Convergent Strategy Research Articles

Coiled Coil Peptide Tiles (CCPTs): Expanding the Peptide Building Block Design with Multivalent Peptide Macrocycles.

Owing to their synthetic accessibility and protein-mimetic features, peptides represent an attractive biomolecular building block for the fabrication of artificial biomimetic materials with emergent properties and functions. Here, we expand the peptide building block design space through unveiling the design, synthesis, and characterization of novel, multivalent peptide macrocycles (96mers), termed coiled coil peptide tiles (CCPTs). CCPTs comprise multiple orthogonal coiled coil peptide domains that are separated by flexible linkers. The constraints, imposed by cyclization, confer CCPTs with the ability to direct programmable, multidirectional interactions between coiled coil-forming "edge" domains of CCPTs and their free peptide binding partners. These fully synthetic constructs are assembled using a convergent synthetic strategy via a combination of native chemical ligation and Sortase A-mediated cyclization. Circular dichroism (CD) studies reveal the increased helical stability associated with cyclization and subsequent coiled coil formation along the CCPT edges. Size-exclusion chromatography (SEC), analytical high-performance liquid chromatography (HPLC), and fluorescence quenching assays provide a comprehensive biophysical characterization of various assembled CCPT complexes and confirm the orthogonal colocalization between coiled coil domains within CCPTs and their designed on-target free peptide partners. Lastly, we employ molecular dynamics (MD) simulations, which provide molecular-level insights into experimental results, as a supporting method for understanding the structural dynamics of CCPTs and their complexes. MD analysis of the simulated CCPT architectures reveals the rigidification and expansion of CCPTs upon complexation, i.e., coiled coil formation with their designed binding partners, and provides insights for guiding the designs of future generations of CCPTs. The addition of CCPTs into the repertoire of coiled coil-based building blocks has the potential for expanding the coiled coil assembly landscape by unlocking new topologies having designable intermolecular interfaces.

A Model for the Gene Regulatory Network Along the Arabidopsis Fruit Medio-Lateral Axis: Rewiring the Pod Shatter Process.

Different convergent evolutionary strategies adopted by angiosperm fruits lead to diverse functional seed dispersal units. Dry dehiscent fruits are a common type of fruit, characterized by their lack of fleshy pericarp and the release of seeds at maturity through openings (dehiscence zones, DZs) in their structure. In previous decades, a set of core players in DZ formation have been intensively characterized in Arabidopsis and integrated in a gene regulatory network (GRN) that explains the morphogenesis of these tissues. In this work, we compile all the experimental data available to date to build a discrete Boolean model as a mechanistic approach to validate the network and, if needed, to identify missing components of the GRN and/or propose new hypothetical regulatory interactions, but also to provide a new formal framework to feed further work in Brassicaceae fruit development and the evolution of seed dispersal mechanisms. Hence, by means of exhaustive in-silico validations and experimental evidence, we are able to incorporate both the NO TRANSMITTING TRACT (NTT) transcription factor as a new additional node, and a new set of regulatory hypothetical rules to uncover the dynamics of Arabidopsis DZ specification.

Effects of trilemma policies patterns on monetary policy credibility

The open economy trilemma refers to the impossibility of a country fully and simultaneously achieving three political objectives: monetary policy independence, exchange rate stability and financial openness. However, corner configurations related to the three policies of the trilemma are increasingly rare. In fact, countries tend to choose a policy combination composed of partial financial integration, managed exchange rate flexibility and partial monetary independence. Given the possibility of intermediate choices, there exists an index able to measure the relative divergence (or convergence) regarding the policy choices of the trilemma. The index identifies whether countries are adopting similar (or divergent) policy mixes in relation to the trilemma policy options. However, the consequences of adopting a more (or less) convergent policy arrangement on monetary policy credibility are unknown. Hence, this study investigates the effects of trilemma policies convergence patterns on monetary policy credibility. The idea is to verify whether a more convergent arrangement of policies related to the trilemma in open economies helps build monetary policy credibility. Our database is formed by 94 (developed and developing) countries with different characteristics. Thus, we run estimates based on a family of Tobit models for different sub-samples of countries, and also considering different periods – before and after the Global Financial Crisis. The study brings important practical implications. In general, the findings show that a convergent strategy increases credibility. The estimates corroborate the idea that countries adopting divergent policies from the global standard tend to be more exposed to economic instability and, as a result, have difficulties in anchoring inflation expectations.

A Sonochemical and Mechanochemical One-Pot Multicomponent/Click Coupling Strategy for the Sustainable Synthesis of Bis-Heterocyclic Drug Scaffolds.

Bis-heterocycles were synthesized via a consecutive one-pot process by a Groebke-Blackburn-Bienaymé reaction (GBB-3CR) followed by Copper-catalyzed Alkyne-Azide Cycloaddition (CuAAC) assisted by alternative sustainable energies (ASE) such as ultrasonic and mechanical. These efficient and convergent strategies allowed the in situ generation of complex azides functionalized with imidazo[1,2-a]pyridines (IMPs), which was used as a synthetic platform. The target molecules contain two privileged scaffolds in medicinal chemistry: IMPs and the heterocyclic bioisostere of trans-amide bond, the 1,4-disubstituted 1H-1,2,3-triazoles (1,4-DS-1,2,3-Ts).

Multi-step synthesis, kinetics and in silico explorations of indole-Phenyl-1,2,4-triazole Bi-heterocyclic hybrids unified with 3-substituted benzamides as elastase inhibitors

In the present research work, a library of unique indole-phenyltriazole hybrids comprising 3-substituted-benzamide moiety was synthesized through convergent multi-step strategy. The structural confirmation of all synthesized molecules was corroborated by IR, 1H NMR, 13C MMR, EI-MS and CHN analysis data. The results of in vitro inhibitory potential of novel benzamides against elastase enzyme revealed that all molecules were potent inhibitors and 10d was most active compound among them having IC50 value of (0.197 ± 0.027 µM), relative to the standard (13.421 ± 0.016 µM). The Kinetics mechanism analyzed by Lineweaver-Burk plots which exposed that 10d inhibited this enzyme competitively by forming an enzyme-inhibitor complex. The inhibition constant Ki determined from Dixon plot for compound 10d was 0.85 µM. Moreover, cytotoxicity of these compounds was also profiled by hemolytic activity and it was observed that almost all these benzamides compounds displayed low cytotoxicity. These molecules also exhibited mild cytotoxicity toward red blood cell membrane. In addition, the in silico computational explorations fully supported the in vitro enzyme inhibitory results. The binding energy ranges from -7.1 to -9.1 kcal/mol, which showed that compound possessed good interaction tendencies to the pancreatic elastase target protein. So, it was anticipated from the experimental results and computational investigations of the current research that these derivatives might lead to further research gateways for obtaining better and safe nontoxic medicinal scaffolds for dealing with the elastase related ailments such as lungs diseases, pruritic skin disease and liver infection.

Unified Synthesis of NOPQ and STUV Rings of Brevisulcenal-F

Abstract The unified synthesis of the NOPQ and STUV rings of brevisulcenal-F was achieved from a common intermediate based on a convergent strategy via two-ring construction. The STUV ring was synthesized via radical reduction of an O, S-acetal, and the NOPQ ring was constructed via ring expansion giving a seven-membered ring ketone, methylation of an O, S-acetal, and introduction of the cis-1,2-diol moiety at C60–C61.

Total synthesis of a structurally complex zwitterionic hexasaccharide repeating unit of polysaccharide B from Bacteroides fragilis via one-pot glycosylation

Zwitterionic polysaccharides (ZPSs) present on the surface of a common gut commensal Bacteroides fragilis are endowed with unique immunological properties as they can directly bind to T-cells in the absence of protein conjugation. ZPSs are therefore considered to be potential antigens for the development of totally carbohydrate-based vaccines. Herein, we disclose the first total synthesis of a highly branched phosphorylated zwitterionic capsular polysaccharide repeating unit of Bacteroides fragilis. The hexasaccharide repeating unit bearing six different monosaccharides comprises three 1,2-cis-glycosidic linkages, a challenging 1,2-trans linkage in D-QuipNAc-β-(1→4)-D-Gal motif, and a 2-aminoethyl phosphonate appendage. The synthesis of target ZPS was accomplished utilizing an expeditious, highly stereoselective and convergent (1 + 2 + 2 + 1) one-pot glycosylation strategy. The striking features include efficient synthesis of rare deoxy amino sugars D- and L-quinovosamine, stereoselective installation of three 1,2-cis glycosidic linkages, glycosylation of D-quinovosamine donor with a sterically crowded, poorly reactive 4-OH galactose moiety, as well as late stage phosphorylation.

Total Synthesis of (-)-Flueggeacosine C.

Herein we describe a total synthesis of the heterodimeric securinega alkaloid (-)-flueggeacosine C (8). The convergent synthetic strategy is based on a Liebeskind-Srogl cross-coupling reaction that combines a benzoquinolizidine fragment with a securinine-type alkaloid. An acyloxy nitroso ring-expansion was employed as the key step in accessing benzoquinolizidine 9, and a novel intramolecular Diels-Alder reaction of an allenic acid-containing pyridone expeditiously delivers the skeleton of the securinine-type fragment (16). Finally, a Cu-catalyzed hydroboration-oxidation sequence was employed to regio- and diastereoselectively introduce the secondary alcohol found in 8.

Insights into the Evolutionary Dynamics: Characterization of Disintegrin and Metalloproteinase Proteins in the Venom Gland Transcriptome of the Hemiscorpius lepturus Scorpion.

The Disintegrin and Metalloproteinase (ADAM) family, also known as the metalloproteinase/disintegrin/cysteine-rich (MDC) proteins, includes both secreted and transmembrane molecules involved in critical biological processes, such as cell migration, adhesion, and signaling. This study aimed to investigate the evolutionary relationships and structural characteristics of disintegrin and metalloproteinase proteins identified in the venom gland transcriptome of the scorpion Hemiscorpius lepturus. Using bioinformatics tools, we analyzed the open reading frame, conserved motifs, and primary, secondary, and tertiary structures of these proteins. Five proteins, named HLDis- Met1, HLDisMet2, HLDisMet3, HLDisMet4, and HLDisMet5, were identified. Their predicted 3- D structures were within normal ranges (Z-score between -4 to -9). Phylogenetic analysis revealed that HLDisMet1 shares similarities with proteins from various spider species (Nephila pilipes, Argiope bruennichi, Araneus ventricosus, and Trichonephila inaurata madagascariensis), HLDisMet2 with the scorpion Centruroides sculpturatus, HLDis- Met4 with the scorpion Tityus serrulatus, and HLDisMet5 with several snake species (Python bivittatus, Vipera anatolica senliki, Protobothrops mucrosquamatus, and Naja naja). These findings highlight the significant similarities between HLDisMet proteins and those found in other venomous species, suggesting a complex and diverse evolutionary pathway for venom components. The cross-species conservation observed may indicate a convergent evolutionary strategy, where different species independently develop similar venom components to adapt to similar ecological niches or prey types. This study highlights the evolutionary significance of venom diversification and its potential applications in understanding venom biology across different species.

A Promising Approach to Target Colorectal Cancer Using Hybrid Triarylmethanes.

Aiming to create an innovative series of anti-colorectal cancer agents, we designed in this work hybrid triarylmethane compounds. Three hybrid triarylmethanes and their corresponding N-oxide analogues were successfully synthesized using an efficient procedure that involved connecting two triarylmethane molecules, through mono-, bi-, and triethylene glycol fragments. In our pursuit to develop more soluble molecules, we synthesized a hybrid triarylmethane featuring a lysine-based spacer through a convergent strategy involving 7 steps. All hybrid compounds were assessed for their antiproliferative activity on human HT-29 and HCT116 colorectal cancer (CRC) cell lines. Three pyridine N-oxide analogs demonstrated notable antiproliferative potential among the set of tested compounds, with IC50 values ranging from 18 to 24 μM on both human CRC cell lines analyzed. A cytotoxicity study conducted on murine fibroblasts revealed that these three active compounds were not toxic at the IC50 values, indicating their suitability for further drug development. A docking study was conducted on two representative compounds, one for each series and protein kinase B (AKT) was identified as a potential target of their in anti-cancer effects. A computational drug-likeness study predicted favourable oral and intestinal absorption efficiency.

(Invited) 3D Carbon-Based Hierarchical Electrodes for Energy Storage

: Carbon-based 3D hierarchical electrodes with appropriate spatial distributions of pores are expected to empower rapid and controllable electrochemical reactions. The ability to fabricate such an electrode, with tunable geometries comprised of continuous nano- and micro-conduits, allows simultaneous optimization of conversion capacity as well as reaction rate. Such manufacturability holds great potential to redefine the future of energy storage, electrocatalysis and chemical production for a sustainable future.In this presentation, I will outline two convergent strategies that involve the integration of additive manufacturing with several decades of advancements in nanomaterials synthesis, coupled with conventional pyrolysis – for creating such electrodes. The primary structure of 3D carbon-based electrodes was fabricated by either direct 3D writing, or the transition metal assisted pyrolysis of 3D-printed polymer templates. The secondary structure was established by employing bottom-up synthesis approaches: (a) SiO2 nanoparticle templates to create nanoscopic porous structures or (b) nanochannels formed through direct growth of carbon nanotubes. We have demonstrated that the primary and secondary structures can be formed by a single step. After monolithic integration of a tertiary structure to reveal sites for electrochemical conversion, these 3D architected electrodes offer impressive charge storage capacities while maintain excellent rate capability.By exploiting the short mass diffusion lengths, we have demonstrated that the new energy storage devices can operate at temperatures as low as -70°C without the requirement of a heater. Furthermore, the incorporation of a high loading of active materials in our 3D electrodes allows for concurrent enhancement of both energy density and power density. These scalable fabrication protocols address two critical challenges – sluggish mass transfer in 3D and the lack of accessible active sites, thereby offering a pathway to harness electrochemical reactions in 3D. This work offers an adaptable solution across a broad spectrum of industries.

Disordered proteins interact with the chemical environment to tune their protective function during drying.

The conformational ensemble and function of intrinsically disordered proteins (IDPs) are sensitive to their solution environment. The inherent malleability of disordered proteins combined with the exposure of their residues accounts for this sensitivity. One context in which IDPs play important roles that is concomitant with massive changes to the intracellular environment is during desiccation (extreme drying). The ability of organisms to survive desiccation has long been linked to the accumulation of high levels of cosolutes such as trehalose or sucrose as well as the enrichment of IDPs, such as late embryogenesis abundant (LEA) proteins or cytoplasmic abundant heat soluble (CAHS) proteins. Despite knowing that IDPs play important roles and are co-enriched alongside endogenous, species-specific cosolutes during desiccation, little is known mechanistically about how IDP-cosolute interactions influence desiccation tolerance. Here, we test the notion that the protective function of desiccation-related IDPs is enhanced through conformational changes induced by endogenous cosolutes. We find that desiccation-related IDPs derived from four different organisms spanning two LEA protein families and the CAHS protein family, synergize best with endogenous cosolutes during drying to promote desiccation protection. Yet the structural parameters of protective IDPs do not correlate with synergy for either CAHS or LEA proteins. We further demonstrate that for CAHS, but not LEA proteins, synergy is related to self-assembly and the formation of a gel. Our results suggest that functional synergy between IDPs and endogenous cosolutes is a convergent desiccation protection strategy seen among different IDP families and organisms, yet, the mechanisms underlying this synergy differ between IDP families.

Nucleotide Immune Signaling in CBASS, Pycsar, Thoeris, and CRISPR Antiphage Defense.

Bacteria encode an arsenal of diverse systems that defend against phage infection. A common theme uniting many prevalent antiphage defense systems is the use of specialized nucleotide signals that function as second messengers to activate downstream effector proteins and inhibit viral propagation. In this article, we review the molecular mechanisms controlling nucleotide immune signaling in four major families of antiphage defense systems: CBASS, Pycsar, Thoeris, and type III CRISPR immunity. Analyses of the individual steps connecting phage detection, nucleotide signal synthesis, and downstream effector function reveal shared core principles of signaling and uncover system-specific strategies used to augment immune defense. We compare recently discovered mechanisms used by phages to evade nucleotide immune signaling and highlight convergent strategies that shape host-virus interactions. Finally, we explain how the evolutionary connection between bacterial antiphage defense and eukaryotic antiviral immunity defines fundamental rules that govern nucleotide-based immunity across all kingdoms of life.

Stereoselective Synthesis of Polyketide Segments of Nemamide A and Euglenatides D–E

AbstractA convergent strategy for the stereoselective synthesis of polyketide segments of hybrid natural products nemamide A and euglenatides D–E has been developed for the first time. The salient features of this gram-scale synthesis include Trost–Rychnovsky alkyne rearrangement, HWE olefination, regioselective epoxide ring opening, Prins–Ritter cyclization, and subsequent reductive cleavage of the substituted THP ring. The optimized route is modular and could be tunable to access the other polyketide counterparts of these families of metabolites.

Eosinophils as drivers of bacterial immunomodulation and persistence.

Traditionally, eosinophils have been linked to parasitic infections and pathological disease states. However, emerging literature has unveiled a more nuanced and intricate role for these cells, demonstrating their key functions in maintaining mucosal homeostasis. Eosinophils exhibit diverse phenotypes and exert multifaceted effects during infections, ranging from promoting pathogen persistence to triggering allergic reactions. Our investigations primarily focus on Bordetella spp., with particular emphasis on Bordetella bronchiseptica, a natural murine pathogen that induces diseases in mice akin to pertussis in humans. Recent findings from our published work have unveiled a striking interaction between B. bronchiseptica and eosinophils, facilitated by the btrS-mediated mechanism. This interaction serves to enhance pathogen persistence while concurrently delaying adaptive immune responses. Notably, this role of eosinophils is only noted in the absence of a functional btrS signaling pathway, indicating that wild-type B. bronchiseptica, and possibly other Bordetella spp., possess such adeptness in manipulating eosinophils that the true function of these cells remains obscured during infection. In this review, we present the mounting evidence pointing toward eosinophils as targets of bacterial exploitation, facilitating pathogen persistence and fostering chronic infections in diverse mucosal sites, including the lungs, gut, and skin. We underscore the pivotal role of the master regulator of Bordetella pathogenesis, the sigma factor BtrS, in orchestrating eosinophil-dependent immunomodulation within the context of pulmonary infection. These putative convergent strategies of targeting eosinophils offer promising avenues for the development of novel therapeutics targeting respiratory and other mucosal pathogens.

Convergent evolution toward a slow pace of life predisposes insular endotherms to anthropogenic extinctions.

Island vertebrates have evolved a number of morphological, physiological, and life history characteristics that set them apart from their mainland relatives. However, to date, the evolution of metabolism and its impact on the vulnerability to extinction of insular vertebrates remains poorly understood. This study used metabolic data from 2813 species of tetrapod vertebrates, including 695 ectothermic and 2118 endothermic species, to reveal that island mammals and birds evolved convergent metabolic strategies toward a slow pace of life. Insularity was associated with shifts toward slower metabolic rates and greater generation lengths in endotherms, while insularity just drove the evolution of longer generation lengths in ectotherms. Notably, a slow pace of life has exacerbated the extinction of insular endemic species in the face of anthropogenic threats. These findings have important implications for understanding physiological adaptations associated with the island syndrome and formulating conservation strategies across taxonomic groups with different metabolic modes.

Chimpanzee gestural exchanges share temporal structure with human language

Humans regularly engage in efficient communicative conversations, which serve to socially align individuals1. In conversations, we take fast-paced turns using a human-universal structure of deploying and receiving signals which shows consistent timing across cultures2. We report here that chimpanzees also engage in rapid signal-to-signal turn-taking during face-to-face gestural exchanges with a similar average latency between turns to that of human conversation. This correspondence between human and chimpanzee face-to-face communication points to shared underlying rules in communication. These structures could be derived from shared ancestral mechanisms or convergent strategies that enhance coordinated interactions or manage competition for communicative 'space'.

CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer

Resistance to chemotherapy has been a major hurdle that limits therapeutic benefits for many types of cancer. Here we systematically identify genetic drivers underlying chemoresistance by performing 30 genome-scale CRISPR knockout screens for seven chemotherapeutic agents in multiple cancer cells. Chemoresistance genes vary between conditions primarily due to distinct genetic background and mechanism of action of drugs, manifesting heterogeneous and multiplexed routes towards chemoresistance. By focusing on oxaliplatin and irinotecan resistance in colorectal cancer, we unravel that evolutionarily distinct chemoresistance can share consensus vulnerabilities identified by 26 second-round CRISPR screens with druggable gene library. We further pinpoint PLK4 as a therapeutic target to overcome oxaliplatin resistance in various models via genetic ablation or pharmacological inhibition, highlighting a single-agent strategy to antagonize evolutionarily distinct chemoresistance. Our study not only provides resources and insights into the molecular basis of chemoresistance, but also proposes potential biomarkers and therapeutic strategies against such resistance.

Communication Strategies and Terrorism Risk Preparedness among the Residents of Nairobi City County

Purpose: The main purpose of the study was to establish the association of communication strategies and terrorism risk preparedness among the residents of Nairobi City County. Materials and Methods: This study followed a mixed-methods design mainly of a questionnaire survey complemented by observation, key informant interviews and document analysis, The design employed the Concurrent Convergent (Triangulation) Parallel strategy. According to the Kenya National Bureau of Statistics, Nairobi City County has a resident population of 4,397,073. A further estimated 2.5 million non-residents troupe to the city-county daily for business and employment or as tourists and travelers in transit to other counties. Therefore, the target population for this study was approximately 6.5 million. The study population was drawn using stratified purposive random sampling technique where the list of all the sampling locations was categorized into four strata. The sample size was 640 respondents who were proportionately drawn randomly drawn from four different strata. Findings: Regression of coefficients showed that research and alerts in communication and terrorism risk preparedness were positively and significantly related (β=0.293, p=0.000). In addition, results showed that emergency action and public education and terrorism risk preparedness were positively and significantly related (β=0.109, p=0.004). Governments that fail to warn their citizens when aware of imminent or possible terror threats will be accused of failing in their duty. Implications to Theory, Practice and Policy: The study concludes that the use effective communication strategies is critical for terrorism risk preparedness, as they enhance message reception and thus motivate preparedness planning and action taking. This in turn can help in detecting and thwarting attacks before they happen, mitigate the impact of attacks, promote public safety during attacks, and build community resilience. Therefore, the study recommends that organizations, be they government agencies, first responders and corporates should incorporate effective Communication strategies into the overall crisis preparedness plans, in order to enhance their ability to communicate and respond effectively during terrorism attacks.

Binding of the TRF2 iDDR motif to RAD50 highlights a convergent evolutionary strategy to inactivate MRN at telomeres.

Telomeres protect chromosome ends from unscheduled DNA repair, including from the MRN (MRE11, RAD50, NBS1) complex, which processes double-stranded DNA breaks (DSBs) via activation of the ATM kinase, promotes DNA end-tethering aiding the non-homologous end-joining (NHEJ) pathway, and initiates DSB resection through the MRE11 nuclease. A protein motif (MIN, for MRN inhibitor)inhibits MRN at budding yeast telomeres by binding to RAD50 andevolved at least twice, in unrelated telomeric proteins Rif2 and Taz1. We identify the iDDR motif of human shelterin protein TRF2 as a third example of convergent evolution for thistelomericmechanism for binding MRN, despite the iDDR lacking sequence homology to the MIN motif. CtIP is required for activation of MRE11 nuclease action, and we provide evidence for binding of a short C-terminal region of CtIP to a RAD50 interface that partly overlaps with the iDDR binding site, indicating that the interaction is mutually exclusive. In addition, we show that the iDDR impairs the DNA binding activity of RAD50. These results highlight direct inhibition of MRN action as a crucial role of telomeric proteins across organisms and point to multiple mechanisms enforced by the iDDR to disable the many activities of the MRN complex.