It has been established that a newly developed cyclopentadienyl rhodium(III) CpARhIII complex, bearing an acidic secondary amide moiety on the Cp ring, is able to catalyze the ortho‐bromination of ...O‐phenyl carbamates with N‐bromosuccinimide (NBS) at room temperature. The presence of the acidic secondary amide moiety on the CpA ligand accelerates the bromination by the hydrogen bond between the acidic NH group of the CpA ligand and the carbonyl group of NBS.
Makes it faster! It has been established that a newly developed cyclopentadienyl rhodium(III) CpARhIII complex, bearing an acidic secondary amide moiety on the Cp ring, is able to catalyze the ortho‐bromination of O‐phenyl carbamates with NBS at room temperature. The hydrogen bond between the acidic NH group of the CpA ligand and the carbonyl group of NBS accelerates the bromination.
Building functional mimics of cell membranes is an important task toward the development of synthetic cells. So far, lipid and amphiphilic block copolymers are the most widely used amphiphiles with ...the bilayers by the former lacking stability while membranes by the latter are typically characterized by very slow dynamics. Herein, a new type of Janus dendrimer containing a zwitterionic phosphocholine hydrophilic headgroup (JDPC) and a 3,5‐substituted dihydrobenzoate‐based hydrophobic dendron is introduced. JDPC self‐assembles in water into zwitterionic dendrimersomes (z‐DSs) that faithfully recapitulate the cell membrane in thickness, flexibility, and fluidity, while being resilient to harsh conditions and displaying faster pore closing dynamics in the event of membrane rupture. This enables the fabrication of hybrid DSs with components of natural membranes, including pore‐forming peptides, structure‐directing lipids, and glycans to create raft‐like domains or onion vesicles. Moreover, z‐DSs can be used to create active synthetic cells with life‐like features that mimic vesicle fusion and motility as well as environmental sensing. Despite their fully synthetic nature, z‐DSs are minimal cell mimics that can integrate and interact with living matter with the programmability to imitate life‐like features and beyond.
The synthesis of a phosphocholine‐based Janus dendrimer is reported, which lacks the “weak points” that result in the chemical and physical instability of natural liposomes. Despite their synthetic nature, the resulting self‐assembled dendrimersomes recapitulate the most important physical properties of cell membranes. This enables functionalization with natural functional molecules as well as mimicry of cellular functions on a basic level.
•Men show higher rates of facial contact than women.•Rates of facial contact can vary in different social situations.•Fatigue and distraction increase rates of facial contact and subsequent infection ...risk.
Decreasing facial contact takes on new urgency as society tries to stem the tide of COVID-19 spread. A better understanding of the pervasiveness of facial contact in social settings is required in order to then take steps to mitigate the action.
YouTube videos of random individuals were included in a behavioral observation study to document rates of contact to the eyes, nose, and mouth area. Factors including age, sex, the presence of eyewear or facial hair, distraction and fatigue were analyzed as possible contributing factors that increase likelihood of facial contact.
The median rate of facial contact was 22 contacts per hour. Men had a significantly higher rate of facial contact compared to women. Age, glasses, and presence of facial hair were not contributing factors. The mouth was the most frequently observed site of contact. Fatigue and distraction may increase rates of facial contact.
Changing personal behavior is a simple and cost-effective action that can be employed to reduce one's risk of acquiring an infectious disease. This study indicates that there are societal differences that put some individuals at higher risk of contracting infectious disease than others.
The immobilization of vesicles has been conceptualized as a method to functionalize biointerfaces. However, the preservation of their integrity post immobilization remains a considerable challenge. ...Interfacial interactions can cause vesicle rupture upon close surface contact and non‐specific protein adsorption impairing surface functions. To date, immobilization of vesicles has relied solely on either entrapment or prior modification of vesicles, both of which require laborious preparation and limit their applications. This work develops a bioinspired strategy to pin vesicles without prior modification while preserving their intact shape. This work introduces antifouling diblock copolymers and ultrathin surface‐attached hydrogels containing a brush‐like interface consisting of a bottle brush copolymer of N‐(2‐hydroxypropyl) methacrylamide (HPMA) and N‐(3‐methacrylamidopropyl)‐N,N‐dimethyldodecan‐1‐aminiumiodide (C12+). The presence of positive charges generates an attractive force that pulls vesicles toward the surface. At the surface, the amphiphilic properties of the combs facilitate their insertion into the membrane, mimicking the harpooning mechanism observed in antimicrobial peptides. Importantly, the antifouling poly(HPMA) backdrop serves to safeguard the vesicles by preventing deformation and breakage. Using a combination of thermodynamic analysis, surface plasmon resonance, and confocal laser scanning microscopy, this work demonstrates the efficiency of this biomimetic system to capture vesicles while maintaining an antifouling interface necessary for bioapplications.
This work presents a novel supramolecular approach that combines three key elements: long‐range attraction, vesicle pinning, and short‐range repulsion to attract and harpoon vesicles, while protecting them at the surface. This work envisions these coatings as universal and biocompatible platforms that can be used not only to study vesicle interactions, but also as tools for biomedical applications.
The integration of active cell machinery with synthetic building blocks is the bridge toward developing synthetic cells with biological functions and beyond. Self‐replication is one of the most ...important tasks of living systems, and various complex machineries exist to execute it. In Escherichia coli, a contractile division ring is positioned to mid‐cell by concentration oscillations of self‐organizing proteins (MinCDE), where it severs membrane and cell wall. So far, the reconstitution of any cell division machinery has exclusively been tied to liposomes. Here, the reconstitution of a rudimentary bacterial divisome in fully synthetic bicomponent dendrimersomes is shown. By tuning the membrane composition, the interaction of biological machinery with synthetic membranes can be tailored to reproduce its dynamic behavior. This constitutes an important breakthrough in the assembly of synthetic cells with biological elements, as tuning of membrane–divisome interactions is the key to engineering emergent biological behavior from the bottom‐up.
The reconstitution of a rudimentary bacterial divisome in fully synthetic bicomponent dendrimersomes is shown. The interactions between this active cell machinery and the synthetic membrane are tailored by adjusting its composition. Such fine‐tuning enables the reproduction of the natural dynamic behavior in a synthetic system and constitutes an important breakthrough in the assembly of synthetic cells with biological elements.
Background Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in childhood, whose prognosis is still poor especially for metastatic, high-grade, and relapsed RMS. New treatments are ...urgently needed, especially systemic therapies. Chimeric Antigen Receptor T cells (CAR Ts) are very effective against hematological malignancies, but their efficacy against solid tumors needs to be improved. CD276 (B7-H3) is a target upregulated in RMS and detected at low levels in normal tissues. FGFR4 is a very specific target for RMS. Here, we optimized CAR Ts for these two targets, alone or in combination, and tested their anti-tumor activity in vitro and in vivo. Methods Four different single-domain antibodies were used to select the most specific FGFR4-CAR construct. RMS cell killing and cytokine production by CD276- and FGFR4-CAR Ts expressing CD8alpha or CD28 HD/TM domains in combination with 4-1BB and/or CD28 co-stimulatory domains were tested in vitro. The most effective CD276- and FGFR4-CAR Ts were used to generate Dual-CAR Ts. Tumor killing was evaluated in vivo in three orthotopic RMS mouse models. Results CD276.V-CAR Ts (276.MG.CD28HD/TM.CD28CSD.3ζ) showed the strongest killing of RMS cells, and the highest release of IFN-gamma and Granzyme B in vitro. FGFR4.V-CAR Ts (F8-FR4.CD28HD/TM.CD28CSD.3ζ) showed the most specific killing. CD276-CAR Ts successfully eradicated RD- and Rh4-derived RMS tumors in vivo, achieving complete remission in 3/5 and 5/5 mice, respectively. In CD276.sup.low JR-tumors, however, they achieved complete remission in only 1/5 mice. FGFR4 CAR Ts instead delayed Rh4 tumor growth. Dual-CAR Ts promoted Rh4-tumors clearance in 5/5 mice. Conclusions CD276- and CD276/FGFR4-directed CAR Ts showed effective RMS cell killing in vitro and eradication of CD276.sup.high RMS tumors in vivo. CD276.sup.low tumors escaped the therapy highlighting a correlation between antigen density and effectiveness. FGFR4-CAR Ts showed specific killing in vitro but could only delay RMS growth in vivo. Our results demonstrate that combined expression of CD276-CAR with other CAR does not reduce its benefit. Introducing immunotherapy with CD276-CAR Ts in RMS seems to be feasible and promising, although CAR constructs design and target combinations have to be further improved to eradicate tumors with low target expression. Keywords: Rhabdomyosarcoma, CAR T cells, CD276 / B7-H3, FGFR4, Immunotherapy, Dual-CAR T cells
Background
Delirium is a clinical condition characterized by an acute change in brain function and is frequently observed in critically ill patients. The condition has been associated with negative ...outcomes, making it crucial to identify patients who are at risk. Two recent prediction models have been developed to estimate the risk of delirium in intensive care unit (ICU) patients; the prediction model for delirium (PRE‐DELIRIC) and the early prediction model for delirium (E‐PRE‐DELIRIC). We aimed to perform an external validation of these models in a Danish cohort of critically ill patients.
Methods
We conducted a prospective, observational multicenter study to validate the PRE‐DELIRIC and E‐PRE‐DELIRIC models in a population of patients admitted to four general ICUs in the Zealand Region of Denmark. From January 2022 to January 2023 all adult patients acutely admitted to the participating ICUs were assessed for eligibility. Patients had to be admitted to the ICU for >24 h to be included in the study. Included patients were screened with E‐PRE‐DELIRIC upon ICU admission and PRE‐DELIRIC after 24 h of admission and followed throughout their ICU stay with CAM‐ICU delirium assessments. Our primary outcomes were the prognostic accuracy measured by Area Under the Receiver Operating Characteristics (AUROC) and the calibration plot for the E‐PRE‐DELIRIC and PRE‐DELIRIC prediction models.
Results
We included 660 patients, of whom 660 were assessed with E‐PRE‐DELIRIC, and 622 were assessed with PRE‐DELIRIC. PRE‐DELIRIC showed acceptable discrimination with AUROC of 0.70 (95% CI 0.66 to 0.74) and good calibration. E‐PRE‐DELIRIC had inadequate discrimination AUROC of 0.63 (95% CI 0.58 to 0.67) and poor calibration.
Conclusion
In a Danish cohort, we found that the PRE‐DELIRIC model demonstrated acceptable performance and E‐PRE‐DELIRIC demonstrated poor performance. In critically ill adult patients PRE‐DELIRIC may be useful in identifying patients at high risk of delirium.
The construction of biomembranes that faithfully capture the properties and dynamic functions of cell membranes remains a challenge in the development of synthetic cells and their application. Here a ...new concept for synthetic cell membranes based on the self‐assembly of amphiphilic comb polymers into vesicles, termed ionic combisomes (i‐combisomes) is introduced. These combs consist of a polyzwitterionic backbone to which hydrophobic tails are linked by electrostatic interactions. Using a range of microscopies and molecular simulations, the self‐assembly of a library of combs in water is screened. It is discovered that the hydrophobic tails form the membrane's core and force the backbone into a rod conformation with nematic‐like ordering confined to the interface with water. This particular organization resulted in membranes that combine the stability of classic polymersomes with the biomimetic thickness, flexibility, and lateral mobility of liposomes. Such unparalleled matching of biophysical properties and the ability to locally reconfigure the molecular topology of its constituents enable the harboring of functional components of natural membranes and fusion with living bacteria to “hijack” their periphery. This provides an almost inexhaustible palette to design the chemical and biological makeup of the i‐combisomes membrane resulting in a powerful platform for fundamental studies and technological applications.
Comb polymers with a zwitterionic backbone and ionically‐linked side chains are self‐assembled into a new class of vesicles that amalgamates the high stability of polymersomes with the biomimetic thickness, flexibility, and lateral mobility of liposomes. The faithful biomimicry enables to integrate functional components and hijack the complex periphery of living cells by fusion.
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