The mTOR complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and v-ATPase-dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Here, we identify SLC38A9, an uncharacterized protein with sequence similarity to amino acid transporters, as a lysosomal transmembrane protein that interacts with the Rag GTPases and Ragulator in an amino acid-sensitive fashion. SLC38A9 transports arginine with a high Km and loss of SLC38A9 represses mTORC1 activation by amino acids, particularly arginine. Overexpression of SLC38A9 or just its Ragulator-binding domain makes mTORC1 signaling insensitive to amino acid starvation but not to Rag activity. Thus, SLC38A9 functions upstream of the Rag GTPases and is an excellent candidate for being an arginine sensor for the mTORC1 pathway.

The polymerization of functional monomers provides direct access to functional polymers without need for postpolymerization modification; however, monomer synthesis can become a bottleneck of this approach. New methods that enable rapid installation of functionality into monomers for living polymerization are valuable. Here, we report the three-step convergent synthesis (two-step longest linear sequence) of a divalent exo-norbornene imide capable of efficient coupling with various nucleophiles and azides to produce diversely functionalized branched macromonomers optimized for ring-opening metathesis polymerization (ROMP). In addition, we describe an efficient iterative procedure for the synthesis of tri-and tetra-valent branched macromonomers. We demonstrate the use of these branched macromonomers for the synthesis of Janus bottlebrush block copolymers as well as for the generation of bottlebrush polymers with up to three conjugated small molecules per repeat unit. This work significantly expands the scalability and diversity of nanostructured macromolecules accessible via ROMP.

We report a stepwise assembly strategy for the integration of metal-organic cages (MOCs) into block copolymers (BCPs). This approach creates "block co-polyMOC" (BCPMOC) materials whose microscopic structures and mechanical properties are readily tunable by adjusting the size and geometry of the MOCs and the composition of the BCPs. In the first assembly step, BCPs functionalized with a pyridyl ligand on the chain end form star-shaped polymers triggered by metal-coordination-induced MOC assembly. The type of MOC junction employed precisely determines the number of arms for the star polymer. In the second step, microphase separation of the BCP is induced, physically cross-linking the star polymers and producing the desired BCPMOC networks in the bulk or gel state. We demonstrate that large spherical M12L24 MOCs, small paddlewheel M2L4 MOCs, or a mixture of both can be incorporated into BCPMOCs to provide materials with tailored branch functionality, phase separation, microdomain spacing, and mechanical properties. Given the synthetic and functional diversity of MOCs and BCPs, our method should enable access to BCPMOCs for a wide range of applications.

We report star polymer metal-organic cage (polyMOC) materials whose structures, mechanical properties, functionalities, and dynamics can all be precisely tailored through a simple three-component assembly strategy. The star polyMOC network is composed of tetra-arm star polymers functionalized with ligands on the chain ends, small molecule ligands, and palladium ions; polyMOCs are formed via metal-ligand coordination and thermal annealing. The ratio of small molecule ligands to polymer-bound ligands determines the connectivity of the MOC junctions and the network structure. The use of large M12L24 MOCs enables great flexibility in tuning this ratio, which provides access to a rich spectrum of material properties including tunable moduli and relaxation dynamics.

PurposeTo evaluate cataract surgery visual outcomes and associated risk factors in rural secondary level eye care centers of L V Prasad Eye Institute (LVPEI), India.MethodsThe Eye Health pyramid of LVPEI has a network of rural secondary care centres (SCs) and attached vision centres (VCs) that provide high quality comprehensive eye care with permanent infrastructure to the most disadvantaged sections of society. The most common procedure performed at SCs is cataract surgery. We audited the outcome of a random sample of 2,049 cataract surgeries done from October 2009-March 2010 at eight rural SCs. All patients received a comprehensive ophthalmic examination, both before and after surgery. The World Health Organization recommended cataract surgical record was used for data entry. Visual outcomes were measured at discharge, 1–3 weeks and 4–11 weeks follow up visits. Poor outcome was defined as best corrected visual acuity <6/18.ResultsMean age was 61.8 years (SD: 8.9 years) and 1,133 (55.3%) surgeries were performed on female patients. Pre-existing ocular co-morbidity was present in 165 patients (8.1%). The most common procedure was small incision cataract surgery (SICS) with intraocular lens (IOL) implantation (91.8%). Intraoperative complications were seen in 29 eyes (1.4%). At the 4–11 weeks follow-up visit, based on presenting visual acuity (PVA), 61.8% had a good outcome and based on best-corrected visual acuity (BCVA), 91.7% had a good outcome. Based on PVA and BCVA, those with less than 6/60 were only 2.9% and 1.6% respectively. Using multivariable analysis, poor visual outcomes were significantly higher in patients aged ≥70 (OR 4.63; 95% CI 1.61, 13.30), in females (OR 1.58; 95% CI 1.04, 2.41), those with preoperative comorbidities (odds ratio 4.68; 95% CI 2.90, 7.57), with intraoperative complications (OR 8.01; 95% CI 2.91, 22.04), eyes that underwent no IOL or anterior chamber-IOL (OR 12.63; 95% CI 2.65, 60.25) and those undergoing extracapsular cataract extraction (OR 9.39; 95% CI 1.18, 74.78).ConclusionsThis study demonstrates that quality cataract surgeries can be achieved at rural SCs. The concept of the LVPEI SCs can be applied to other developing countries, allowing rural patients to attain better vision through cataract surgery. Despite improvements in quality of cataract surgery, gender discrimination in terms of outcome continues to be an issue and needs further investigation.

OBJECTIVE The establishment of mechanical thrombectomy (MT) as a first-line treatment for select patients with acute ischemic stroke (AIS) and the expansion of stroke systems of care have been major advancements in the care of patients with AIS. In this study, the authors aimed to identify temporal trends in the usage of tissue-type plasminogen activator (tPA) and MT within the AIS population from 2012 to 2018, and the relationship to mortality. METHODS Using a nationwide private health insurance database, 117,834 patients who presented with a primary AIS between 2012 and 2018 in the United States were identified. The authors evaluated temporal trends in tPA and MT usage and clinical outcomes stratified by treatment and age using descriptive statistics. RESULTS Among patients presenting with AIS in this population, the mean age was 69.1 years (SD ± 12.3 years), and 51.7% were female. Between 2012 and 2018, the use of tPA and MT increased significantly (tPA, 6.3% to 11.8%, p < 0.0001; MT, 1.6% to 5.7%, p < 0.0001). Mortality at 90 days decreased significantly in the overall AIS population (8.7% to 6.7%, p < 0.0001). The largest reduction in 90-day mortality was seen in patients treated with MT (21.4% to 14.1%, p = 0.0414) versus tPA (11.8% to 7.0%, p < 0.0001) versus no treatment (8.3% to 6.3%, p < 0.0001). Age-standardized mortality at 90 days decreased significantly only in patients aged 71–80 years (11.4% to 7.8%, p < 0.0001) and > 81 years (17.8% to 11.6%, p < 0.0001). Mortality at 90 days stagnated in patients aged 18 to 50 years (3.0% to 2.2%, p = 0.4919), 51 to 60 years (3.8% to 3.9%, p = 0.7632), and 61 to 70 years (5.5% to 5.2%, p = 0.2448). CONCLUSIONS From 2012 to 2018, use of tPA and MT increased significantly, irrespective of age, while mortality decreased in the entire AIS population. The most dramatic decrease in mortality was seen in the MT-treated population. Age-standardized mortality improved only in patients older than 70 years, with no change in younger patients.

Despite decades of extensive studies on the reactivity of magnesium alkyls towards O2, the isolation and structural characterization of discrete products of these reactions still remains a challenge. Although the formation of the most frequently encountered magnesium alkoxides through unstable alkylperoxide intermediates has commonly been accepted, the latter species have been elusive for over 100 years. Probing the oxygenation of a seemingly simple well‐defined neo‐pentylmagnesium complex stabilized by a β‐diketiminate ligand, (dippBDI)MgCH2CMe3, we report on the isolation and structure characterization of both a dimeric magnesium alkoxide [(dippBDI)Mg(μ‐OCH2CMe3)]2 and the first example of monomeric magnesium alkylperoxide [(dippBDI)Mg(thf)OOCH2CMe3] (dippBDI=[(ArNCMe)2CH]− and Ar=C6H3iPr2‐2,6). The formation of monomeric magnesium alkylperoxide demonstrates a crucial role of an additional Lewis base for stabilizing the most elusive oxygenation products likely due to increasing of the electron density on the metal centre. Moreover, the 1H NMR studies at −80 °C revealed that the dissociation of a coordinated Lewis base from the solvated complex (dippBDI)Mg(L)CH2CMe3 (where L=thf or 4‐methylpyridine) is likely not required prior to the effective attack of an O2 molecule on the metal centre and the four‐coordinate alkylmagnesium complex reacts smoothly with O2 under these conditions. The results can be expected to aid future engineering of various organomagnesium/O2‐based reaction systems.

We report star polymer metal-organic cage (polyMOC) materials whose structures, mechanical properties, functionalities, and dynamics can all be precisely tailored through a simple threecomponent assembly strategy. The star polyMOC network is composed of tetra-arm star polymers functionalized with ligands on the chain ends, small molecule ligands, and palladium ions; polyMOCs are formed via metal-ligand coordination and thermal annealing. The ratio of small molecule ligands to polymer-bound ligands determines the connectivity of the MOC junctions and the network structure. The use of large M 12 L 24 MOCs enables great flexibility in tuning this ratio, which provides access to a rich spectrum of material properties including tunable moduli and relaxation dynamics. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptA three-component assembly strategy is reported that enables the creation of a versatile class of polymer metal-organic cage (polyMOC) networks with tailored microstructures, mechanical properties, functionalities, and network dynamics. KeywordsMetal-organic cage; Metal-organic polyhedra; Polymer network; Metallosupramolecular assembly; Gel; PolyMOC Polymer networks are versatile materials with a wide range of structures and properties suitable for industrial and academic applications. [1][2][3] In a typical network, macromolecules of choice are connected to branched junctions of a particular type; the nature of these components determines the material's properties such as stiffness, toughness, responsiveness, etc. [2] Several strategies have been developed to tune polymer network structure in order to realize desirable properties. For example, interpenetrating networks, [4][5] nanocomposites, [6] and reversible and/or dynamic covalent bonds [7] are employed to yield materials with self-healing, stimuli-responsive, and other valuable behaviors. [7][8] In all of these cases, control over network structure and dynamics is critical. In this communication, we describe a versatile and simple strategy for controlling structure, function, and dynamics in a relatively new class of polymer networks that is based on the use of large metal-organic cages/polyhedra (MOCs).MOCs are discrete 3D structures assembled from x metal ions and y organic ligands via coordination bonds. [9][10][11][12][13][14][15][16][17][18][19][20][21][22] By rational design of the ligands and proper choice of the metal ions, MOCs of different M x L y stoichiometries, sizes, and geometries can be synthesized. [23][24][25][26][27][28][29] Inspired by this structural versatility and potential applications such as mechanical enhancement, catalysis, encapsulation, sensing, etc., much effort has been recently devoted to installing MOCs into polymer networks to provide 'polyMOC' hybrid materials with tunable viscoelasticity and functionality. [30][31][32][33][34][35][36][37] One [30,[38][39][40][41][42] ; however, there is still a great need to understand how polyMOC microstructure translates to bulk ...