Molecular Candidates Research Articles

2D Quantum Spin-Liquid Candidate Including a Chiral Anion: κ-(BEDT-TTF)2[BR/S(salicylate)2

The quantum spin-liquid state was first theorized by Anderson 50 years ago and the challenge remains to realize a quantum spin-liquid material. A handful of two-dimensional molecular candidates have attracted huge attention over the past 30 years owing to their triangular lattice possessing S = 1/2 spin systems. We present a new quantum spin-liquid candidate in 2D Mott insulator κ-(BEDT-TTF)2[BR/S(salicylate)]2. The structure has a double-width anion layer giving it a strong 2D character. The spiroborate anion is chiral and the salt is an inversion twin, having no inversion symmetry center and crystallizing in space group P21. This offers the possibility of novel behavior owing to the low symmetry not previously seen in molecular spin-liquid candidates. The peak height of the 6K anomaly of κ-(BEDT-TTF)2[BR/S(salicylate)2] is 2 or 3 times larger than that of κ-(BEDT-TTF)2Cu2(CN)3 and EtMe3Sb[Pd(dmit)2]2. The structure presents many opportunities for crystal engineering through atom-by-atom changes to the ligands on the spiroborate anion to produce a family of materials which lie in and around the QSL region of the phase diagram for these salts. This gives the prospect of an experimental playground to deepen understanding of the QSL state. Electrical resistivity, SQUID magnetometry, band calculations, heat capacity, Infrared and Raman spectroscopy are reported for κ-(BEDT-TTF)2[BR/S(salicylate)2].

Deciphering Microbially Driven Labile and Refractory Molecular Candidates in Dissolved Organic Matter

Deciphering Microbially Driven Labile and Refractory Molecular Candidates in Dissolved Organic Matter

Molecular Pψ pentaquarks from light-meson exchange saturation

Theoretical predictions of the spectrum of heavy meson-baryon bound states are a fundamental tool for disentangling the nature of the different pentaquark states that have been observed in experimental facilities. Here we explore this spectrum in a phenomenological model that describes the heavy meson-baryon interaction in terms of a contact-range interaction, where the coupling strength is saturated by the exchange of light scalar and vector mesons, i.e., σ, ρ, and ω exchanges. Saturation determines the couplings modulo an unknown proportionality constant that can be calibrated from a molecular candidate. If we use the PψN(4312) as input, we predict a series of molecular pentaquarks including the PψN(4440) and PψN(4457), the recent PψsΛ(4338) and the PψsΛ(4459). Published by the American Physical Society 2025

Design, synthesis, and in silico studies of new quinazolinones tagged thiophene, thienopyrimidine, and thienopyridine scaffolds as antiproliferative agents with potential p38α MAPK kinase inhibitory effects.

The current work focuses on the creation of novel derivatives of the quinazolinone ring system, with various substituted thiophene, thienopyrimidine, and thienopyridine scaffolds 3a,b-11. Employing the standard MTT assay, every target compound's in vitro antiproliferative efficacy was evaluated in comparison with doxorubicin against both normal WI-38 cells and various cancer cell lines. Derivatives 6, 8a, and 8b demonstrated the most potent activity, alongside their safety profiles against WI-38. The in vitro enzyme assay showed that the new analogues had a better ability to inhibit p38α MAPK kinase than SB 202190 (IC50s = 0.18 ± 0.02, 0.23 ± 0.05, 0.31 ± 0.04, and 0.27 ± 0.06 μM, respectively). Additionally, apoptosis tests conducted on MCF-7 cells revealed that 6, 8a, and 8b significantly increased the levels of Bax (by approximately 7.31, 13.8, and 8.86 fold) and caspase 3 (by approximately 3.55, 4.22, and 3.87 fold), respectively, in comparison to the untreated cells. They decreased the amount of Bcl-2 by ∼1.99, 3.69, and 2.66 fold, respectively. The most powerful counterpart, 8a, underwent additional investigation of the cell cycle and apoptosis. It caused necrotic and apoptotic effects in the late stages and stopped the MCF-7 cell cycle at the G2/M phase. Based on the molecular docking study, candidates 6, 8a, and 8b all fit well within p38α MAPK kinase, with energy scores of -10.88, -11.28, and -10.96 kcal mol-1, respectively. Based on the in silico computer examination of physico-chemical and ADMET properties, the latter analogues seem to be promising candidates for further development and optimization in research.

Genome-Wide Scans for Selection Signatures in Haimen Goats Reveal Candidate Genes Associated with Growth Traits.

Understanding the genetic characteristics of indigenous goat breeds is vital for their conservation and breeding. Haimen goats, native to China's Yangtze River Delta, possess distinctive traits such as white hair, moderate growth rate, high-quality meat, and small body size. However, knowledge regarding the genetic structure and germplasm characteristics of Haimen goats remains limited. In this study, we performed 20× whole-genome resequencing of 90 goats (60 Haimen goats and 30 Boer goats) to identify single-nucleotide polymorphisms (SNPs) and insertions/deletions (Indels) associated with growth traits. Here, we analyzed population genetic structure and genome-wide selection signatures between the Haimen and Boer goats based on whole-genome resequencing data. The principal component analysis (PCA) and neighbor-joining (N-J) tree results demonstrated significant genetic differentiation between the Haimen and Boer goats. The nucleotide diversity (Pi) and linkage disequilibrium (LD) decay results indicated higher genomic diversity in the Haimen goat population. Furthermore, selective sweep analysis identified candidate genes associated with growth traits. These genes exhibited strong selection signatures and were related to body size (DONSON, BMPR1B, and EPHA5), muscle development (GART, VGLL3, MYH15), and fat metabolism (ADAMTS5, LRP6, XDH, CPT1A, and GPD1). We also identified growth-related candidate genes (NCOR1, DPP6, NOTCH2, and FGGY) specific to Haimen goats. Among these genes, pancreatic lipase-related protein 1 (PNLIPRP1) emerged as the primary candidate gene influencing growth phenotypes. Further analysis revealed that a 26 bp Indel in PNLIPRP1 increased its gene expression, suggesting that this Indel could serve as a molecular marker for early marker-assisted selection, potentially enhancing early growth in goats. These findings provide valuable molecular markers and candidate genes for improving growth traits in Haimen goat breeding.

Spectroscopic properties of double-strangeness molecular tetraquarks

Inspired by recent advances in the study of the K(*)K¯(*) molecular tetraquarks and the H-dibaryon, we focus on the spectroscopic properties of the K¯(*)K¯(*) systems, which exhibit an exotic flavor quantum number of ssq¯q¯. A dynamical analysis is performed using the one-boson-exchange model to describe the effective interactions for these systems, accounting for both S−D wave mixing and coupled-channel effects. By solving the coupled-channel Schrödinger equation, we identify the I(JP)=0(1+) K¯K¯* and I(JP)=0(1+)K¯*K¯* states as the most likely candidates for double-strangeness molecular tetraquarks. Furthermore, we estimate their strong decay behaviors based on the effective Lagrangian approach, with several channels exhibiting considerable decay widths. Meanwhile, we investigate their magnetic moments and M1 radiative decay widths, shedding light on their inner structures, within the constituent quark model. Finally, we encourage experimentalists to focus on these predicted double-strangeness molecular tetraquark candidates, particularly in B meson decays. Such efforts could pave the way for establishing the molecular tetraquark states in the light-quark sector. Published by the American Physical Society 2024

From PψN and PψsΛ to T¯ccf : Symmetry analysis of the interactions in the (c¯q)(c¯q) , (ccq)(c¯q) , and (ccq)(ccq) dihadron systems

We investigate the interactions of (c¯q)(c¯q)/(ccq)(c¯q)/(ccq)(ccq) dihadron systems based on a contact Lagrangian possessing the SU(3) flavor and SU(2) spin symmetries. Under the assumptions of two scenarios for the JP quantum numbers of PψN(4440) and PψN(4457) states, we obtain the parameters (g˜s, g˜a) introduced from this contact Lagrangian. Then we include the SU(3) breaking effect by introducing a factor gx, this quantity can be constrained by the experimental mass of PψsΛ(4338) state. We can reproduce the mass of Tccf(3875) state with the parameters extracted from the observed PψN states, the fairly good description of the masses of the observed PψN/PψsΛ/Tccf states motivates us to investigate the possible molecular candidates in the T¯ccf/PψcΛ/HΩccccΛ systems within the same framework. Then we proceed to discuss the existences of T¯ccs¯θ/PψcsN/HΩccccsN states by investigating the SU(3) breaking effects. Our results show that the states in the T¯ccs¯θ/PψcsN systems can hardly form bound states, while the states in the HΩccccsN system can form bound states due to their larger reduced masses. Published by the American Physical Society 2024

Quantum Chemical Determination of Molecular Dye Candidates for Non-Invasive Bioimaging.

Molecular dyes containing carbazole-based π bridges and/or julolidine-based donors should be promising molecules for intense SWIR emission with potential application to molecular bioimaging. This study stochastically analyzes the combinations of more than 250 organic dyes constructed within the D-π-D (or equivalently D-B-D) motif. These dyes are built from 22 donors (D) and 14 π bridges (B) and are computationally examined using density functional theory (DFT). The DFT computations provide optimized geometries from which the excited state transition wavelengths and associated oscillator strengths and orbital overlaps are computed. While absorption is used as a stand-in for emission, the longer the absorption wavelength, the longer the emission should be as well for molecules of this type. Nearly 100 novel dyes reported in this work have electronic absorptions at or beyond 1200 nm, opening the possibility for future synthesis and experimental characterization of new molecular dyes with promising properties for bioimaging.

Multi-omics and in-silico approach reveals AURKA, AURKB, and RSAD2 as therapeutic biomarkers in OSCC progression

Oral squamous cell carcinoma (OSCC), a prevalent form of head and neck cancer, poses a significant health challenge with limited improvements in patient outcomes over the years. Its development is influenced by a complex interplay of genetic alterations and environmental factors. While progress has been made in understanding the molecular mechanisms driving OSCC, pinpointing critical molecular markers and potential drug candidates has proven elusive. This study uniquely endeavors to conduct a meta-analysis to unveil therapeutic genes responsible for OSCC tumorigenesis. A multi-omics approach identified 951 differentially expressed genes (DEGs) associated with OSCC by analyzing microarray data from the NCBI GEO database. Weighted gene co-expression network analysis (WGCNA) detected a significant hub gene module comprising 805 genes, followed by the construction of protein-protein interaction network resulting in two small clusters of 7 gene-encoded proteins each. These clusters were filtered out based on top 10 significant pathways and gene ontology terms to identify six key target proteins with elevated expression levels, acting as potential therapeutic biomarkers for OSCC. Notably, RSAD2 emerged as a novel biomarker linked to OSCC progression. Furthermore, we identified potential inhibitors targeting AURKA, AURKB, and RSAD2 proteins and validated their interactions through molecular dynamics simulation studies. The simulations confirmed the stability of receptor-ligand complexes, suggesting ZINC03839281, ZINC04026167, and ZINC00718292 compounds hold promise as potential inhibitors for therapeutically targeting AURKA, AURKB, and RSAD2 as significant OSCC biomarkers. We recommend further comprehensive studies, including experimental and preclinical investigations, to validate the effectiveness of these lead compounds for OSCC treatment.

Molecular diagnoses and candidate gene identification in the congenital heart disease cohorts of the 100,000 genomes project.

Congenital heart disease (CHD) describes a structural cardiac defect present from birth. A cohort of participants recruited to the 100,000 Genomes Project (100 kGP) with syndromic CHD (286 probands) and familial CHD (262 probands) were identified. "Tiering" following genome sequencing data analysis prioritised variants in gene panels linked to participant phenotype. To improve diagnostic rates in the CHD cohorts, we implemented an agnostic de novo Gene Discovery Pipeline (GDP). We assessed de novo variants (DNV) for unsolved CHD participants following filtering to select variants of interest in OMIM-morbid genes, as well as novel candidate genes. The 100kGP CHD cohorts had low rates of pathogenic diagnoses reported (combined CHD "solved" 5.11% (n = 28/548)). Our GDP provided diagnostic uplift of nearly one third (1.28% uplift; 5.11% vs. 6.39%), with a new or potential diagnosis for 9 additional participants with CHD. When a filtered DNV occurred within a non-morbid gene, our GDP prioritised biologically-plausible candidate CHD genes (n = 79). Candidate variants occurred in both genes linked to cardiac development (e.g. AKAP13 and BCAR1) and those currently without a known role (e.g. TFAP2C and SETDB1). Sanger sequencing of a cohort of patients with CHD did not identify a second de novo variant in the candidate dataset. However, literature review identified rare variants in HMCN1, previously reported as causative for pulmonary atresia, confirming the approach utility. As well as diagnostic uplift for unsolved participants of the 100 kGP, our GDP created a dataset of candidate CHD genes, which forms an important resource for further evaluation.

Polymorphisms Within the IQGAP2 and CRTAC1 Genes of Gannan Yaks and Their Association with Milk Quality Characteristics.

The IQ motif containing GTPase activating protein 2 (IQGAP2) gene functions as a tumor suppressor, reducing the malignant properties of breast cancer cells. The circulating cartilage acidic protein 1 (CRTAC1) gene, present in the whey protein fraction of dairy cows throughout lactation, is significantly correlated with fatty acids in milk. In this study, we investigated the correlation between single nucleotide polymorphisms (SNPs) in the IQGAP2 and CRTAC1 genes and milk quality traits in Gannan yaks, aiming to identify potential molecular marker loci for enhancing milk quality. Using the Illumina Yak cGPS 7K liquid chip, we genotyped 162 yaks and identified five SNPs in the IQGAP2 (g.232,769C>G, g.232,922G>C) and CRTAC1 (g.4,203T>C, g.5,348T>G, g.122,451T>C) genes. Genetic polymorphism analysis revealed that these five SNPs were moderately polymorphic and in Hardy-Weinberg equilibrium. An association analysis results showed that, at the g.232,769C>G locus of the IQGAP2 gene, the heterozygous CG genotype had significantly higher lactose content than the CC and GG homozygous genotypes (p < 0.05). Similarly, at the g.232,922G>C locus, the heterozygous GC and mutant CC genotypes significantly increased the contents of milk fat, lactose, and total solids (TS) (p < 0.05). In the CRTAC1 gene (g.4,203T>C, g.5,348T>G, g.122,451T>C), the mutant CC genotype significantly increased milk fat content, while the heterozygous TG genotype significantly increased lactose content (p < 0.05). In summary, mutations at the loci of g.232,769C>G, g.232,922G>C, g.4,203T>C, g.5,348T>G, and g.122,451T>C significantly elevated the lactose, milk fat, and TS content in Gannan yak milk, providing potential molecular marker candidates for improving Gannan yak milk quality.

Abstract B038: Establishing a screening platform to identify key signaling molecules regulating cold tumor formation through immune evasion and exclusion

Abstract Many trial data have shown that cancer immunotherapy can successfully induce long lasting anti-cancer immune responses and increased the survival rate of cancer patients. One of the key challenges facing cancer immunotherapy is the low response rate of cancer patients to immunotherapy, suggesting that these cancer patients may have acquired resistance toward immunotherapy before treatments. Therefore, there is an unmet need for identifying the underlying mechanisms that promote resistance. One important hypothesis is that immune-excluded tumors (so called cold tumors) that lack of functional T cells have been often found in cancer patients who cannot respond well to cancer immunotherapy. To address this, we have successfully established a preclinical model for cold lung tumors, conducted RNA-seq, performed hallmark gene set enrichment analysis (GSEA) on cold tumor cells sorted in vivo, and identified several candidates associated with epithelial-mesenchymal transition, Wnt signaling, type I and II interferon (IFN) signaling, and p53 signaling. We hypothesize that their roles may either promote or inhibit the formation of cold tumors. One of the molecular candidates we identified, a molecule designated as IRC001, represents a crucial proof of concept for our experimental tumor model. We have unveiled a novel role for IRC001 in enhancing anti-tumor immunity, leading to the transformation of cold tumors into hot tumors and facilitating swift tumor regression through pathways reliant on T cells and type I IFN signaling. Our mechanistic studies have shown that IRC001 can trigger type I IFN signaling by engaging STING/TBK-1/IRF3-dependent pathways. To delve deeper into the spatial and molecular distinctions in mouse tumors (± IRC001), we initiated a preliminary study utilizing 10x Genomics/Visium to examine the spatial variations between these tumor types. Significantly, our spatial transcriptomic analysis revealed consistent immune-excluded and immune-enriched characteristics compared to traditional RNA sequencing methods. We conducted an analysis of TCGA datasets (The Cancer Genome Atlas) and observed that elevated IRC001 expression is associated with improved prognosis in SKCM (Skin Cutaneous Melanoma). Furthermore, our bioinformatics analysis revealed that melanoma patients exhibiting heightened IRC001 expression displayed positive responses to immune checkpoint blockade therapies. Therefore, we believe that our experimental tumor model can provide vital insights into the cold tumor microenvironment, shaping future therapeutic strategies, and pinpointing molecular candidates that can assist in selecting patients for successful immunotherapy. Citation Format: Yi-Ting Liao, Li-Mei Chen, Wen-Jye Lin. Establishing a screening platform to identify key signaling molecules regulating cold tumor formation through immune evasion and exclusion [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr B038.

Diffusion Monte Carlo calculation of fully heavy pentaquarks

Using a diffusion Monte Carlo algorithm, we calculated the spectra of all possible S-wave fully heavy pentaquarks within the framework of the quark model. Our aim was to compare the masses of different spin-color configurations corresponding to the same spatial wave function for each quark composition. In particular, we computed the masses of the configuration with the maximum number of undistinguishable quarks and those of all the possible baryon+meson splittings compatible with the total number of b’s and c’s for a given pentaquark. What we found was that, in all cases, compact baryon+meson configurations had lower masses than their more symmetric counterparts. Moreover, those “molecular” associations were unstable (with larger masses) that their infinitely separated noninteracting pieces except in the case of (ccb)(cb¯) and (bbc)(bc¯) pentaquarks. In any case, even for unstable arrangements, the excess masses are so small (∼20–60 MeV) as to make those compact molecular structures serious candidates to be experimentally detected. Published by the American Physical Society 2024

Zipper‐Like Dynamic Switching of Coordination Bonds Gives a Polar Bimetallic Halide Toward Self‐Driven X‐Ray Detection

AbstractPolar molecular crystals hold a promise for controlling bulk physical properties originated in their unique switchable polarity via structural transformation. However, the mechanisms for switching polarization are mainly limited to displacive and disorder‐order phase transitions, which rarely involve the reconstruction of chemical bonds. Here, we have switched and tuned electric polarization in a bimetallic halide, (Neopentylammonium)4AgBiBr8 (1), as verified by light‐excited pyroelectric effect. Most notably, its Ag−Br coordination bonds show a zipper‐like dynamic switching behavior from the ‘locked’ to ‘unlocked’ state, namely, reconstruction of chemical bonds. Coupling with the dynamic ordering of organic cations, this bond‐switching transition makes a contribution to switchable polarization of 1. As expected, its polarity creates pyroelectric effect for self‐driven X‐ray detection with high sensitivity (3.8×103 μC Gy−1 cm−2) and low limit of detection (4.8 nGy s−1). This work on the bond‐switching mechanism provides an avenue to design polar molecular candidate for smart optoelectronic devices.

Zipper-Like Dynamic Switching of Coordination Bonds Gives a Polar Bimetallic Halide Toward Self-Driven X-Ray Detection.

Polar molecular crystals hold a promise for controlling bulk physical properties originated in their unique switchable polarity via structural transformation. However, the mechanisms for switching polarization are mainly limited to displacive and disorder-order phase transitions, which rarely involve the reconstruction of chemical bonds. Here, we have switched and tuned electric polarization in a bimetallic halide, (Neopentylammonium)4AgBiBr8 (1), as verified by light-excited pyroelectric effect. Most notably, its Ag-Br coordination bonds show a zipper-like dynamic switching behavior from the 'locked' to 'unlocked' state, namely, reconstruction of chemical bonds. Coupling with the dynamic ordering of organic cations, this bond-switching transition makes a contribution to switchable polarization of 1. As expected, its polarity creates pyroelectric effect for self-driven X-ray detection with high sensitivity (3.8×103 μC Gy-1 cm-2) and low limit of detection (4.8 nGy s-1). This work on the bond-switching mechanism provides an avenue to design polar molecular candidate for smart optoelectronic devices.

Exploring the response of yellow lupine (Lupinus luteus L.) root to drought mediated by pathways related to phytohormones, lipid, and redox homeostasis.

Yellow lupine (Lupinus luteus L.) is a high-protein crop of considerable economic and ecological significance. It has the ability to fix atmospheric nitrogen in symbiosis with Rhizobium, enriching marginal soils with this essential nutrient and reducing the need for artificial fertilizers. Additionally, lupine produces seeds with a high protein content, making it valuable for animal feed production. However, drought negatively affects lupine development, its mutualistic relationship with bacteria, and overall yield. To understand how lupine responds to this stress, global transcriptome sequencing was conducted, along with in-depth biochemical, chromatography, and microscopy analyses of roots subjected to drought. The results presented here contribute to strategies aimed at mitigating the effects of water deficit on lupine growth and development. Based on RNA-seq, drought-specific genes were identified and annotated to biological pathways involved in phytohormone biosynthesis/signaling, lipid metabolism, and redox homeostasis. Our findings indicate that drought-induced disruption of redox balance characterized by the upregulation of reactive oxygen species (ROS) scavenging enzymes, coincided with the accumulation of lipid-metabolizing enzymes, such as phospholipase D (PLD) and lipoxygenase (LOX). This disruption also led to modifications in lipid homeostasis, including increased levels of triacylglycerols (TAG) and free fatty acids (FFA), along with a decrease in polar lipid content. Additionally, the stress response involved alterations in the transcriptional regulation of the linolenic acid metabolism network, resulting in changes in the composition of fatty acids containing 18 carbons. The first comprehensive global transcriptomic profiles of lupine roots, combined with the identification of key stress-responsive molecules, represent a significant advancement in understanding lupine's responses to abiotic stress. The increased expression of the Δ12DESATURASE gene and enhanced PLD activity lead to higher level of linoleic acid (18:2), which is subsequently oxidized by LOX, resulting in membrane damage and malondialdehyde (MDA) accumulation. Oxidative stress elevates the activities of superoxide dismutase (SOD), ascorbate peroxidase (APX), and catalase (CAT), while the conversion of FFAs into TAGs provides protection against ROS. This research offers valuable molecular and biochemical candidates with significant potential to enhance drought tolerance . It enables innovative strategies in lupine breeding and crop improvement to address critical agricultural challenges.

HDAC6 as a Prognostic Factor and Druggable Target in HER2-Positive Breast Cancer.

Adjuvant trastuzumab is the standard of care for HER2+ breast cancer (BC) patients. However, >50% of patients become resistant. This study aimed at the identification of the molecular factors associated with disease relapse and their further investigation as therapeutically exploitable targets. Analyses were conducted on formalin-fixed paraffin-embedded tissues of the primary tumors of relapsed (cases) and not relapsed (controls) HER2+ BC patients treated with adjuvant trastuzumab. The nCounter Human Breast Cancer Panel 360 was used. Logistic regression and partitioning around medoids were employed to identify the genes associated with disease recurrence. Cytotoxicity experiments using trastuzumab-resistant cell lines and a network pharmacology approach were carried out to investigate drug efficacy. A total of 52 patients (26 relapsed and 26 not relapsed) were analyzed. We found that a higher expression of HDAC6 was significantly associated with an increased risk of recurrence, with an adjusted OR of 3.20 (95% CI 1.38-9.91, p = 0.016). Then, we investigated the cytotoxic activity of the selective HDAC6 inhibitor Nexturastat A (NextA) on HER2+ cell lines, which were both sensitive and trastuzumab-resistant. A sub-cytotoxic concentration of NextA, combined with trastuzumab, showed a synergistic effect on BC cell lines. Finally, using a network pharmacology approach, we identified HSP90AA1 as the putative molecular candidate responsible for the synergism observed in vitro. Our findings encourage the exploration of the role of HDAC6 as a prognostic factor and the combinatorial use of HDAC6 selective inhibitors combined with trastuzumab in HER2+ BC, in particular for those patients experiencing drug resistance.

Lipids Determine the Toxicity of Human Islet Polypeptide Aggregates in Vivo

The onset and progression of type 2 diabetes is linked to the accumulation and aggregation of human islet amyloid polypeptide (hIAPP) in the pancreas. Amyloid oligomers and fibrils formed as a result of such aggregation exert high cytotoxicity. Although some pieces of evidence suggest that lipids could alter the rate of hIAPP aggregation, the effect of lipids on the aggregation properties of this peptide remains unclear. In this study, we investigate the effect of sphingo-, anionic and zwitterionic phospholipids with different lengths of fatty acids on the aggregation of hIAPP. We found that anionic lipids drastically accelerate peptide aggregation, whereas this effect was substantially weaker for sphingo- and zwitterionic phospholipids. Biophysical analysis revealed that the presence of lipids resulted in substantial differences in morphology and secondary structure of hIAPP fibrils compared to the protein aggregates grown in the lipid-free environment. We also found that zwitterionic phospholipids drastically increased cytotoxicity of hIAPP aggregates, whereas this effect was less evident for sphingo- and anionic phospholipids. Our results showed that drastic differences in lipid-determined cytotoxicity of hIAPP aggregates were linked to molecular mechanisms of autophagy, exocytosis, and unfolded protein response. These findings suggest that molecular candidates that could disrupt protein-lipid interactions would allow for deceleration of the onset and progression of type 2 diabetes.

Plastic Events of the Vestibular Nucleus: the Initiation of Central Vestibular Compensation.

Vestibular compensation is a physiological response of the vestibular organs within the inner ear. This adaptation manifests during consistent exposure to acceleration or deceleration, with the vestibular organs incrementally adjusting to such changes. The molecular underpinnings of vestibular compensation remain to be fully elucidated, yet emerging studies implicate associations with neuroplasticity and signal transduction pathways. Throughout the compensation process, the vestibular sensory neurons maintain signal transmission to the central equilibrium system, facilitating adaptability through alterations in synaptic transmission and neuronal excitability. Notable molecular candidates implicated in this process include variations in ion channels and neurotransmitter profiles, as well as neuronal and synaptic plasticity, metabolic processes, and electrophysiological modifications. This study consolidates the current understanding of the molecular events in vestibular compensation, augments the existing research landscape, and evaluates contemporary therapeutic strategies. Furthermore, this review posits potential avenues for future research that could enhance our comprehension of vestibular compensation mechanisms.

MsFtsH8 Enhances the Tolerance of PEG-Simulated Drought Stress by Boosting Antioxidant Capacity in Medicago sativa L.

Drought is a major abiotic stress that limits the growth and yield of alfalfa, a vital forage legume. The plant metalloproteinase Filamentation temperature-sensitive H (FtsH) is an ATP- and Zn2+-dependent enzyme that plays a significant character in the plant's response to environmental stress. However, its functional role in drought resistance remains largely unexplored. This study investigates the drought tolerance role of alfalfa MsFtsH8 by analyzing the growth, physiology, and gene expression of overexpressing plants under drought conditions. The results demonstrated that both MsFtsH8-overexpressing Arabidopsis and alfalfa plants exhibited superior growth condition and enhanced membrane stability. The overexpressing alfalfa plants also showed reduced MDA levels, higher proline content, lower H2O2 accumulation, an increased activity of antioxidant-related enzymes (SOD, POD, and CAT) activity, and an elevated expression of antioxidant-related genes. These results indicated that the overexpression of MsFtsH8 enhanced growth, improved osmotic regulation, reduced ROS levels, and increased antioxidative capacity, ultimately leading to greater drought tolerance in alfalfa. Our findings suggest that MsFtsH8 mitigates oxidative damage caused by drought by modulating the plant's antioxidant system, thus improving drought tolerance in alfalfa. This study provides a molecular basis and candidate genes for enhancing drought resistance in alfalfa through genetic engineering.