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The formulation of high-concentration monoclonal antibody (mAb) solutions in low dose volumes for autoinjector devices poses challenges in manufacturability and patient administration due to elevated solution viscosity. Often many therapeutically potent mAbs are discovered, but their commercial development is stalled by unfavourable developability challenges. In this work, we present a systematic experimental framework for the computational screening of molecular descriptors to guide the design of 24 mutants with modified viscosity profiles accompanied by experimental evaluation. Our experimental observations using a model anti-IL8 mAb and eight engineered mutant variants reveal that viscosity reduction is influenced by the location of hydrophobic interactions, while targeting positively charged patches significantly increases viscosity in comparison to wild-type anti-IL-8 mAb. We conclude that most predicted in silico physicochemical properties exhibit poor correlation with measured experimental parameters for antibodies with suboptimal developability characteristics, emphasizing the need for comprehensive case-by-case evaluation of mAbs. This framework combining molecular design and triage via computational predictions with experimental evaluation aids the agile and rational design of mAbs with tailored solution viscosities, ensuring improved manufacturability and patient convenience in self-administration scenarios.

Abstract Background Peanut allergy is a common food allergy with potentially life-threatening implications. Early oral immunotherapy for peanut allergy (P-EOIT) has been shown to be effective and safe in research and specialty clinic settings. Provision of P-EOIT in primary care would make it available to more patients. We sought to assess the safety of P-EOIT in a primary care setting by documenting the rates of peanut-related allergic reactions leading to emergency department (ED) visits and use of epinephrine. We also examined adherence by assessing the percentage of patients reaching maintenance phase and continuing ingestion after one year of P-EOIT. Methods This retrospective study included all patients aged less than 36 months who started P-EOIT at a primary care allergy clinic in New Brunswick, Canada, from 2016 to 2020. The population included patients who (1) had a history of an allergic reaction to peanuts with a positive skin prick test or positive peanut specific IgE level (ps-IgE) or (2) no history of ingestion and a baseline ps-IgE ≥5 kU/L. Patients had biweekly clinic visits with graded increases in peanut protein up to a maintenance dose of 300 mg of peanut protein daily. A blinded retrospective review of paper charts and electronic medical records was conducted along with phone interviews regarding ED visits and epinephrine use. Results All 69 consented patients reached maintenance dose over a median of 29 weeks, and 66 patients (95.7%) were still regularly consuming peanut protein after 1 year of maintenance. One patient had a peanut ingestion-related ED visit requiring epinephrine during the escalation phase of peanut protein dosing (1.4%). During the first year of maintenance phase, no patients had peanut ingestion-related ED visits nor required epinephrine. Conclusion Early oral immunotherapy for peanut allergy in a primary care setting appears to be safe and our findings suggest that it does not lead to an increased burden of emergency department visits. Our population had high adherence rates, with the majority achieving maintenance dose and staying on this dose for one year.

Setting goals that are context-specific, relevant, and collectively shared is critical in adaptation. As necessary elements in target setting, imaginaries for adaptation and the language connected to them remain vague. Visuals produced through art-science collaborations can be great allies to (de)construct imaginaries and deglobalise discourses of adaptation.

Autoimmune Hepatitis (AIH) is a progressive form of chronic hepatitis, with periods of remissions and exacerbations. Diagnosis includes abnormally high levels of immunoglobulins and multiple autoantibodies. Clinical presentation is variable, with a spectrum extending from asymptomatic cases to fulminant liver failure. Symptoms include abdominal pain, malaise, fatigue, and small joint arthralgia. We present a case of a 36-year-old male with a past medical history of alcohol dependence and acute pancreatitis who was diagnosed with AIH. There is limited data regarding patients with concomitant AIH and pancreatitis. Our patient presented with AIH with secondary acute on chronic pancreatitis, in the absence of additional autoimmune manifestations. The mechanism of AIH remains poorly understood; however, there is an association between the HLA gene and AIH. Genetic studies have shown HLA-DRB1*0301 and HLA-DRB1*0401 as primary and secondary genotypes susceptible to AIH, as well as genetic variants with CARD10 and SH2B3. Products secondary to metabolism of ETOH such as alcohol dehydrogenase, malondialdehyde, and acetaldehyde, can lead to development of autoantibodies. Additional research is indicated to evaluate the relationship between AIH and acute pancreatitis.

Quantification of anion binding by molecular receptors within lipid bilayers is challenging. Here, the authors synthesise a high-affinity macrocyclic anion receptor which provides insights into determinants of anion binding within lipid bilayers.

Metronidazole is a common antibiotic agent for hepatic abscesses, which require both gram-negative and anaerobic coverage. Rarely, this antibiotic has been found to induce encephalopathy. Here, we describe a 65-year-old male who was treated with metronidazole for his hepatic abscess, who presented with syncope and questionable seizure and was found to have magnetic resonance imaging (MRI) brain findings consistent with metronidazole toxicity. Our patient demonstrated striking brain MRI findings which can be used to further understand the process behind this medication-induced toxicity. Hypotheses of this mechanism include swelling of axons secondary to increased water or vasospasm leading to reversible ischemia that is localized in the brain. In terms of MRI findings, brain lesions tend to populate bilaterally with focus at the dorsal pons, midbrain, cerebellar dentate nuclei (as with our patient), dorsal medulla, or splenium of corpus callosum. Additional research is warranted regarding this rare manifestation and timely removal of the offending agent is crucial for reversal of symptoms.

Tradução de Exploration of the Valley of the Amazon (cap. Xiv) (1853)

Ruthenium complexes of phosphinocarboxamide ligands, and their use to form metallacycles using halide abstraction/deprotonation reactions are reported. Thus, [Ru(p-cym){PPh2C(=O)NHR}Cl2; R = iPr (1), Ph (2), p-tol (3)] and [Ru(p-cym){PPh2C(=O)N(R)C(=O)N(H)R}Cl2; R = Ph (4), p-tol (5)] were synthesized from [(p-cym)RuCl2]2 (p-cym = para-cymene) and phosphinocarboxamides or phosphinodicarboxamides, respectively. Single-crystal X-ray diffraction measurements on 1–5 reveal coordination to ruthenium through the phosphorus donor, with an intramolecular hydrogen bond between the amine-bound proton and a metal-bound chloride. Six-membered metallacycles formed by halide abstraction/deprotonation of complexes 4 and 5 afforded [Ru(p-cym){κ2-P,N-PPh2C(=O)N(R)C(=O)NR}Cl] [R = Ph (6), p-tol (7)]. These species exist as a mixture of two rotational isomers in solution, as demonstrated by NMR spectroscopy.

Porous coordination frameworks that undergo reversible structural transformations are promising for sensing, switching and separations. Here, the authors report an electroactive framework that exhibits a reversible single crystal-to-single crystal double [2+2] photocyclisation, leading to property changes.

An organic–inorganic hybrid species based on the Wells–Dawson polyoxotungstate [P2W18O62]6− and novel fluorescent benzothiadiazole–imidazolium cations, [BTD-4,7-ImH]2+, has been synthesized. X-ray crystallographic analysis shows that the inorganic and organic components form a hydrogen-bonded superstructure and that the cations are revealed to be non-equivalent with varying degrees of rotation between the BTD and imidazolium rings due to competition between weak intra- and intermolecular interactions. The UV–vis diffuse reflectance spectra indicate that the hybrid has a band gap of 3.13 eV, while the solid-state fluorescence properties of the cation are quenched in the hybrid material, suggesting the existence of electron transfer between the inorganic and organic components. The highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) energies of the polyoxometalate (POM) and BTD-4,7-ImH precursors, estimated through UV–vis absorption spectroscopy and cyclic voltammetry, indicate that electron transfer from the BTD cations to the POM may occur in the excited state.

Metal-mediated activation of CO for C-C coupling reactions is a valuable approach to carbon monoxide valorization. Here, the authors use low-coordinate iron(II) complexes for the selective scission and homologation of CO affording unusual squaraines and iron carboxylates under mild conditions.

Owing to the propensity for uranium(III) compounds to undergo disproportionation, uranium-element multiple bonds involving uranium(III) oxidation states remain rare. Here the authors report hexauranium-methanediide rings that formally contain uranium(III)- and uranium(IV)-methanediides supported by alternating halide and arene bridges.

The inverse-trans-influence has been shown to operate in high oxidation state actinide complexes. Here, the authors report tetravalent cerium, uranium and thorium bis(carbene) complexes with trans C=M=C cores where experimental and theoretical data also suggest the presence of an inverse-trans-effect.

This study provides an evaluation of multiple sensors by examining their precision and ability to capture topographic complexity. Five different small unmanned aerial systems (sUAS) were evaluated, each with a different camera, Global Navigation Satellite System (GNSS), and Inertial Measurement Unit (IMU). A lidar was also used on the largest sUAS and as a mobile scanning system. The quality of each of the seven platforms were compared to actual surface measurements gathered with real-time kinematic (RTK)-GNSS and terrestrial laser scanning. Rigorous field and photogrammetric assessment workflows were designed around a combination of structure-from-motion to align images, Monte Carlo simulations to calculate spatially variable error, object-based image analysis to create objects, and MC32-PM algorithm to calculate vertical differences between two dense point clouds. The precision of the sensors ranged 0.115 m (minimum of 0.11 m for MaRS with Sony A7iii camera and maximum of 0.225 m for Mavic2 Pro). In a heterogenous test location with varying slope and high terrain roughness, only three of the seven mobile platforms performed well (MaRS, Inspire 2, and Phantom 4 Pro). All mobile sensors performed better for the homogenous test location, but the sUAS lidar and mobile lidar contained the most noise. The findings presented herein provide insights into cost–benefit of purchasing various sUAS and sensors and their ability to capture high-definition topography.

Actinide electronic structure determination is fundamentally challenging. Here, the authors assemble a family of uranium(V)-nitrides and quantify the electronic structure of the molecules, defining the relative importance of spin orbit coupling and crystal field interactions.

Synthetic anion transporters that facilitate chloride transport are promising candidates for channelopathy treatments. However, most anion transporters exhibit an undesired side effect of facilitating proton transport via interacting with fatty acids present in the membrane. To address the limitation, we here report the use of a new tetrapodal scaffold to maximize the selective interaction with spherical chloride over binding the carboxylate headgroup of fatty acids. One of the new transporters demonstrated a high selectivity for chloride uniport over fatty acid-induced proton transport while being >10 times more active in chloride uniport than strapped calixpyrroles that were previously the only class of compounds known to possess similar selectivity properties.

Functionalization of 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) chromophores at the 2,6-positions with iodo substituents and morpholino-substituted α-methyl groups affords molecules with strong absorbance in the visible spectrum. The effect of such substitution on the solid-state arrangements, absorption, fluorescence and electronic properties of these dye molecules is reported. The spectroscopic and spectroelectrochemical measurements display intense absorptions in the UV-visible spectrum with bathochromic shifts, in comparison to unfunctionalized BODIPY, and a positive shift in redox potentials due to functionalisation of the BODIPY core. Halogen bonds are observed in the solid-state structures of both halogenated BODIPY species, which in one case leads to the formation of an unusual halogen bonded framework.

1,4-Diols resulting from the double addition of ArCCLi (Ar = Ph, substituted phenyl, 2-thienyl) to ortho-C6H4(CHO)2 undergo cascades to tetracenes on simple admixture of LiHDMS, CS2 and MeI. Acene formation proceeds by [3,3]-sigmatropic rearrangement of xanthate anions followed by 6π electrocyclisations. The reactions are terminated by E2 or anionic Chugaev-type eliminations. Structural packing motifs and electronic properties are reported for the tetracenes.

We report the extension of the series of {BIPMTMSH}− (BIPMR = C{PPh2NR}2, TMS = trimethylsilyl) derived rare earth methanides by the preparation of [Ln(BIPMTMSH)(I)2(THF)] (Ln = Nd, Gd, Tb), 1a–c, in 34–50% crystalline yields via the reaction of [Ln(I)3(THF)3.5] with [Cs(BIPMTMSH)]. Similarly, we have extended the range of {BIPMMesH}− (Mes = 2,4,6-trimethylphenyl) derived rare earth methanides with the preparation of [Gd(BIPMMesH)(I)2(THF)2], 3, (49%) and [Yb(BIPMMesH)(I)2(THF)], 4, (26%), via the reaction of [Ln(I)3(THF)3.5] with [{K(BIPMMesH)}2]. Attempts to prepare dysprosium and erbium analogues of 3 or 4 were not successful, with the ion pair species [Ln(BIPMMesH)2][BIPMMesH] (Ln = Dy, Er), 5a–b, isolated in 31–39% yield. The TMEDA (N',N',N",N"-tetramethylethylenediamine) adducts [Ln(BIPMMesH)(I)2(TMEDA)] (Ln = La, Gd), 6a–b, were prepared in quantitative yield via the dissolution of [La(BIPMMesH)(I)2(THF)] or 3 in a TMEDA/THF solution. The reactions of [Ln(BIPMMesH)(I)2(THF)] [Ln = La, Ce, Pr, and Gd (3)] or 6a–b with a selection of bases did not afford [La(BIPMMes)(I)(S)n] (S = solvent) as predicted, but instead led to the isolation of the heteroleptic complexes [Ln(BIPMMes)(BIPMMesH)] (Ln = La, Ce, Pr and Gd), 7a–d, in low yields due to ligand scrambling.

Nature Communications 8: Article number: 14137 (2017); Published: 3 February 2017; Updated: 5 February 2018 The original version of this Article contained a typographical error in Fig. 2, where reagent H2C(Ph2PNSiMe3)2 was incorrectly given as H2C(PNSiMe3)2. This has now been corrected in both the PDF and HTML versions of the Article.

It is well documented that PPARα and PPARβ/δ share overlapping functions in regulating myocardial lipid metabolism. However, previous studies demonstrated that cardiomyocyte-restricted PPARβ/δ deficiency in mice leads to severe cardiac pathological development, whereas global PPARα knockout shows a benign cardiac phenotype. It is unknown whether a PPARα-null background would alter the pathological development in mice with cardiomyocyte-restricted PPARβ/δ deficiency. In the present study, a mouse model with long-term PPARβ/δ deficiency in PPARα-null background showed a comparably reduced cardiac expression of lipid metabolism to those of single PPAR-deficient mouse models. The PPARα-null background did not rescue or aggravate the cardiac pathological development linked to cardiomyocyte-restricted PPARβ/δ deficiency. Moreover, PPARα-null did not alter the phenotypic development in adult mice with the short-term deletion of PPARβ/δ in their hearts, which showed mitochondrial abnormalities, depressed cardiac performance, and cardiac hypertrophy with attenuated expression of key factors in mitochondrial biogenesis and defense. The present study demonstrates that cardiomyocyte-restricted deletion of PPARβ/δ in PPARα-null mice causes impaired mitochondrial biogenesis and defense, but no further depression of fatty acid oxidation. Therefore, PPARβ/δ is essential for maintaining mitochondrial biogenesis and defense in cardiomyocytes independent of PPARα.

The reaction of a sulfur ylide with a chiral non-racemic sulfinyl imine afforded the desired aziridine in excellent yield and subsequent oxidation of the sulfinyl moiety dissolved in anhydrous dichloromethane using a 75% aqueous solution of 3-chloroperoxybenzoic acid afforded the title compound, C14H27NO6S. The configuration of the newly formed stereogenic center at the point of attachment of the 1,4-dioxane ring to the aziridine ring is S. The configurations of the pre-existing sites 2-, 5-, and 6-positions of the 1,4-dioxane ring prior to reaction of sulfinyl imine with the sulfur ylide are S, R, and R, respectively. The C—N bond lengths of the aziridine are 1.478 (2) and 1.486 (2) Å.