Defining the principles of T cell migration in structurally and mechanically complex tumor microenvironments is critical to understanding escape from antitumor immunity and optimizing T cell-related ...therapeutic strategies. Here, we engineered nanotextured elastic platforms to study and enhance T cell migration through complex microenvironments and define how the balance between contractility localization-dependent T cell phenotypes influences migration in response to tumor-mimetic structural and mechanical cues. Using these platforms, we characterize a mechanical optimum for migration that can be perturbed by manipulating an axis between microtubule stability and force generation. In 3D environments and live tumors, we demonstrate that microtubule instability, leading to increased Rho pathway-dependent cortical contractility, promotes migration whereas clinically used microtubule-stabilizing chemotherapies profoundly decrease effective migration. We show that rational manipulation of the microtubule-contractility axis, either pharmacologically or through genome engineering, results in engineered T cells that more effectively move through and interrogate 3D matrix and tumor volumes. Thus, engineering cells to better navigate through 3D microenvironments could be part of an effective strategy to enhance efficacy of immune therapeutics.
Aminated derivatives of 5-hydroxymethylfurfural (HMF) and furfural are critical intermediates for the pharmaceutical industry. The state-of-the-art catalysts currently used for these syntheses are ...mostly homogeneous in nature, motivating the design of recyclable, heterogeneous catalytic systems. As such, the present study illustrates a new method for the design of metal-organic framework (MOF)/polymer composites containing well-defined metal nanoparticles in a sustainable way. One such palladium functionalized MOF/polymer composite is then employed in the reductive amination of HMF under mild conditions. The catalyst shows excellent activity, including a high TON/TOF (h
−1
) of 604.8/302.4 and ∼94% amine yield, which is maintained over a larger number of reaction cycles (up to 15) when compared to several state-of-the-art materials, such as a commercial Pd/C (3 cycles). It is thought that the origin of the improved catalyst recyclability is due to the added polymer, poly-
para
-phenylenediamine (P
p
PDA), which helps to prevent the aggregation and leaching of the palladium nanoparticles. The synthetic approach is further extended to design other potential catalysts with different metallic nanoparticles (NPs).
Making heterogeneous catalysis greener by improving nanoparticle stability in a MOF support modified with short polymeric chains.
There is a strong need for a new broad-spectrum antiinfluenza therapeutic, as vaccination and existing treatments are only moderately effective. We previously engineered a lectin, H84T banana lectin ...(H84T), to retain broad-spectrum activity against multiple influenza strains, including pandemic and avian, while largely eliminating the potentially harmful mitogenicity of the parent compound. The amino acid mutation at position 84 from histidine to threonine minimizes the mitogenicity of the wild-type lectin while maintaining antiinfluenza activity in vitro. We now report that in a lethal mouse model H84T is indeed nonmitogenic, and both early and delayed therapeutic administration of H84T intraperitoneally are highly protective, as is H84T administered subcutaneously. Mechanistically, attachment, which we anticipated to be inhibited by H84T, was only somewhat decreased by the lectin. Instead, H84T is internalized into the late endosomal/lysosomal compartment and inhibits virus–endosome fusion. These studies reveal that H84T is efficacious against influenza virus in vivo, and that the loss of mitogenicity seen previously in tissue culture is also seen in vivo, underscoring the potential utility of H84T as a broad-spectrum antiinfluenza agent.
Covering: 1997 to 2023
The shikimate pathway is the metabolic process responsible for the biosynthesis of the aromatic amino acids phenylalanine, tyrosine, and tryptophan. Seven metabolic steps ...convert phosphoenolpyruvate (PEP) and erythrose 4-phosphate (E4P) into shikimate and ultimately chorismate, which serves as the branch point for dedicated aromatic amino acid biosynthesis. Bacteria, fungi, algae, and plants (yet not animals) biosynthesize chorismate and exploit its intermediates in their specialized metabolism. This review highlights the metabolic diversity derived from intermediates of the shikimate pathway along the seven steps from PEP and E4P to chorismate, as well as additional sections on compounds derived from prephenate, anthranilate and the synonymous aminoshikimate pathway. We discuss the genomic basis and biochemical support leading to shikimate-derived antibiotics, lipids, pigments, cofactors, and other metabolites across the tree of life.
The shikimate pathway is the metabolic process responsible for the biosynthesis of proteinogenic, aromatic amino acids as well as a bevy of specialized metabolites in bacteria, fungi, and plants.
Objective and designPatients with type 2 diabetes mellitus (T2D) have an increased fracture risk despite a normal or elevated bone mineral density (BMD). The aim of this cross-sectional in vivo study ...was to assess parameters of peripheral bone microarchitecture, estimated bone strength and bone remodeling in T2D patients with and without diabetic microvascular disease (MVD+ and MVD− respectively) and to compare them with healthy controls.MethodsFifty-one T2D patients (MVD+ group: n=25) were recruited from Funen Diabetic Database and matched for age, sex and height with 51 healthy subjects. High-resolution peripheral quantitative tomography (HR-pQCT) was used to assess bone structure at the non-dominant distal radius and tibia. Estimated bone strength was calculated using finite element analysis. Biochemical markers of bone turnover were measured in all participants.ResultsAfter adjusting for BMI, MVD+ patients displayed lower cortical volumetric BMD (P=0.02) and cortical thickness (P=0.02) and higher cortical porosity at the radius (P=0.02) and a trend towards higher cortical porosity at the tibia (P=0.07) compared to controls. HR-pQCT parameters did not differ between MVD− and control subjects. Biochemical markers of bone turnover were significantly lower in MVD+ and MVD− patients compared to controls (all P<0.01). These were no significant correlations between disease duration, glycemic control (average glycated hemoglobin over the previous 3 years) and HR-pQCT parameters.ConclusionCortical bone deficits are not a characteristic of all T2D patients but of a subgroup characterized by the presence of microvascular complications. Whether this influences fracture rates in these patients needs further investigation.
Abstract
SN 2014C was originally classified as a Type Ib supernova, but at phase
ϕ
= 127 days, post-explosion strong H
α
emission was observed. SN 2014C has since been observed in radio, infrared, ...optical and X-ray bands. Here we present new optical spectroscopic and photometric data spanning
ϕ
= 947–2494 days post-explosion. We address the evolution of the broadened H
α
emission line, as well as broad O
iii
emission and other lines. We also conduct a parallel analysis of all publicly available multiwavelength data. From our spectra, we find a nearly constant H
α
FWHM velocity width of ∼2000 km s
−1
that is significantly lower than that of other broadened atomic transitions (∼3000–7000 km s
−1
) present in our spectra (O
i
λ
6300; O
iii
λ
λ
4959, 5007; He
i
λ
7065; Ca
ii
λ
λ
7291, 7324). The late radio data demand a fast forward shock (∼10,000 km s
−1
at
ϕ
= 1700 days) in rarified matter that contrasts with the modest velocity of the H
α
. We propose that the infrared flux originates from a toroidal-like structure of hydrogen surrounding the progenitor system, while later emission at other wavelengths (radio, X-ray) likely originates predominantly from the reverse shock in the ejecta and the forward shock in the quasi-spherical progenitor He-wind. We propose that the H
α
emission arises in the boundary layer between the ejecta and torus. We also consider the possible roles of a pulsar and a binary companion.
Three dimensional (3D) topological insulators (TIs) are an important class of materials with applications in electronics, spintronics and quantum computing. With the recent development of truly bulk ...insulating 3D TIs, it has become possible to realize surface dominated phenomena in electrical transport measurements e.g. the quantum Hall (QH) effect of massless Dirac fermions in topological surface states (TSS). However, to realize more advanced devices and phenomena, there is a need for a platform to tune the TSS or modify them e.g. gap them by proximity with magnetic insulators, in a clean manner. Here we introduce van der Waals (vdW) heterostructures in the form of topological insulator/insulator/graphite to effectively control chemical potential of the TSS. Two types of gate dielectrics, normal insulator hexagonal boron nitride (hBN) and ferromagnetic insulator Cr2Ge2Te6 (CGT) are utilized to tune charge density of TSS in the quaternary TI BiSbTeSe2. hBN/graphite gating in the QH regime shows improved quantization of TSS by suppression of magnetoconductivity of massless Dirac fermions. CGT/graphite gating of massive Dirac fermions in the QH regime yields half-quantized Hall conductance steps and a measure of the Dirac gap. Our work shows the promise of the vdW platform in creating advanced high-quality TI-based devices.
Contact guidance due to extracellular matrix architecture is a key regulator of carcinoma invasion and metastasis, yet our understanding of how cells sense guidance cues is limited. Here, using a ...platform with variable stiffness that facilitates uniaxial or biaxial matrix cues, or competing E-cadherin adhesions, we demonstrate distinct mechanoresponsive behavior. Through disruption of traction forces, we observe a profound phenotypic shift towards a mode of dendritic protrusion and identify bimodal processes that govern guidance sensing. In contractile cells, guidance sensing is strongly dependent on formins and FAK signaling and can be perturbed by disrupting microtubule dynamics, while low traction conditions initiate fluidic-like dendritic protrusions that are dependent on Arp2/3. Concomitant disruption of these bimodal mechanisms completely abrogates the contact guidance response. Thus, guidance sensing in carcinoma cells depends on both environment architecture and mechanical properties and targeting the bimodal responses may provide a rational strategy for disrupting metastatic behavior.
Electrically conductive two‐dimensional (2D) metal–organic frameworks (MOFs) have emerged as good candidates for thermoelectric applications due to their high electrical and low thermal ...conductivities. This work studies the microscopic origin of the thermoelectric properties of copper benzenehexathiol (Cu‐BHT), a highly electrically conductive 2D MOF. 2D MOFs usually have polycrystalline domains because of the bottom‐up synthesis, and the polycrystallinity makes it challenging to understand the intrinsic properties of 2D MOFs. Mesoscopic‐scale devices are fabricated to measure the thermal conductivity, electrical conductivity, and Seebeck coefficient of Cu‐BHT by exfoliating the synthesized Cu‐BHT samples into thin films of thickness ranging from 30 to 400 nm. It is verified that the low thermal conductivity of Cu‐BHT originates from the unique intrinsic structure of 2D MOFs, while our data indicates that the electrical conductivity is largely controlled by the polycrystallinity. The Seebeck effect measurement reveals the presence of robust electronic bands arising from definite crystallinity, which differentiates 2D MOFs from conductive polymers. This work points to opportunities in optimizing the thermoelectric figure of merit of 2D MOFs through the appropriate combination of metal ions and organic ligands.
Thermoelectric properties of copper benzenehexathiol (CuBHT)—a highly electrically conductive 2D metalorganic framework (MOF)—are investigated. It is found that the intrinsic nanopore structure is responsible for the low thermal conductivity of CuBHT, while the extrinsic polycrystallinity controls the electrical conductivity. The presence of robust electronic bands arising from definite crystallinity makes CuBHT a unique candidate material for organic thermoelectrics.
Herpes simplex virus (HSV) infection triggered n-methyl-D-aspartate (NMDA) encephalitis can lead to varied neuropsychiatric manifestations, including movement disorders and manic symptoms. HSV is ...known to affect the same brain regions as in secondary mania.
We present a 35-year-old female diagnosed with recurrent depressive disorder (RDD) who developed NMDA encephalitis triggered by HSV infection.
HSV-triggered NMDA encephalitis led to a manic switch in a woman with RDD on antidepressants, along with the new onset of dyskinetic movements.
A neurological insult predisposed our patient to the variable effects of antidepressant drugs.
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