Our establishment of this approach allows for the rapid development of genetically encoded, small molecule-regulated transcription factors to explore the biologic and therapeutic impact of physiologic levels of transcription factor activity in cells

Unfolded Protein Response Activation Reduces Secretion and Extracellular Aggregation of Amyloidogenic Immunoglobulin Light Chain

Light-chain amyloidosis (AL) is a degenerative disease characterized by the extracellular aggregation of a destabilized amyloidogenic Ig light chain (LC) secreted from a clonally expanded plasma cell. Current treatments for AL revolve around ablating the cancer plasma cell population using chemotherapy regimens. Unfortunately, this approach is limited to the ∼70% of patients who do not exhibit significant organ proteotoxicity and can tolerate chemotherapy. Thus, identifying new therapeutic strategies to alleviate LC organ proteotoxicity should allow AL patients with significant cardiac and/or renal involvement to subsequently tolerate established chemotherapy treatments. Using a small-molecule screening approach, the unfolded protein response (UPR) was identified as a cellular signaling pathway whose activation selectively attenuates secretion of amyloidogenic LC, while not affecting secretion of a nonamyloidogenic LC. Activation of the UPR-associated transcription factors XBP1s and/or ATF6 in the absence of stress recapitulates the selective decrease in amyloidogenic LC secretion by remodeling the endoplasmic reticulum proteostasis network. Stress-independent activation of XBP1s, or especially ATF6, also attenuates extracellular aggregation of amyloidogenic LC into soluble aggregates. Collectively, our results show that stress-independent activation of these adaptive UPR transcription factors offers a therapeutic strategy to reduce proteotoxicity associated with LC aggregation

Antithrombotic/anticoagulant and anticancer activities of selected medicinal plants from South Africa

Nine plants available in the Eastern Cape Province of South Africa were tested for antithrombotic and/or anticoagulant activity. Organic (methanol) and aqueous (distilled water) extractions were performed on the various plant parts. The thrombin assay and clotting time assays (thrombin-induced and CaCl 2 -induced) were utilised. Several extracts displayed activity, but in most cases this was due to the presence of tannins. Only the aqueous extracts displayed activity after tannin removal. The Sutherlandia frutescens leaf extract displayed antithrombotic activity, with an IC 50 value of 2.17 mg/ml. Gloriosa superba and Zantedeschia aethiopica leaf extracts displayed anticoagulant properties by inhibiting thrombin-induced clotting, with IC 50 values of 2.97 and 3.05 mg/ml, respectively. The Leonotis leonurus root extract was found to decrease the CaCl 2 -induced clotting time by 50% at 8.88 mg/ml. A decrease in this value accompanied by a decrease in fibrin formation was preferable for the CaCl 2 -induced assay, since decreased fibrin formation may have a role in the prevention of cancer metastasis. As tannins were found to contribute minimally to the anticoagulant effect of L. leonurus, the cytotoxicity potential of the extracts of this species against five cell lines was determined. Only the organic extract yielded significant cytotoxity

Antithrombotic/anticoagulant and anticancer activities of selected medicinal plants from South Africa

Nine plants available in the Eastern Cape Province of South Africa were tested for antithrombotic and/or anticoagulant activity. Organic (methanol) and aqueous (distilled water) extractions were performed on the various plant parts. The thrombin assay and clotting time assays (thrombin-induced and CaCl 2 -induced) were utilised. Several extracts displayed activity, but in most cases this was due to the presence of tannins. Only the aqueous extracts displayed activity after tannin removal. The Sutherlandia frutescens leaf extract displayed antithrombotic activity, with an IC 50 value of 2.17 mg/ml. Gloriosa superba and Zantedeschia aethiopica leaf extracts displayed anticoagulant properties by inhibiting thrombin-induced clotting, with IC 50 values of 2.97 and 3.05 mg/ml, respectively. The Leonotis leonurus root extract was found to decrease the CaCl 2 -induced clotting time by 50% at 8.88 mg/ml. A decrease in this value accompanied by a decrease in fibrin formation was preferable for the CaCl 2 -induced assay, since decreased fibrin formation may have a role in the prevention of cancer metastasis. As tannins were found to contribute minimally to the anticoagulant effect of L. leonurus, the cytotoxicity potential of the extracts of this species against five cell lines was determined. Only the organic extract yielded significant cytotoxity

How hornbills handle heat : sex-specific thermoregulation in the southern yellow-billed hornbill

At a global scale, thermal physiology is correlated with climatic variables such as temperature and aridity. There is also evidence that thermoregulatory traits vary with fine-scale microclimate, but this has received less attention in endotherms. Here, we test the hypothesis that avian thermoregulation varies with microclimate and behavioural constraints in a non-passerine bird. Male and female southern yellowbilled hornbills (Tockus leucomelas) experience markedly different microclimates while breeding, with the female sealing herself into a tree cavity and moulting all her flight feathers during the breeding attempt, becoming entirely reliant on the male for provisioning. We examined interactions between resting metabolic rate (RMR), evaporative water loss (EWL) and core body temperature (Tb) at air temperatures (Ta) between 30°C and 52°C in male and female hornbills, and quantified evaporative cooling efficiencies and heat tolerance limits. At thermoneutral Ta, neither RMR, EWL nor Tb differed between sexes. At Ta >40°C, however,RMRand EWL of females were significantly lower than those of males, by ∼13% and ∼17%, respectively, despite similar relationships between Tb and Ta, maximum ratio of evaporative heat loss to metabolic heat production and heat tolerance limits (∼50°C). These sex-specific differences in hornbill thermoregulation support the hypothesis that avian thermal physiology can vary within species in response to fine-scalemicroclimatic factors. In addition,Q10 for RMR varied substantially, with Q10 ≤2 in some individuals, supporting recent arguments that active metabolic suppression may be an underappreciated aspect of endotherm thermoregulation in the heat.The National Research Foundation SARChI chair for Mammal Behavioural Ecology and Physiology, the SARChI chair of Conservation Physiology, the Centre of Excellence at the FitzPatrick Institute of African Ornithology and the Claude Leon Foundation.http://jeb.biologists.orgam2022Mammal Research InstituteZoology and Entomolog

Evolution of the physical properties of dust and cometary dust activity from 67P/Churyumov-Gerasimenko measured in situ by Rosetta/COSIMA

The Cometary Secondary Ion Mass Analyzer (COSIMA) collects dust particles in the coma of 67P/Churyumov-Gerasimenko, images them with a resolution of 14 mu m x 14 mu m, and measures their composition via time-of-flight secondary ion mass spectrometry. The particles are collected on targets exposed to the cometary flux for periods ranging from several hours to a week. Images are acquired with the internal camera, the COSISCOPE, before and after each exposure period. This paper focuses on the evolution of the dust flux and of the size distribution of the particles derived from the COSISCOPE images during the two years of the mission. The dust flux reaches its maximum at perihelion. We suggest that the delay of 20 d between the activity measured by COSIMA and the gas activity measured by the other instruments on Rosetta is caused by the presence of a volatile-poor dust layer on the nucleus that is removed around perihelion, uncovering volatile-rich layers that then become active. The difference in morphology between the northern and southern hemispheres observed by OSIRIS, the south being more sintered, is also recorded in the COSIMA data by a change in the size distribution during the southern summer, as the large porous aggregates disappear from the COSIMA collection. The properties of the particles collected during an outburst in early September 2016 indicate that these particles were ejected by a violent event and might originate from regions of low tensile strength

Biochemical characterization of Acacia schweinfurthii serine proteinase inhibitor

One of the many control mechanisms of serine proteinases is their specific inhibition by protein proteinase inhibitors. An extract of Acacia schweinfurthii was screened for potential serine proteinase inhibition. It was successfully purified to homogeneity by precipitating with 80% (v/v) acetone and sequential chromatographic steps, including ion-exchange, affinity purifica- Q2 tion and RP-HPLC. Reducing SDS-PAGE conditions revealed an inhibitor (ASTI) consisting of two polypeptide chains A and B of approximate molecular weights of 16 and 10 kDa, respectively, and under non-reducing conditions, 26 kDa was observed. The inhibitor was shown to inhibit bovine trypsin (Ki of 3.45 nM) at an approximate molar ratio of inhibitor: trypsin (1:1). The A- and B-chains revealed complete sequences of 140 and 40 amino acid residues, respectively. Sequence similarity (70%) was reported between ASTI A-chain and ACTI A-chain (Acacia confusa) using the ClustalW. The B-chain produced a 76% sequence similarity between ASTI and Leucaena leucocephala trypsin inhibitor

Understanding continent-wide variation in vulture ranging behavior to assess feasibility of Vulture Safe Zones in Africa: Challenges and possibilities

Protected areas are intended as tools in reducing threats to wildlife and preserving habitat for their long-term population persistence. Studies on ranging behavior provide insight into the utility of protected areas. Vultures are one of the fastest declining groups of birds globally and are popular subjects for telemetry studies, but continent-wide studies are lacking. To address how vultures use space and identify the areas and location of possible vulture safe zones, we assess home range size and their overlap with protected areas by species, age, breeding status, season, and region using a large continent-wide telemetry datasets that includes 163 individuals of three species of threatened Gyps vulture. Immature vultures of all three species had larger home ranges and used a greater area outside of protected areas than breeding and non-breeding adults. Cape vultures had the smallest home range sizes and the lowest level of overlap with protected areas. Rüppell\u27s vultures had larger home range sizes in the wet season, when poisoning may increase due to human-carnivore conflict. Overall, our study suggests challenges for the creation of Vulture Safe Zones to protect African vultures. At a minimum, areas of 24,000 km2 would be needed to protect the entire range of an adult African White-backed vulture and areas of more than 75,000 km2 for wider-ranging Rüppell\u27s vultures. Vulture Safe Zones in Africa would generally need to be larger than existing protected areas, which would require widespread conservation activities outside of protected areas to be successful

SERENA:Particle Instrument Suite for Determining the Sun-Mercury Interaction from BepiColombo

International audienceThe ESA-JAXA BepiColombo mission to Mercury will provide simultaneous measurements from two spacecraft, offering an unprecedented opportunity to investigate magnetospheric and exospheric particle dynamics at Mercury as well as their interactions with solar wind, solar radiation, and interplanetary dust. The particle instrument suite SERENA (Search for Exospheric Refilling and Emitted Natural Abundances) is flying in space on-board the BepiColombo Mercury Planetary Orbiter (MPO) and is the only instrument for ion and neutral particle detection aboard the MPO. It comprises four independent sensors: ELENA for neutral particle flow detection, Strofio for neutral gas detection, PICAM for planetary ions observations, and MIPA, mostly for solar wind ion measurements. SERENA is managed by a System Control Unit located inside the ELENA box. In the present paper the scientific goals of this suite are described, and then the four units are detailed, as well as their major features and calibration results. Finally, the SERENA operational activities are shown during the orbital path around Mercury, with also some reference to the activities planned during the long cruise phase

Correction to: SERENA: Particle Instrument Suite for Determining the Sun-Mercury Interaction from BepiColombo

International audienc