Linear Analog Research Articles

Structural and Functional Characterization of an Amidase Targeting a Polyurethane for Sustainable Recycling.

Global plastic production exceeded 400 million tons in 2022, urgently demanding improved waste management and recycling strategies for a circular plastic economy. While the enzymatic hydrolysis of polyethylene terephthalate (PET) has become feasible on industrial scales, efficient enzymes targeting other hydrolysable plastic types such as polyurethanes (PURs) are lacking. Recently, enzymes of the amidase signature (AS) family, capable of cleaving urethane bonds in a polyether-PUR analog and a linear polyester-PUR, have been identified. Herein, we present high-resolution crystal structures of the AS enzyme UMG-SP3 in three states: ligand-free, bound with a suicidal inhibitor mimicking the transition state, and bound with a monomeric PUR degradation product. Besides revealing the conserved core and catalytic triad akin to other AS family members, the UMG-SP3 structures show remarkable flexibility of loop regions. Particularly, Arg209 in loop 3 adopts two induced-fit conformations upon ligand binding. Through structure-guided kinetic studies and enzyme engineering, we mapped structural key elements that determine the enhanced hydrolysis of urethane and amide bonds in various small molecules including a linear PUR fragment analog. Our findings contribute critical insights into urethanase activity, aiding PUR degradation campaigns and sustainable plastic recycling efforts in the future.

Smart and Efficient Synthesis of Cyclic Poly(N-isopropylacrylamide)s by Ring Expansion RAFT (RE-RAFT) Polymerization and Analysis of Their Unique Temperature-Responsive Properties.

Cyclic polymers have many interesting properties compared to their linear analogs, but there are very few examples of their synthesis. This is because most cyclic polymers have been synthesized by stepwise processes, including synthesizing homo- or hetero-telechelic end-functionalized precursor polymers and consecutive intramolecularly coupling of both ends of the polymers. This requires a complicated synthesis, and the product yields are very low because the target cyclic polymers are usually synthesized under highly dilute conditions, consequently, making it difficult to systematically analyze the properties of cyclic polymers. In the present research, we have synthesized cyclic polymers using a ring expansion polymerization method. Particularly, the ring expansion RAFT polymerization (RE-RAFT polymerization) that we have developed using a cyclic chain transfer agent is a smart method that can synthesize cyclic polymers very efficiently. In this paper, we successfully synthesized cyclic-poly(N-isopropylacrylamide), which is widely known as a thermo-responsive polymer, by RE-RAFT polymerization. Furthermore, we have compared the thermo-responsive properties of the cyclic-poly(N-isopropylacrylamide)s with those of their linear analogs.

Directed modification of characteristics of syntetyc analogue of proline-rich peptide ChBac3.4 through dendrimerisation

BACKGROUND: According to the World Health Organization, microbial resistance to antibiotics is one of the most serious threats to human health, food safety and economic development. Antimicrobial peptides of animal origin, to which resistance is difficult to develop, appear to be a promising option to overcome this problem. To solve one of the problems in the practical use of peptides — their rapid degradation in blood plasma — dendrimerization of linear analogues of already existing antimicrobial peptides can be used. This work shows that dendrimers of shortened analogue of the natural proline-rich peptide ChBac3.4 are superior in antimicrobial activity to the original peptide and are much more stable in blood serum. At the same time, as the original peptide, branched analogues do not have hemolytic activity. AIM: The aim of this study is to develop new structural analogues of a peptide that have improved stability in blood serum while maintaining high antimicrobial activity. To achieve this, we intend to create dendrimeric (branched) molecules by synthesizing peptides using solid-phase methods. MATERIALS AND METHODS: We will investigate the antimicrobial properties of the peptides using the method of serial dilutions in a liquid nutrient medium against both Gram-positive and Gram-negative bacteria. We will also assess the stability of the peptides by culturing them in the presence of human blood serum. RESULTS: After making modifications to the original peptide, we expect to see a significant increase in its antimicrobial activity against all strains tested. Additionally, we anticipate that the resistance of these peptides will increase many times over. CONCLUSIONS: Overall, our findings suggest that dendrimerization can effectively improve the properties of proline-rich peptides, making them more suitable for use in medical applications.

Frailty, cognition and patient-reported outcomes in middle-aged and older adults with congenital heart disease: insights from an international multicentric study

Abstract Background Prior research has demonstrated that a significant proportion of older patients with congenital heart disease (CHD) are frail or pre-frail and experience cognitive impairment. However, it remains unclear whether frailty and cognition are related to patient-reported outcomes (PROs) such as perceived health, anxiety and depression symptoms or quality of life in CHD. Purpose The objective of this study was to explore the relationships between frailty, cognitive function, and PROs in middle-aged and older adults with CHD ranging from mild to severe complexity. Methods As part of the cross-sectional ‘Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart disease – International Study II’ (APPROACH-IS II), we enrolled 814 individuals aged 40 years and older (median age: 52.0 years [45.0-61.0]; 51.4% female; 12.7% mild, 70.1% moderate, 17.2% complex CHD; 41.9% pre-frail, 5.8% frail; 38.7% cognitively impaired) across 17 centers in 11 countries. Frailty status was assessed using the Fried criteria, which categorize individuals into robust, pre-frail, and frail based on five factors: weakness, slow gait, unintentional weight loss, exhaustion, and low physical activity levels. Cognitive function was determined using the Montréal Cognitive Assessment. Participants completed questionnaires to evaluate perceived health (RAND-12 Health Survey, yielding both Physical and Mental Component Summaries, and EuroQOL-5D Visual Analog Scale), depressive symptoms (Patient Health Questionnaire-8), anxiety symptoms (General Anxiety Disorder scale-7), and quality of life (QoL Linear Analog Scale). Results Frailty was significantly associated with all PROs, with frail and pre-frail individuals reporting less favorable outcomes (see Figure). Cognitive function was linked to perceived health and anxiety, with patients exhibiting cognitive impairments reporting poorer perceived health and more anxiety symptoms. Conclusion This study indicates that concepts of frailty, cognitive functioning and PROs are closely related in adults with CHD. Frailty and cognition thus represent important domains when developing strategies to optimize PROs in adults with CHD. Moreover, when working with patients who are frail or cognitively impaired, healthcare workers are encouraged to consider and inquire about potential impact on PROs. Longitudinal research is needed to explore the direction of the association.

Variability in patient-reported outcomes among different congenital heart defects: a comparative analysis of 7,498 patients from 32 countries

Abstract Background Patient-reported outcomes (PROs) may not always correlate with the complexity of congenital heart defects (CHDs), as significant variation has been observed between CHDs within complexity levels. Accurate comparisons across various types of CHDs necessitate large sample sizes. Purpose The objective of this study was to compare PROs across different CHDs in a large international sample. Methods ‘Assessment of Patterns of Patient-Reported Outcomes in Adults with Congenital Heart disease – International Study II’ (APPROACH-IS II) was an international cross-sectional investigation, in which 8,415 patients from 32 countries in 6 continents were enrolled (20 high; 7 upper-middle; 4 lower-middle; and 1 low income). For the comparison across different CHDs, conditions with at least 50 patients were included in the analysis. Hence, the sample consisted of 7,498 patients (median age=33y; 53.1% women). Patients completed questionnaires to measure perceived health status (RAND-12 Health Survey; EuroQOL-5D Visual Analog Scale); depressive symptoms (Patient Health Questionnaire-8); anxiety (General Anxiety Disorder-7) and quality of life (Linear Analog Scale). Generalized linear mixed models (GLMMs) were performed with center as random effect. Results Cyanotic heart defects were associated with the lowest scores for physical functioning, mental health, self-rated health, and quality of life (see Figure). Other CHDs found to be associated with poor PRO scores encompassed unrepaired secundum atrial septal defect, Ebstein anomaly, single ventricle, and truncus arteriosus. Conversely, the most favorable scores for all PROs, except for anxiety, were observed with isolated pulmonic stenosis. Other CHDs with favorable PRO scores comprised coarctation of the aorta, isolated small ventricular septal defect, congenital aortic valve disease, and repaired ventricular septal defect. Adjusted for sociodemographic and physiological factors, GLMMs revealed significant differences across defects, using the best score for each PRO as the reference (see Figure). Conclusion Substantial variation in PROs was observed among different types of CHDs. Interestingly, some complex heart defects demonstrated relatively good PRO scores, comparable to some simple defects. On the other hand, unrepaired simple defects or those with residual lesions, were associated with worse PROs.

Structural basis of μ-opioid receptor targeting by a nanobody antagonist

The μ-opioid receptor (μOR), a prototypical G protein-coupled receptor (GPCR), is the target of opioid analgesics such as morphine and fentanyl. Due to the severe side effects of current opioid drugs, there is considerable interest in developing novel modulators of μOR function. Most GPCR ligands today are small molecules, however biologics, including antibodies and nanobodies, represent alternative therapeutics with clear advantages such as affinity and target selectivity. Here, we describe the nanobody NbE, which selectively binds to the μOR and acts as an antagonist. We functionally characterize NbE as an extracellular and genetically encoded μOR ligand and uncover the molecular basis for μOR antagonism by determining the cryo-EM structure of the NbE-μOR complex. NbE displays a unique ligand binding mode and achieves μOR selectivity by interactions with the orthosteric pocket and extracellular receptor loops. Based on a β-hairpin loop formed by NbE that deeply protrudes into the μOR, we design linear and cyclic peptide analogs that recapitulate NbE’s antagonism. The work illustrates the potential of nanobodies to uniquely engage with GPCRs and describes lower molecular weight μOR ligands that can serve as a basis for therapeutic developments.

Learning environment and its relationship with quality of life and burn-out among undergraduate medical students in Pakistan: a cross-sectional study

ObjectiveThis study was conducted to determine the association between the learning environment, quality of life (QoL), and burn-out among students from selected public-sector and private-sector medical colleges in Lahore, Pakistan.DesignThis...

Artificial Channels Based on Bottlebrush Polymers: Enhanced Ion Transport Through Polymer Topology Control.

Synthetic structures mimicking the transport function of natural ion channel proteins have a wide range of applications, including therapeutic treatments, separation membranes, sensing, and biotechnologies. However, the development of polymer-based artificial channels has been hampered due to the limitation on available models. In this study, we demonstrate the great potential of bottlebrush polymers as accessible and versatile molecular scaffolds for developing efficient artificial ion channels. Adopting the bottlebrush configuration enhanced ion transport activity of the channels compared to their linear analogs. Matching the structure of lipid bilayers, the bottlebrush channel with a hydrophilic-hydrophobic-hydrophilic triblock architecture exhibited the highest activity among the series. Functionalized with urea groups, these channels displayed high anion selectivity. Additionally, we illustrated that the transport properties could be fine-tuned by modifying the chemistry of ion binding sites. This work not only highlights the importance of polymer topology control in channel design, but also reveals the great potential for further developing bottlebrush channels with customized features and diverse functionalities.

Artificial Channels Based on Bottlebrush Polymers: Enhanced Ion Transport Through Polymer Topology Control

AbstractSynthetic structures mimicking the transport function of natural ion channel proteins have a wide range of applications, including therapeutic treatments, separation membranes, sensing, and biotechnologies. However, the development of polymer‐based artificial channels has been hampered due to the limitation on available models. In this study, we demonstrate the great potential of bottlebrush polymers as accessible and versatile molecular scaffolds for developing efficient artificial ion channels. Adopting the bottlebrush configuration enhanced ion transport activity of the channels compared to their linear analogs. Matching the structure of lipid bilayers, the bottlebrush channel with a hydrophilic‐hydrophobic‐hydrophilic triblock architecture exhibited the highest activity among the series. Functionalized with urea groups, these channels displayed high anion selectivity. Additionally, we illustrated that the transport properties could be fine‐tuned by modifying the chemistry of ion binding sites. This work not only highlights the importance of polymer topology control in channel design, but also reveals the great potential for further developing bottlebrush channels with customized features and diverse functionalities.

Highly branched thermoresponsive polysaccharide derivative in water. Partly substituted highly branched cyclic dextrin ethylcarbamate

A thermoresponsive highly branched polysaccharide derivative was revealed from commercially available highly branched cyclic dextrin (HBCD), originally synthesized from amylopectin. Eight samples of partially substituted ethyl carbamate derivatives of HBCD (HEC) were prepared with a degree of substitution DS ranging from 0.27 to 1.46. Three samples with DS = 0.88, 1.05, and 1.22 showed LCST type phase separation in water. The intrinsic viscosity and form factor in water were typical of the hyperbranched structure. The intermolecular interactions between HEC and iodine or 1-anilinonaphthalene-8-sulfonic acid (ANS) were appreciably different from those of the linear analog (AEC), suggesting that the locally bent helical conformation of highly branched HEC chains has a different interaction with small molecules. The phase diagram of HEC-water systems was accidentally similar to that of the linear chain with the same molar mass and DS, although the one phase region of the branched polymer chain-poor solvent system is usually wider than that of the corresponding linear chain. This is likely due to the lower hydration nature of the polymer segment of HEC chains than that of the corresponding linear chain.

Self-Replicating DNA-Based Nanoassemblies.

The properties of DNA that make it an effective genetic material also allow it to be ideal for programmed self-assembly. Such DNA-programmed assembly has been utilized to construct responsive DNA origami and wireframe nanoassemblies, yet replicating these hybrid nanomaterials remains challenging. Here we report a strategy for replicating DNA wireframe nanoassemblies using the isothermal ligase chain reaction lesion-induced DNA amplification (LIDA). We designed a triangle wireframe structure that can be formed in one step by ring-closing of its linear analog. Introducing a small amount of the wireframe triangle to an excess of the linear analog and complementary fragments, one of which contains a destabilizing abasic lesion, leads to rapid, sigmoidal self-replication of the wireframe triangle via cross-catalysis. Using the same cross-catalytic strategy we also demonstrate rapid self-replication of a hybrid wireframe triangle containing synthetic vertices as well as the self-replication of circular DNA. This work reveals the suitability of isothermal ligase chain reactions such as LIDA to self-replicate complex DNA architectures, opening the door to incorporating self-replication, a hallmark of life, into biomimetic DNA nanotechnology.

Triazole-Bridged Peptides with Enhanced Antimicrobial Activity and Potency against Pathogenic Bacteria.

There are still no linear antimicrobial peptides (AMPs) available as a treatment option against bacterial infections. This is caused by several drawbacks that come with AMPs such as limited proteolytic stability and low selectivity against human cells. In this work, we screened a small library of rationally designed new peptides based on the cell-penetrating peptide sC18* toward their antimicrobial activity. We identified several effective novel AMPs and chose one out of this group to further increase its potency. Therefore, we introduced a triazole bridge at different positions to provide a preformed helical structure, assuming that this modification would improve (i) proteolytic stability and (ii) membrane activity. Indeed, placing the triazole bridge within the hydrophilic part of the linear analogue highly increased membrane activity as well as stability against enzymatic digestion. The new peptides, 8A and 8B, demonstrated high activity against several bacterial species tested including pathogenic N.gonorrhoeae and methicillin-resistant S. aureus. Since they exhibited significantly good tolerability against human fibroblast and blood cells, these novel peptides offer true alternatives for future clinical applications and are worth studying in more detail.

Analysis and design of a 0.9 V 1 GHz-BW 14.6 dBm-OIP3 broadband receiver with current-mode analog baseband in 12 nm FinFET CMOS

This study introduces a wideband LNTA-based receiver employing full current mode (FCM) signal transmission, leveraging a broadband and highly linear current-mode analog baseband (CMAB). The CMAB module comprises a shunt feedback low pass filter and a programmable gain amplifier (PGA) with wide bandwidth, utilizing a regulated CG current mirror design, enriched by gm-boosting methodology and positive feedback capacitance reutilization through an identical boost amplifier. Fabricated in 12 nm FinFET CMOS process, the FCM receiver attains notable characteristics including a baseband bandwidth of 1 GHz, a conversion gain of 30 dB, a noise figure of 5.2 dB, and an OIP3 of 14.6 dBm, while operating with a low supply voltage of merely 0.9 V. Simulation results validate the efficacy of this FCM receiver for wideband communication, effectively addressing the linearity constraints associated with low supply voltages and maximizing the advantages of FinFET technology in current-mode signal transmission. The total layout area is 0.484 mm2.

Structural, topological, and rheological characteristics of entangled short-chain branched polymer melts under shear flow in comparison with the linear analog

We present a detailed analysis of the general influence of short branches on the structural, topological, and rheological behaviors of entangled short-chain branched (SCB) polyethylene (PE) melt systems under shear flow via direct comparison with the corresponding linear analogs using extensive atomistic nonequilibrium molecular dynamics (NEMD) simulations, for a wide range of flow strengths. In comparison with the linear melt, the SCB systems generally exhibit more compact chain structures and larger dynamic resistance, in response to an imposed flow field at all flow strengths. These features essentially arise from (i) the increased chain stiffness due to the torsional restriction of backbone atoms around the branch points and (ii) the fast random Brownian motion of short branches via their very short characteristic relaxation time. We analyzed various structural and rheological properties, such as anisotropic chain dimension and orientation and their detailed distributions, topological characteristics of the entanglement network, material functions, chain rotation dynamics, and flow birefringence. Distinctive physical characteristics of the entangled SCB systems exposed by these individual properties can be consistently understood based on the fundamental structural and dynamical roles of short branches. These findings are considered informative in our systematic understanding and prediction for the general rheological behaviors of long entangled SCB polymer systems under flow, and in tuning the material properties of SCB polymers in practical applications.

A 10-Gb/s Wireline Receiver Using Linear Baud-Rate CDR and Analog Equalizer for Free Space Optical Communication Over 10- and 100-m Distances

A 10-Gb/s Wireline Receiver Using Linear Baud-Rate CDR and Analog Equalizer for Free Space Optical Communication Over 10- and 100-m Distances

Correlation between peripheral perfusion index and total vasopressor dose, nausea/ vomiting, and uterine contraction after spinal anesthesia in cesarean section: A correlative cross-sectional observational study

Background and AimsHypotension and other complications following spinal anaesthesia, such as nausea, vomiting, and poor uterine contractions during caesarean section, are common. There is no tool to predict the possibility of hypotension, nausea and vomiting, and poor uterine contractions to make proper anticipations. Peripheral Perfusion Index (PPI) is a noninvasive monitoring tool using an oximeter and can be used to indicate a patient's Systemic Vascular Resistance (SVR). This study aimed to find the correlation between pre-anaesthesia PPI and total vasopressor administration, nausea and vomiting, and uterine contraction using Linear Analogue Scale (LAS) after spinal anaesthesia for caesarean section. MethodsThe research subjects were 65 pregnant patients with the American Society of anaesthesiology II (ASA II) who underwent caesarean section at Hasan Sadikin General Hospital, Bandung, from November 2022 to April 2023. PPI was measured before spinal anaesthesia, and monitoring of nausea and vomiting, vasopressor administration, and LAS was performed intraoperatively. ResultsThe results of this study showed that PPI had a strong positive correlation (r = 0.795) with total vasopressor administration, a moderate positive correlation (r = 0.506) with nausea and vomiting, and a moderate negative correlation (r = 0.574) with LAS. The AUC analysis revealed an excellent hypotension prediction with a cut-off value of 3.5 (AUC 0.868; CI 95%). ConclusionWe conclude that PPI can be used as a predictor of vasopressor administration, nausea and vomiting, and uterine contractions.

Breaking Cycles: Saponification-Enhanced NMR Fingerprint Matching for the Identification and Stereochemical Evaluation of Cyclic Lipodepsipeptides from Natural Sources.

We previously described NMR based fingerprint matching with peptide backbone resonances as a fast and reliable structural dereplication approach for Pseudomonas cyclic lipodepsipeptides (CLiPs). In combination with total synthesis of a small library of configurational CLiP congeners this also allows unambiguous determination of stereochemistry, facilitating structure-activity relationship studies and enabling three-dimensional structure determination. However, the on-resin macrocycle formation in the synthetic workflow brings considerable burden and limits universal applicability. This drawback is here removed altogether by also transforming the native CLiP into a linearized analogue by controlled saponification of the ester bond. This eliminates the need for macrocycle formation, limiting the synthesis effort to linear peptide analogues. NMR fingerprints of such linear peptide analogues display a sufficiently distinctive chemical shift fingerprint to act as effective discriminators. The approach is developed using viscosin group CLiPs and subsequently demonstrated on putisolvin, leading to a structural revision, and tanniamide from Pseudomonas ekonensis COR58, a newly isolated lipododecapeptide that defines a new group characterized by a ten-residue large macrocycle, the largest to date in the Pseudomonas CLiP portfolio. These examples demonstrate the effectiveness of the saponification- enhanced approach that broadens applicability of NMR fingerprint matching for the determination of the stereochemistry of CLiPs.

Comparison of Cyclic and Linear PEG Conjugates.

Bioconjugation of polymers to proteins is a method to impart improved stability and pharmacokinetic properties to biologic systems. However, the precise effects of polymer architecture on the resulting bioconjugates are not well understood. Particularly, cyclic polymers are known to possess unique features such as a decreased hydrodynamic radius when compared to their linear counterparts of the same molecular weight, but have not yet been studied. Here, we report the first bioconjugation of a cyclic polymer, poly(ethylene glycol) (PEG), to a model protein, T4 lysozyme, containing a single engineered cysteine residue (V131C). We compare the stability and activity of this conjugate with those of a linear PEG-T4 lysozyme analogue of similar molecular weight. Furthermore, we used molecular dynamics (MD) simulations to determine the behavior of the polymer-protein conjugates in solution. We introduce cyclic polymer-protein conjugates as potential candidates for the improvement of biologic therapeutics.

Responsive antibacterial surface based on looped poly(methacrylic acid)

The adhesion of bacteria to surfaces poses a significant challenge to public health and many industries, making the development of antibacterial surfaces an urgent issue. In this work, α,ω-bisthiol poly(methacrylic acid) (HS-PMAA-SH) was synthesized and grafted in loop conformation onto a substrate primed with polydopamine, in conjunction with Ag NPs prepared in-situ to create a pH responsive composite surface with synergistic fouling-resistant and bacterial killing and releasing capabilities. A monofunctional analogue of half the chain length, PMAA-SH, was also synthesized and used to construct the composite surface with the PMAA in linear conformation for comparison. Quartz crystal microbalance with dissipation experiments revealed that PMAA loops allowed much less protein to adsorb than their linear analogues. Confocal laser scanning microscopy results showed that both composite surfaces were effective in killing the bacteria attached due to the presence of Ag NPs, and exhibited good initial resistance to bacterial adhesion and ability to release the killed bacteria under mild conditions due to the PMAA component; the composite surface conjugated with PMAA-loop was superior to the one with PMAA-linear, presenting lower initial bacterial adhesion and higher release rates, maintaining a low bacterial coverage even after five resist/kill/release cycles. The research opens a new avenue for antibacterial surfaces that integrate fouling-resistance, bacterial killing and release functions.

Development of Ring-Expansion RAFT Polymerization of tert-Butyl Acrylate with a Cyclic Trithiocarbonate Derivative toward the Facile Synthesis of Cyclic Polymers.

Polymers with cyclic topology have no terminal structure and, therefore, exhibit various unique physical and functional properties compared to those of linear analogs. In this paper, we report an innovative methodology for the synthesis of cyclic polymers via ring-expansion RAFT (RE-RAFT) polymerization of vinyl monomers using a cyclic trithiocarbonate derivative (CTTC) as a RAFT agent. RE-RAFT of tert-butyl acrylate (TBA) was performed to yield a mixture of polymers exhibiting a bimodal size exclusion chromatography (SEC) trace. Both the peak top molecular weights shifted to higher-molecular-weight regions as the monomer conversion increased. The structure of the resulting polymer mixture was examined by 1H NMR and MALDI-TOF-MS. Detailed studies indicated that the obtained polymer of higher molecular weight was one of the large-sized cyclic polymers generated by the fusion of smaller-sized cyclic polymers during the RE-RAFT polymerization process. This approach opens the door to the simple synthesis of well-controlled cyclic polymers with complex structures, such as alternating and multi-block repeat unit sequences.