On-orbit assembly using superquadric potential fields

The autonomous on-orbit assembly of a large space structure is presented using a method based on superquadric artificial potential fields. The final configuration of the elements which form the structure is represented as the minimum of some attractive potential field. Each element of the structure is then considered as presenting an obstacle to the others using a superquadric potential field attached to the body axes of the element. A controller is developed which ensures that the global potential field decreases monotonically during the assembly process. An error quaternion representation is used to define both the attractive and superquadric obstacle potentials allowing the final configuration of the elements to be defined through both relative position and orientation. Through the use of superquadric potentials, a wide range of geometric objects can be represented using a common formalism, while collision avoidance can make use of both translational and rotation maneuvers to reduce total maneuver cost for the assembly process

Accelerated gas-liquid visible light photoredox catalysis with continuous-flow photochemical microreactors

In this protocol, we describe the construction and use of an operationally simple photochemical microreactor for gas-liquid photoredox catalysis using visible light. The general procedure includes details on how to set up the microreactor appropriately with inlets for gaseous reagents and organic starting materials, and it includes examples of how to use it to achieve continuous-flow preparation of disulfides or trifluoromethylated heterocycles and thiols. The reported photomicroreactors are modular, inexpensive and can be prepared rapidly from commercially available parts within 1 h even by nonspecialists. Interestingly, typical reaction times of gas-liquid visible light photocatalytic reactions performed in microflow are lower (in the minute range) than comparable reactions performed as a batch process (in the hour range). This can be attributed to the improved irradiation efficiency of the reaction mixture and the enhanced gas-liquid mass transfer in the segmented gas-liquid flow regime

A preexisting rare PIK3CA e545k subpopulation confers clinical resistance to MEK plus CDK4/6 inhibition in NRAS melanoma and is dependent on S6K1 signaling

Combined MEK and CDK4/6 inhibition (MEKi + CDK4i) has shown promising clinical outcomes in patients with NRAS- mutant melanoma. Here, we interrogated longitudinal biopsies from a patient who initially responded to MEKi + CDK4i therapy but subsequently developed resistance. Whole-exome sequencing and functional validation identified an acquired PIK3CA E545K mutation as conferring drug resistance. We demonstrate that PIK3CA E545K preexisted in a rare subpopulation that was missed by both clinical and research testing, but was revealed upon multiregion sampling due to PIK3CA E545K being nonuniformly distributed. This resistant population rapidly expanded after the initiation of MEKi + CDK4i therapy and persisted in all successive samples even after immune checkpoint therapy and distant metastasis. Functional studies identified activated S6K1 as both a key marker and specific therapeutic vulnerability downstream of PIK3CA E545K -induced resistance. These results demonstrate that difficult-to-detect preexisting resistance mutations may exist more often than previously appreciated and also posit S6K1 as a common downstream therapeutic nexus for the MAPK, CDK4/6, and PI3K pathways. SIGNIFICANCE: We report the first characterization of clinical acquired resistance to MEKi + CDK4i, identifying a rare preexisting PIK3CA E545K subpopulation that expands upon therapy and exhibits drug resistance. We suggest that single-region pretreatment biopsy is insufficient to detect rare, spatially segregated drug-resistant subclones. Inhibition of S6K1 is able to resensitize PIK3CA E545K -expressing NRAS-mutant melanoma cells to MEKi + CDK4i. © 2018 AAC

Triad3a induces the degradation of early necrosome to limit RipK1-dependent cytokine production and necroptosis.

Understanding the molecular signaling in programmed cell death is vital to a practical understanding of inflammation and immune cell function. Here we identify a previously unrecognized mechanism that functions to downregulate the necrosome, a central signaling complex involved in inflammation and necroptosis. We show that RipK1 associates with RipK3 in an early necrosome, independent of RipK3 phosphorylation and MLKL-induced necroptotic death. We find that formation of the early necrosome activates K48-ubiquitin-dependent proteasomal degradation of RipK1, Caspase-8, and other necrosomal proteins. Our results reveal that the E3-ubiquitin ligase Triad3a promotes this negative feedback loop independently of typical RipK1 ubiquitin editing enzymes, cIAPs, A20, or CYLD. Finally, we show that Triad3a-dependent necrosomal degradation limits necroptosis and production of inflammatory cytokines. These results reveal a new mechanism of shutting off necrosome signaling and may pave the way to new strategies for therapeutic manipulation of inflammatory responses

Seminaphthofluorescein-Based Fluorescent Probes for Imaging Nitric Oxide in Live Cells

Fluorescent turn-on probes for nitric oxide based on seminaphthofluorescein scaffolds were prepared and spectroscopically characterized. The Cu(II) complexes of these fluorescent probes react with NO under anaerobic conditions to yield a 20–45-fold increase in integrated emission. The seminaphthofluorescein-based probes emit at longer wavelengths than the parent FL1 and FL2 fluorescein-based generations of NO probes, maintaining emission maxima between 550 and 625 nm. The emission profiles depend on the excitation wavelength; maximum fluorescence turn-on is achieved at excitations between 535 and 575 nm. The probes are highly selective for NO over other biologically relevant reactive nitrogen and oxygen species including NO3–, NO2–, HNO, ONOO–, NO2, OCl–, and H2O2. The seminaphthofluorescein-based probes can be used to visualize endogenously produced NO in live cells, as demonstrated using Raw 264.7 macrophages.National Science Foundation (U.S.) (CHE-0611944)National Institutes of Health (U.S.) (K99GM092970

Method and apparatus for the synthesis of dihydroartemisinin and artemisinin derivatives

The present invention is directed to a method for continuous production of dihydroartemisinin and also artemisinin derivatives derived from dihydroartemisinin by using artemisinin or dihydroartemisinic acid (DHAA) as starting material as well as to a continuous flow reactor for producing dihydroartemisinin as well as the artemisinin derivatives. It was found that the reduction of artemisinin to dihydroartemisinin in a continuous process requires a special kind of reactor and a special combination of reagents comprising a hydride reducing agent, at least one activator such as an inorganic activator, at least one solid base, at least one aprotic solvent and at least one C1-C5 alcohol

Mechanistic insight into the sensing of nitroaromatic compounds by metal-organic frameworks

There has been extensive research on the sensing of explosive nitroaromatic compounds (NACs) using fluorescent metal-organic frameworks (MOFs). However, ambiguity in the sensing mechanism has hampered the development of efficient explosive sensors. Here we report the synthesis of a hydroxyl-functionalized MOF for rapid and efficient sensing of NACs and examine in detail its fluorescence quenching mechanisms. In chloroform, quenching takes place primarily by exciton migration to the ground-state complex formed between the MOF and the analytes. A combination of hydrogen-bonding interactions and ??????? stacking interactions are responsible for fluorescence quenching, and this observation is supported by single-crystal structures. In water, the quenching mechanism shifts toward resonance energy transfer and photo-induced electron transfer, after exciton migration as in chloroform. This study provides insight into florescence-quenching mechanisms for the selective sensing of NACs and reduces the ambiguity regarding the nature of interactions between the MOF and NACs

The Attorney-Client Privilege and the Work-Product Doctrine in Michigan

In Upjohn Co v. United States, the United States Supreme Court acknowledged that the attorney-client privilege - the oldest of the privileges for confidential communications known to the common law - has the crucial purpose of encourag[ing] full and frank communication between attorneys and their clients and thereby promote[s] broader public interests in the observance of law and administration of justice. Similarly, in Hickman v Taylor, the Court stressed the importance of the work-product doctrine, noting that [n]ot even the most liberal of discovery theories can justify unwarranted inquiries into the files and the mental impressions of an attorney. It is beyond question that, at a theoretical level, the attorney-client privilege and the work-product doctrine serve significant interests and that, at a practical level, attorneys constantly encounter issues involving these principles. Nevertheless, many attorneys do not acquire their familiarity with these crucial principles in any systematic way. Law school courses and casebooks often treat these principles superficially, and busy practicing lawyers tend to research specific issues only as they arise in the course of their work. As a result, many attorneys (and perhaps some judges) may not clearly understand the significance, scope, and limits of these doctrines. This publication is an attempt to solve this problem by offering a systematic and thorough examination of the attorney-client privilege and the work-product doctrine under Michigan law. Part II of this text addresses the attorney-client privilege; Part III addresses the work-product doctrine; and Part IV addresses ethics concepts of confidences and secrets. Wherever possible, Michigan authority has been cited and quoted. In some instances, federal cases are instructive in interpreting Michigan law or in filling an apparent gap in Michigan law; under those circumstances, the text freely cites and quotes from federal authority. The goal is to provide a comprehensive examination of these principles as interpreted by the Michigan courts.https://repository.law.umich.edu/books/1117/thumbnail.jp