Complex Modulation Research Articles

Design, Production and Impact Test of Multi-Axle Heavy Commercial Vehicle Cab

The main and most complex superstructure module of heavy-duty and heavy commercial vehicles is the driver-passenger cabin. While cabin design and production; It must be safe, light, rigid, ergonomic, modular, suitable for lean production, user-friendly and serviceable. But the most important of these criteria is the life safety of the crew in the cab. In this context, the cabin strength must be at a very high level. To determine the cabin strength, it is subjected to the R29 - Cabin strength test within the ECE regulations. Thanks to this test, it is possible to see the skeletal strength and behavior of the cabin in the event of an accident or collision. According to this test, the life safety of the crew inside the cabin must be prioritized, and the necessary designs and production must be carried out to ensure that the cabin suffers as little damage as possible in the event of an accident. In this way, it is aimed to maximize the security (safe area) inside the cabin by providing cabin rigidity. This scope of work; The objectives of lighter weight, shorter and easier production, assembly and disassembly, lower production costs, less labor and equipment or consumable expenses have been achieved. Additionally, in this study, the seat configuration in the cabin was increased from 1+4 to 1+5 and a crash test was performed by including another door option.

D03-ordered Fe3Al magnetic nanopowders synthesized by low oxygen induction thermal plasma

D03-ordered Fe3Al alloy with a large anomalous Nernst coefficient is considered as a promising candidate for a low-cost, flexible, and durable magneto-thermoelectric generator (MTG). To improve the thermoelectric performance of the more and more complex and smaller MTG modules, the incorporation of high-quality magnetic nanopowders (MNPs) is one solution. However, synthesizing fully chemically ordered MNPs without coalescence and/or oxidation with a conventional approach is challenging. In this study, we demonstrated, for the first time, D03-ordered (degree of ordering = 0.48) Fe3Al MNPs synthesized via a low oxygen thermal plasma process combined with appropriate post-annealing treatment. The resulting single crystalline MNPs are spherical in shape with a mean particle diameter of 116 ± 96 nm and exhibit a soft magnetic characteristic (saturation magnetization ≈ 112 emu/g; and coercivity ≈ 5 Oe at room temperature). The fundamental alloying mechanism during the thermal plasma process was investigated via numerical calculations, confirming that the alloying followed the route through the Fe-Al droplet. Our results will potentially aid the mass synthesis of chemical ordered MNPs for wearable energy harvesting and self-powered Internet of things applications.

Structure-guided screening of protein-protein interaction for the identification of Myc-Max heterodimer complex modulators

De-regulation of oncogenic myelocytomatosis (c-Myc or Myc) transcription factor is one of the most common molecular anomalies encountered in human cancers, and it is typically linked to many aggressive malignancies including breast, lung, cervix, colon glioblastomas, and other haematological organs. The Myc belongs to the basic helix-loop-helix zipper protein family (bHLH-ZIP), and its dimerization with another principal interactor protein partner Myc-associated factor X (Max) is essentially required for cellular transformation, cell growth and proliferation, and transcriptional activation. Intermolecular interactions have been evaluated between hetero-dimer Myc-Max protein, which identified protein-protein interaction (PPI) specific modulators using highly précised molecular docking study followed by long-range interaction stability analyzed through molecular dynamic (MD) simulation. Moreover, ADME profile analyses have been estimated for screened hit compounds. MM-GBSA-based binding free energy (ΔG) estimations have been performed for all screened hit compounds obtained from multi-step molecular docking-based virtual screening technique. According to the employed various rigorous multi-chemometric techniques, four identified inhibitors/modulators appear to have a considerable number of intermolecular contacts with hotspot residues in the hetero-dimer interface region of the Myc-Max PPI complex. However, identified hit compounds might need further structural optimization or extensive biophysical analyses for better understanding of the molecular mechanism for exhibiting the Myc-Max PPI interface binding stability. Communicated by Ramaswamy H. Sarma

Design of a Dual-Band Load-Modulated Sequential Amplifier with Extended Back-off

This letter presents a dual-band load-modulated sequential amplifier (LMSA). The proposed amplifier changed the attenuator terminated at the isolation port of the four-port combiner of the traditional sequential power amplifier (SPA) architecture into a reactance modulation network (RMN) for load modulation. The impedance can be maintained pure resistance by designing RMN, thus realizing high efficiency and a good portion of the output power in the multiple bands. Compared to the dual-band Doherty power amplifier with a complex dual-band load modulation network (LMN), the proposed LMSA has advantages as maintaining high output power back-off (OBO) efficiency, wide bandwidth and simple construction. A 10-watt dual-band LMSA is simulated and measured in 1.7-1.9 GHz and 2.4-2.6 GHz with saturated efficiencies 61.2-69.9% and 54.4-70.8%, respectively. The corresponding 9 dB OBO efficiency is 46.5-57.1% and 46.4-54.4%, respectively.

Acoustic coherent perfect absorption based on a PT symmetric coupled Mie resonator system

Parity-time (PT) symmetric coupled resonator systems have exhibited intriguing and unexpected properties in optics and electronics. Here, we extend it to acoustics and report a coupled Mie resonators (MRs) system respecting PT symmetry. The system is constructed with two parallel waveguides connected by an aperture and two MRs placed symmetrically at both sides of the aperture. Instead of using active elements or complex refractive index modulation without gain, we exploit the incident waves of the waveguide as an effective gain so that PT symmetry with balanced loss and gain is realized by only passive materials. Coherent perfect absorption (CPA), which can completely absorb the in-phase excitations with the same intensity provided from two opposite directions, is observed in the PT symmetric phase and at the exceptional point but not in the broken phase. In addition, by varying the relative phase between the two incident waves, the coherent absorption can be tuned from CPA to zero. Our design may provide a flexible platform to research PT symmetry in acoustics and may have applications in tunable noise control, acoustic modulators, and switches.

Complex RGB spatial light modulation with a dual-layer in-plane switching liquid crystal panel

Complex RGB spatial light modulators are required to produce full-color holographic displays. In particular, complex spatial light modulation, which modulates the amplitude and phase of incident light is essential for noiseless dynamic computer-generated hologram synthesis. The feasibility of full-color holographic image generation through the dual-layer in-plane switching liquid crystal plane is theoretically validated and experimentally demonstrated.

Efficiency and Power Loss Distribution in a High-Frequency, Seven-Level Diode-Clamped Inverter

The paper presents efficiency and power loss analysis in a high-frequency, seven-level diode-clamped inverter (7LDCB). The inverter is composed of four-level (4L) diode-clamped branches based on MOSFET transistors and Si Schottky diodes. The range of DC-link voltages enables the operation of the inverter in connection with a single-phase power grid. The tested inverter can be controlled using various modulation concepts that affect its parameters, but also energy losses. Carrier-based modulation, which may be useful in a few applications, is compared to selective modulation based on the state machine (SM-based) algorithm. The article demonstrates the efficiency level of the inverter as well as the influence of the modulation method and switching frequency on the efficiency and loss distribution in semiconductor devices. The article also shows the hardware implementation of a complex modulation algorithm based on selective switching states used to maintain voltage balance on three DC-link capacitors. Redundant switching states allow the generation of the same voltage but with the use of a selected DC-link capacitor. This makes it possible to balance the DC-link voltage with the load current. The article presents experimental results, which show the advantage of using the modulation method with selective switching states. First, it allows for equalizing the loading of DC-link capacitors. The second advantage is a more uniform distribution of losses in semiconductor components.

Loss-induced multiple modal coalescences in an acoustic ring cavity

Chiral exceptional points refer to a class of non-Hermitian degeneracies where two counter-propagating whispering-gallery-like eigenmodes coalesce into one travelling eigenmode, which have been utilized to create orbital angular momentum in various wave systems. However, most studies in this field have so far focused on the modal coalescence for a specific azimuthal order. In this work, we investigate the eigenmodes evolution of an acoustic ring cavity under complex spatial modulation of refractive index along the azimuthal direction. We show that a careful engineering of the complex modulation, possibly realized with acoustic metamaterials, can lead to multiple modal coalescences to produce a series of travelling eigenmodes with different orbital angular momentum orders. These coalesced eigenmodes can be directly excited by a simple source at their resonant frequencies. Our work provides a straightforward approach to the generation and manipulation of acoustic orbital angular momentum.

Novel Clinically Useful Inhibitor of Mediator Complex, RVU120, Relives Differentiation Block in MDS/AML

Background: Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemias (AML) are characterized by a block in hematopoietic differentiation that can often be traced to aberrant stage-specific transcription. The kinase module of the mediator complex, consisting of CDK8, its paralog CDK19, Cyclin C, MED12, and MED13, have been identified as a molecular switch that regulates gene expression. A variety of cancers have exploited this mechanism to maintain stemness and an undifferentiated state. RVU120 is a first-in-class, specific, and selective inhibitor of CDK8/19, currently in Phase Ib clinical trial in patients with AML or High-Risk MDS (HR-MDS) (NCT04021368). RVU120 has been shown to stimulate erythroid differentiation in transformed CD34+ cord blood (CB) cells and in CD34+ cells from Diamond-Blackfan Anemia (DBA). To evaluate the further therapeutic potential of CDK8/19 inhibition, we confirmed aberrant expression of mediator complex components and erythroid-stimulating activity in a collection of CD34+ primary samples of AML and MDS. Results: We investigated the expression of mediator complex components in a large database of MDS CD34+ marrow samples and age-matched controls. Our findings revealed that MED12, a critical component of the mediator complex, was significantly overexpressed in MDS samples from refractory anemia with excess blasts (RAEB), a higher risk subset of MDS(p=0.018) (Fig A). Furthermore, we observed that this overexpression of MED12 was associated with a higher rate of transformation to AML. To delve deeper, we examined the expression of MED12 in sorted leukemic stem cells from primary AML samples and found significantly elevated levels in Long Term Hematopoietic Stem Cells from AML samples with both normal karyotype and complex karyotypes compared to healthy controls. Next, we conducted an evaluation of the efficacy of the mediator kinase module inhibition in MDS-derived cell line (MDS-L). Inhibition of CDK8/19 with RVU120 led to increased erythroid differentiation in this model which confirmed our observations in transformed CD34+ CB cells in CB cells, these phenotypic changes were correlated with the inhibition of CDK8-dependent phosphorylation marker S726 on STAT5 and a profound increase in the expression of genes involved in erythroid commitment and hemoglobin metabolism. In order to confirm therapeutic potential of CDK8/CDK19 inhibition in MDS and AML, we performed colony-forming assay on primary samples of MDS and AML (n= 15). The treatment with RVU120 resulted in increased erythroid differentiation in a majority of samples, evident from an augmented number of colonies. Detailed analysis indicated changes in the expression of erythroid differentiation markers, including increased CD71 and Glycophorin A expression on colonies, as assessed by FACS analysis (Figure B, shows representative sample). Conclusion Our data highlight that inhibition of the overexpressed mediator complex proteins can alleviate the differentiation blocks seen in MDS/AML. These results provide a compelling rationale for further developing the CDK8/19 inhibitor RVU120 for transfusion- dependent MDS/AML patients.

Subunit-Specific Analysis of Cohesin-Mutant Myeloid Malignancies Reveals Distinct Ontogeny and Outcomes

Introduction:Loss of function mutations in the cohesin complex ring components and modulators STAG2, RAD21, SMC1A, SMC3, and PDS5B are recurrent genetic drivers in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and MDS/myeloproliferative neoplasm (MPN) overlap syndromes. However, whether different cohesin subunit mutations share disease characteristics and prognostic impact is not well understood. Methods: We assembled a cohort of 4,439 patients with hematologic neoplasms at the Dana-Farber Cancer Institute (DFCI) and the Munich Leukemia Laboratory (MLL), and identified a subset of 790 cohesin-mutant patients, the largest cohesin-mutant cohort to date. We performed a retrospective analysis of the incidence, clinical presentation, genomic landscape, and clinical outcomes in a cohesin subunit-specific way. Results: STAG2 mutations were most common and present in 610 cases (diagnosed as MDS (50%), AML (36%), MDS/MPN (10%)), followed by RAD21 in 104 (20% MDS, 64% AML, 2% MDS/MPN), SMC3 in 26 (35% MDS, 42% AML, no MDS/MPN), SMC1A in 22 (27% MDS, 55% AML, 5% MDS/MPN), PDS5B in 16 (13% MDS, 38% AML and 6% MDS/MPN), and 12 cases with more than one mutated cohesin gene (50% MDS, 33% AML, 8% MDS/MPN). Within the DFCI cohort, 256 (82%) patients were diagnosed with a myeloid malignancy and 55 (18%) patients with a non-myeloid hematologic malignancy. We focused our subsequent analysis on 735 patients diagnosed with MDS, MDS/MPN or AML, and compared them to 3,649 cohesin-wildtype (WT) patients in the DFCI and MLL cohorts. We found that STAG2 mutations were acquired at the MDS stage and were associated with MDS with increased blasts (75% cases with MDS-IB1 or IB2) and secondary AML. We also noted their co-occurrence with secondary AML-type mutations, such as ASXL1 (64%, OR=5.5, FDR=5e-29), SRSF2 (45%, OR=7.4, FDR=5-e31) and RUNX1 (37%, OR=3.5, FDR=2e-13), and trisomy 8 (OR=10.6, FDR= 2.2e-50). In contrast, mutations in RAD21, SMC1A, SMC3 and PDS5B shared features with de novo AML, including co-occurrence with NPM1 (32%, OR 4.3, FDR=1e-6) and FLT3 (23%, OR= 2.8, FDR= 0.01), and association of RAD21 and SMC1A with t(8;21) AML (OR= 131;134; FDR= 3.8e-5;4.1e-19). Of note, both STAG2 and RAD21 mutations shared a mutational exclusivity with TP53 mutations (OR=0.04-0.06, FDR < 0.001, Figure 1A). We next assessed the impact of different cohesin mutations on clinical outcomes. We conducted independent analyses of overall survival (OS) and progression free survival (PFS) in MDS and AML. Given our observations that cohesin mutations were mutually exclusive with TP53 mutations, and the established prognostic impact of TP53 mutations, we compared the overall survival (OS) and AML-free survival (PFS) of patients with STAG2-mutant MDS (n=119) to TP53-mutant MDS (n=280) and cohesin/ TP53-WT MDS (n=1,023). With a median follow-up (FU) of 51.1 months we observed a significantly worse OS of STAG2-mutant MDS compared to cohesin and TP53-WT MDS (HR 1.44, CI= 1.10-1.89, p=0.007) and a similar risk of leukemic transformation as TP53-mutant MDS cases (median AML-PFS of 15.4 months for STAG2, and 12.1 months for TP53, p=0.3). Furthermore, STAG2-mutant AML (n=148) had significantly worse OS than AML without myelodysplasia related changes (MR) (n=1384) (HR= 0.62, 95% CI=0.5-0.76, p<0.001, median FU 42.8 months), and similar outcomes as AML-MR without TP53 mutations (n=567), (HR=1.25, 95% CI= 1.01-1.55, p=0.04). Importantly, this pattern was distinct from outcomes of RAD21-mutant AML (n=39), which was almost identical to AML-non-MR and significantly better than STAG2-mutant AML OS (HR= 0.56, 95% CI= 0.34-0.93, p=0.024) ( Figure 1B). The effects of STAG2 and RAD21 mutations on OS remained significant when censored for allogeneic stem cell transplantation. Our findings suggest that only STAG2 mutations confer a negative impact on MDS and AML, and this is attributed to secondary ontogeny. Conclusions: In summary, our study establishes a role for different cohesin subunit mutations in distinct subtypes of MDS and AML, which has significant prognostic implications and expands our current understanding of this important group of driver genes. The findings from our subunit-specific analysis demonstrate that while STAG2 mutations are characterized by secondary AML ontogeny arising from MDS and associated with a worse prognosis, RAD21 mutations are associated with de novo AML and better survival.

Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis

Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death, that has been implicated in Alzheimer’s disease and Parkinson’s disease. Inhibition of cystine/glutamate antiporter could lead to mitochondrial fragmentation, mitochondrial calcium ([Ca2+]m) overload, increased mitochondrial ROS production, disruption of the mitochondrial membrane potential (ΔΨm), and ferroptotic cell death. The observation that mitochondrial dysfunction is a characteristic of ferroptosis makes preservation of mitochondrial function a potential therapeutic option for diseases associated with ferroptotic cell death. Mitochondrial calcium levels are controlled via the mitochondrial calcium uniporter (MCU), the main entry point of Ca2+ into the mitochondrial matrix. Therefore, we have hypothesized that negative modulation of MCU complex may confer protection against ferroptosis. Here we evaluated whether the known negative modulators of MCU complex, ruthenium red (RR), its derivative Ru265, mitoxantrone (MX), and MCU-i4 can prevent mitochondrial dysfunction and ferroptotic cell death. These compounds mediated protection in HT22 cells, in human dopaminergic neurons and mouse primary cortical neurons against ferroptotic cell death. Depletion of MICU1, a [Ca2+]m gatekeeper, demonstrated that MICU is protective against ferroptosis. Taken together, our results reveal that negative modulation of MCU complex represents a therapeutic option to prevent degenerative conditions, in which ferroptosis is central to the progression of these pathologies.

Orthosteric and allosteric modulation of human HCAR2 signaling complex

Hydroxycarboxylic acids are crucial metabolic intermediates involved in various physiological and pathological processes, some of which are recognized by specific hydroxycarboxylic acid receptors (HCARs). HCAR2 is one such receptor, activated by endogenous β-hydroxybutyrate (3-HB) and butyrate, and is the target for Niacin. Interest in HCAR2 has been driven by its potential as a therapeutic target in cardiovascular and neuroinflammatory diseases. However, the limited understanding of how ligands bind to this receptor has hindered the development of alternative drugs able to avoid the common flushing side-effects associated with Niacin therapy. Here, we present three high-resolution structures of HCAR2-Gi1 complexes bound to four different ligands, one potent synthetic agonist (MK-6892) bound alone, and the two structures bound to the allosteric agonist compound 9n in conjunction with either the endogenous ligand 3-HB or niacin. These structures coupled with our functional and computational analyses further our understanding of ligand recognition, allosteric modulation, and activation of HCAR2 and pave the way for the development of high-efficiency drugs with reduced side-effects.

All-passive microwave-diode nonreciprocal metasurface

Breaking reciprocity in the microwave frequency range is strongly desirable in the development of modern electronic systems, as it enables nonreciprocal wave absorbing, nonreciprocal beam steering, frequency conversion, and protection of sensitive devices from high energy sources. However, the typical approaches involve bulky biasing magnets or complex spatial-temporal modulations. As such, resorting to lightweight and all-passive platforms would result in optimal configurations and efficient integration. Starting from a circuit model, we theoretically demonstrate the nonreciprocal behavior on a transmission line building block creating a strong field asymmetry with a switchable matching stub to enable two distinct working states. After translating to an electromagnetic model, this concept is first proved by simulation and then experimentally verified on a microstrip-line-based diode-integrated metasurface showing nonreciprocal transmission. This printed circuit board design is expected to find various applications in electromagnetic protecting layers, communication systems, microwave isolators and circulators.

Near-Infrared Light-Driven MXene/Liquid Crystal Elastomer Bimorph Membranes for Closed-Loop Controlled Self-Sensing Bionic Robots.

More recently, soft actuators have evoked great interest in the next generation of soft robots. Despite significant progress, the majority of current soft actuators suffer from the lack of real-time sensory feedback and self-control functions, prohibiting their effective sensing and multitasking functions. Therefore, in this work, a near-infrared-driven bimorph membrane, with self-sensing and feedback loop control functions, is produced by layer by layer (LBL) assembling MXene/PDDA (PM) onto liquid crystal elastomer (LCE) film. The versatile integration strategy successfully prevents the separation issues that arise from moduli mismatch between the sensing and the actuating layers, ultimately resulting in a stable and tightly bonded interface adhesion. As a result, the resultant membrane exhibited excellent mechanical toughness (tensile strengths equal to 16.3MPa (||)), strong actuation properties (actuation stress equal to 1.56MPa), and stable self-sensing (gauge factor equal to 4.72) capabilities. When applying the near-infrared (NIR) laser control, the system can perform grasping, traction, and crawling movements. Furthermore, the wing actuation and the closed-loop controlled motion are demonstrated in combination with the insect microcontroller unit (MCU) models. The remote precision control and the self-sensing capabilities of the soft actuator pave a way for complex and precise task modulation in the future.

Chemical and Genetic Modulation of Complex I of the Electron Transport Chain Enhances the Biotherapeutic Protein Production Capacity of CHO Cells.

Chinese hamster ovary (CHO) cells are the cell line of choice for producing recombinant therapeutic proteins. Despite improvements in production processes, reducing manufacturing costs remains a key driver in the search for more productive clones. To identify media additives capable of increasing protein production, CHOZN® GS-/- cell lines were screened with 1280 small molecules, and two were identified, forskolin and BrdU, which increased productivity by ≥40%. While it is possible to incorporate these small molecules into a commercial-scale process, doing so may not be financially feasible or could raise regulatory concerns related to the purity of the final drug substance. To circumvent these issues, RNA-Seq was performed to identify transcripts which were up- or downregulated upon BrdU treatment. Subsequent Reactome pathway analysis identified the electron transport chain as an affected pathway. CRISPR/Cas9 was utilized to create missense mutations in two independent components of the electron transport chain and the resultant clones partially recapitulated the phenotypes observed upon BrdU treatment, including the productivity of recombinant therapeutic proteins. Together, this work suggests that BrdU can enhance the productivity of CHO cells by modulating cellular energetics and provides a blueprint for translating data from small molecule chemical screens into genetic engineering targets to improve the performance of CHO cells. This could ultimately lead to more productive host cell lines and a more cost-effective method of supplying medication to patients.

Review of 1.55 μm Waveband Integrated External Cavity Tunable Diode Lasers

The 1.55 μm waveband integrated external cavity tunable diode lasers have excellent merits such as their small volume, low cost, low power consumption, wide tuning range, narrow linewidth, large side mode suppression ratio, and high output power. These merits have attracted many applications for the lasers, such as in wavelength division multiplexing, passive optical networks, mobile backhaul, and spectral sensing technology. In this paper, firstly, the basic structure and principle of integrated external cavity tunable diode lasers are introduced, and then two main integrated structures of 1.55 μm waveband external cavity tunable diode lasers are reviewed and compared in detail, namely the hybrid integrated structure and monolithic integrated structure of 1.55 μm waveband integrated external cavity tunable diode lasers. Finally, the research progress in 1.55 μm waveband integrated external cavity tunable diode lasers in the last decade are summarised, and the advantages and disadvantages of 1.55 μm waveband integrated external cavity tunable diode lasers are analysed. The results show that, with the transformation of optical communication into more complex modulation formats, it is necessary to integrate miniature 1.55 μm waveband external cavity tunable diode lasers. Low-cost integrated 1.55 μm waveband external cavity tunable diode lasers are expected to be used in the next generation of optical transceivers in small-factor modules.

THE IMPORTANCE OF PHAGOCYTOSIS IN ASSESSING CELLULAR IMMUNITY AT LAMBS

"The scientific research reflected in these investigations constituted the study of some immunological aspects of the immune defence mechanisms in various periods at lambs. As a result of the immunological investigation, various indices characteristic of phagocytic activity and intensity were revealed. It was found that the phagocytic activity in these periods of the lambs' life is primarily attributed to neutrophils, the rest being carried out by macrophages. At the same time, the investigations have demonstrated that the defence mechanisms of the investigated animals are not triggered enough to protect the aggression of microorganisms, viruses and other pathogenic agents. The results of the study determined that the regulation of the humoral or cellular immune response is a complex modulation process involving a series of means through which the body's specific defence is maintained at a certain level and with a certain duration, in order to achieve homeostasis and preserve health status."

Main targets of ibogaine and noribogaine associated with its putative anti-addictive effects: A mechanistic overview.

There is a growing interest in studying ibogaine (IBO) as a potential treatment for substance use disorders (SUDs). However, its clinical use has been hindered for mainly two reasons: First, the lack of randomized, controlled studies informing about its safety and efficacy. And second, IBO's mechanisms of action remain obscure. It has been challenging to elucidate a predominant mechanism of action responsible for its anti-addictive effects. To describe the main targets of IBO and its main metabolite, noribogaine (NOR), in relation to their putative anti-addictive effects, reviewing the updated literature available. A comprehensive search involving MEDLINE and Google Scholar was undertaken, selecting papers published until July 2022. The inclusion criteria were both theoretical and experimental studies about the pharmacology of IBO. Additional publications were identified in the references of the initial papers. IBO and its main metabolite, NOR, can modulate several targets associated with SUDs. Instead of identifying key targets, the action of IBO should be understood as a complex modulation of multiple receptor systems, leading to potential synergies. The elucidation of IBO's pharmacology could be enhanced through the application of methodologies rooted in the polypharmacology paradigm. Such approaches possess the capability to describe multifaceted patterns within multi-target drugs. IBO displays complex effects through multiple targets. The information detailed here should guide future research on both mechanistic and therapeutic studies.

Genetic diversity and natural selection of apical membrane antigen-1 (ama-1) in Cameroonian Plasmodium falciparum isolates

Antigenic variation associated with genetic diversity in global Plasmodium falciparum apical membrane antigen-1 (PfAMA-1) is a major impediment to designing an effective malaria vaccine. Here, we report the first study on genetic diversity and natural selection of the Pfama-1 gene in P. falciparum isolates from Cameroon. A total of 328 P. falciparum positive samples collected during 2016 and 2019 from five localities of Cameroon were analysed. The ectodomain coding fragment of Pfama-1 gene was amplified for polymorphism profiling and natural selection analysis. A total of 108 distinct haplotypes were found in 203 P. falciparum isolates with considerable nucleotide diversity (π = 0.016) and haplotype diversity (Hd = 0.976). Most amino acid substitutions detected were scattered in ectodomain-I and few specific mutations viz P145L, K148Q, K462I, L463F, N471K, S482L, E537G, K546R and I547F were seen only in Cameroonian isolates. A tendency of natural selection towards positive diversifying selection was observed (Taj-D = 2.058). Five positively selected codon sites (P145L, S283L, Q308E/K, P330S and I547F) were identified, which overlapped with predicted B-cell epitopes and red blood cell (RBC) binding sites, suggesting their potential implication in host immune pressure and parasite-RBC binding complex modulation. The Cameroonian P. falciparum populations indicated a moderate level of genetic differentiation when compared with global sequences, with few exceptions from Vietnam and Venezuela. Our findings provide baseline data on existing Pfama-1 gene polymorphisms in Cameroonian field isolates, which will be useful information for malaria vaccine design.

ZmELF3.1 integrates the RA2-TSH4 module to repress maize tassel branching.

Tassel branch number (TBN) is a key agronomic trait for adapting to high-density planting and grain yield in maize. However, the molecular regulatory mechanisms underlying tassel branching are still largely unknown. Here, we used molecular and genetic studies together to show that ZmELF3.1 plays a critical role in regulating TBN in maize. Previous studies showed that ZmELF3.1 forms the evening complex through interacting with ZmELF4 and ZmLUX to regulate flowering in maize and that RA2 and TSH4 (ZmSBP2) suppresses and promotes TBN in maize, respectively. In this study, we show that loss-of-function mutants of ZmELF3.1 exhibit a significant increase of TBN. We also show that RA2 directly binds to the promoter of TSH4 and represses its expression, thus leading to reduced TBN. We further demonstrate that ZmELF3.1 directly interacts with both RA2 and ZmELF4.2 to form tri-protein complexes that further enhance the binding of RA2 to the promoter of TSH4, leading to suppressed TSH4 expression and consequently decreased TBN. Our combined results establish a novel functional link between the ELF3-ELF4-RA2 complex and miR156-SPL regulatory module in regulating tassel branching and provide a valuable target for genetic improvement of tassel branching in maize.