Pancreatitis pain quality changes at year 1 follow-up, but GP130 remains a biomarker for pain.

BACKGROUND/OBJECTIVES: Debilitating abdominal pain is a common symptom affecting patients with chronic pancreatitis (CP). CP pain is dynamic due to multiple underlying mechanisms. The objective of this study was to 1) evaluate changes in pain phenotype at one year follow-up and 2) validate putative pain biomarkers in a prospective cohort study. METHODS: The Neuropathic and Nociceptive PROMIS-PQ questionnaires were used to classify pain for participants with in the PROCEED study. Putative serum biomarkers were measured via immunoassay. RESULTS: At enrollment, 17.6 % (120/681) subjects with CP reported no pain in the previous year. Of those, 29 % experienced pain during the 1 yr follow-up whereas 18 % of those with pain prior to enrollment reported no pain during the 1 yr follow-up period. Of the 393 subjects with PROMIS-PQ data at enrollment, 212 also had follow-up data at 1 yr. Approximately half (53.3 %) of those individuals changed pain phenotype between baseline and follow-up. At 1 yr, serum TGFß1 level was negatively correlated with nociceptive T-scores (p = 0.006). GP130 was significantly correlated with both nociceptive (p = 0.012) and neuropathic T-scores (p = 0.043) at 1 yr, which is consistent with the previously published findings. CONCLUSIONS: The positive association between TGFß1 and pain is not maintained over time, suggesting it is a poor pain biomarker. However, serum GP130 is a consistent biomarker for mixed-type pain in CP. Preclinical studies show that targeting TGFß1 or IL-6 (ligand for GP130) is sufficient to inhibit CP pain supporting further investigation of this as a potential therapeutic target.

An intelligent fluorescence sensing platform based on entropy-driven toehold-mediated strand displacement cycle reaction for point-of-care testing of miRNA.

BACKGROUND: MicroRNA (miRNA) has gradually become an emerging biomarker for early diagnosis and prognosis of various diseases due to its specific gene expression and high stability. With the development of molecular diagnosis and point-of-care testing (POCT) technology, developing simple, fast, sensitive, efficient, and low-cost miRNA sensors is of great significance for clinical applications and emergency rapid diagnosis. At present, entropy-driven toehold mediated chain displacement reaction, as a promising enzyme free isothermal amplification technique, is an important tool for ultra-sensitive biosensing applications. RESULTS: In this study, we used gold nanoparticles (AuNPs) as carriers and quenchers, modified them using self-assembled triple chain composite substrates AuNPs@A@B1/B2, and used dual reporter molecules for cascade cyclic amplification to amplify fluorescence signals, which proposed a fluorescent biosensor based on this reaction and build an intelligent fluorescence sensing platform for rapid detection of miRNA. We designed a highly specific self-programmable sensor using the acute ischemic stroke (AIS) biomarker miRNA-125a-5p as a sample, and achieved sensitive detection of miRNA in the range of 0.01 µM∼10 µ M under optimal conditions. It broke through the traditional detection limitations of weak signals and liberated the fluorescence detection environment. SIGNIFICANCE: In summary, this creative miRNA biosensor combined with POCT has demonstrated extraordinary detection potential, broad application prospects in the early diagnosis and prognosis monitoring of AIS, provides a novel miRNA universal detection strategy for the fields of biological and life sciences.

Anemia, blood cell indices, genetic correlations, and brain structures: A comprehensive analysis of roles in Parkinson's disease risk.

INTRODUCTION: Anemia may contribute significantly to the onset of Parkinson's disease (PD). Current research on the association between anemia and PD risk is inconclusive, and the relationships between anemia-related blood cell indices and PD incidence require further clarification. This study aims to investigate the relationships between anemia, blood cell indicators, and PD risk using a thorough prospective cohort study. METHODS: We used data from the UK Biobank, a prospective cohort study of 502,649 participants, and ultimately, 365,982 participants were included in the analysis. Cox proportional hazards models were utilized to adjust for confounding factors, aiming to thoroughly explore the associations between anemia and blood cell indices with the risk of incident PD. The interaction between anemia and Polygenic Risk Score (PRS) for PD was also examined. Linear regression and mediation analyses assessed potential mechanisms driven by brain structures, including grey matter volume. RESULTS: During a median follow-up of 14.24 years, 2513 participants were diagnosed with PD. Anemia considerably increased PD risk (hazard ratio [HR] 1.98, 95 % confidence interval [CI]: 1.81-2.18, P < 0.001) after adjustments. Those with high PRS for anemia had an 83 % higher PD incidence compared to low PRS participants. Sensitivity analyses confirmed result robustness. Linear regression showed that anemia correlated with grey matter volumes and most white matter tracts. Furthermore, mediation analyses identified that the volume of grey matter in Thalamus mediates the relationship between anemia and PD risk. CONCLUSION: In summary, we consider there to be a substantial correlation between anemia and increased PD risk.

A Whole-Genome Scan Revealed Genomic Features and Selection Footprints of Mengshan Cattle.

(1) Background: Mengshan cattle from the Yimeng mountainous region in China stand out as a unique genetic resource, known for their adaptive traits and environmental resilience. However, these cattle are currently endangered and comprehensive genomic characterization remains largely unexplored. This study aims to address this gap by investigating the genomic features and selection signals in Mengshan cattle. (2) Methods: Utilizing whole-genome resequencing data from 122 cattle, including 37 newly sequenced Mengshan cattle, we investigated population structure, genetic diversity, and selection signals. (3) Results: Our analyses revealed that current Mengshan cattle primarily exhibit European taurine cattle ancestry, with distinct genetic characteristics indicative of adaptive traits. We identified candidate genes associated with immune response, growth traits, meat quality, and neurodevelopment, shedding light on the genomic features underlying the unique attributes of Mengshan cattle. Enrichment analysis highlighted pathways related to insulin secretion, calcium signaling, and dopamine synapse, further elucidating the genetic basis of their phenotypic traits. (4) Conclusions: Our results provide valuable insights for further research and conservation efforts aimed at preserving this endangered genetic resource. This study enhances the understanding of population genetics and underscores the importance of genomic research in informing genetic resources and conservation initiatives for indigenous cattle breeds.

Bovine serum albumin-bound homologous targeted nanoparticles for breast cancer combinatorial therapy.

Breast cancer, the most common lethal cancer among women, is characterized by the uncontrolled growth of abnormal cells in breast tissue. Therefore, synergistic anticancer strategies are essential, particularly for maximizing drug delivery to tumor sites. Herein, bovine serum albumin (BSA)-bound nanoparticles encapsulating the photosensitizer chlorin e6 (Ce6) (BC) with a CuO2 core (BC/CuO2 NPs) were developed for cuproptosis-promoted cancer photodynamic therapy (PDT). The cancer cell membrane (CC) was then coated onto the surfaces to produce BC/CuO2@CC NPs for breast cancer combinatorial therapy. BSA serves dual functions as both a stabilizing scaffold for metal peroxide nanomaterials and a molecular connector for Ce6. The BC/CuO2@CC NPs group showed the stronger internalization capability than the other groups. BC/CuO2@CC NPs could effectively induce the greatest degree of apoptosis and death ratio (81.77 %), and lead to cuproptosis by downregulating the expression of DLAT, LIAS, and FDX1 protein in vitro. The intra-tumoral accumulation of BC/CuO2@CC NPs was 8.3- and 7.7-fold higher than that of Ce6 and BC/CuO2@CC NPs at 24 h postinjection, respectively. Moreover, synergistic efficacy of cuproptosis and PDT not only inhibited tumor growth but also prevented liver metastases. Thus, our work may be a novel approach for efficient and targeted cancer treatment.

A New Orthonairovirus Associated with Human Febrile Illness.

BACKGROUND: In June 2019, a patient presented with persistent fever and multiple organ dysfunction after a tick bite at a wetland park in Inner Mongolia. Next-generation sequencing in this patient revealed an infection with a previously unknown orthonairovirus, which we designated Wetland virus (WELV). METHODS: We conducted active hospital-based surveillance to determine the prevalence of WELV infection among febrile patients with a history of tick bites. Epidemiologic investigation was performed. The virus was isolated, and its infectivity and pathogenicity were investigated in animal models. RESULTS: WELV is a member of the orthonairovirus genus in the Nairoviridae family and is most closely related to the tickborne Hazara orthonairovirus genogroup. Acute WELV infection was identified in 17 patients from Inner Mongolia, Heilongjiang, Jilin, and Liaoning, China, by means of reverse-transcriptase-polymerase-chain-reaction assay. These patients presented with nonspecific symptoms, including fever, dizziness, headache, malaise, myalgia, arthritis, and back pain and less frequently with petechiae and localized lymphadenopathy. One patient had neurologic symptoms. Common laboratory findings were leukopenia, thrombocytopenia, and elevated d-dimer and lactate dehydrogenase levels. Serologic assessment of convalescent-stage samples obtained from 8 patients showed WELV-specific antibody titers that were 4 times as high as those in acute-phase samples. WELV RNA was detected in five tick species and in sheep, horses, pigs, and Transbaikal zokors (Myospalax psilurus) sampled in northeastern China. The virus that was isolated from the index patient and ticks showed cytopathic effects in human umbilical-vein endothelial cells. Intraperitoneal injection of the virus resulted in lethal infections in BALB/c, C57BL/6, and Kunming mice. The Haemaphysalis concinna tick is a possible vector that can transovarially transmit WELV. CONCLUSIONS: A newly discovered orthonairovirus was identified and shown to be associated with human febrile illnesses in northeastern China. (Funded by the National Natural Science Foundation of China and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences.).

Hyaluronan and Glucose Dual-targeting Probe: Synthesis and Application.

In this work, we developed a dual-targeting probe consisted of well-defined hyaluronan (HA) oligosaccharide and glucose (Glc) labeled with Rhodamine B (HGR). The probe was designed to enhance tumor targeting both in vitro and in vivo, by simultaneously targeting CD44 and Glc transporter 1 (GLUT1). The HA oligosaccharide component was crucial for accurately assessing the impact of sugar chain structure on targeting efficacy, while its unoccupied carboxyl groups could minimize interference with HA's binding affinity to CD44. In vitro studies demonstrated that HGR possessed remarkable cytocompatibility and superior targeting abilities compared to single-targeting probes. It displayed a marked preference for CD44high/GLUT1high cells rather than CD44low/GLUT1low cells. In vivo studies using murine models further confirmed the significantly enhanced targeting efficacy and excellent biocompatibility of HGR. Therefore, this designed dual-targeting probe holds potential for clinical tumor detection.

Fluoride Exposure from Drinking Water Increases the Risk of Stroke: An Ecological Study in Changwu Town, China.

BACKGROUND: Stroke is a major cause of death globally and the leading cause in China. Excessive fluoride exposure has been linked to cardiovascular conditions related to stroke risk factors such as hypertension, atherosclerosis, dyslipidemia, and cardiomyopathy. However, evidence supporting the association between fluoride exposure and stroke risk is limited. METHODS: We constructed an ecological study in Changwu Town, Heilongjiang Province, China, a typical endemic fluorosis area caused by excessive fluoride exposure from drinking water. We collected demographic data, stroke prevalence, and mortality information from 2017 to 2021. Fluoride exposure data were obtained from the national monitoring project on endemic fluorosis. Water fluoride concentrations were measured using the standardized methods. Trend changes in stroke rates were assessed using annual percentage change (APC). Differences in stroke rates among fluoride exposure groups were analyzed using chi-square tests. RESULTS: From 2017 to 2021, the all-ages and age-standardized stroke prevalence rates of permanent residents in Changwu Town increased year by year, while the all-ages and age-standardized mortality rates did not change significantly. The prevalence rates of stroke were significantly higher in endemic fluorosis areas compared to non-endemic areas (p < 0.001). Stratifying the population into tertile groups based on the water fluoride cumulative exposure index (WFCEI) revealed statistically significant differences in stroke prevalence rates (p < 0.001), showing a dose-response relationship with the WFCEI. However, the all-ages and age-standardized mortality rates of stroke were not found to be related to fluoride exposure. CONCLUSIONS: Long-term excessive fluoride exposure from drinking water may increase the risk of stroke prevalence, indicating fluoride overexposure as a potential risk factor for stroke.

Characteristics and phylogenetic analysis of the complete chloroplast genome of Mesembryanthemum cordifolium L. F. (Aizoaceae).

Mesembryanthemum cordifolium, a perennial plant with crassulacean acid metabolism (CAM) in the Aizoaceae family, has significant ornamental and medicinal values. In this study, we reported the first complete chloroplast genome sequence of this species. The total genome size was 153,734 bp in length, including a large single-copy (LSC) region of 85,692 bp, a small single-copy (SSC) region of 18,212 bp, and a pair of inverted repeat (IR) regions of 24,915 bp by each. The overall GC content of the M. cordifolium chloroplast genome was 37.08%. The genome encodes 131 genes, comprising 87 protein-coding genes (PCGs), 36 transfer RNA genes (tRNAs), and eight ribosomal RNA genes (rRNAs). Phylogenetic analysis shows this species was relatively close to M. crystallinum. This chloroplast genome sequence will be valuable for species discrimination and for understanding phylogenetic relationships within the genus Mesembryanthemum.

The use of DTI in the differentiation and surgical planning of suprasellar hypothalamic-opticochiasmatic glioma and craniopharyngioma in children.

BACKGROUND AND OBJECTIVES: Suprasellar hypothalamic-opticochiasmatic glioma (HOCG) and craniopharyngioma (CP) have similar appearances on conventional MRI and are difficult to distinguish. Moreover, these tumors are situated near vital structures like the optic chiasm and hypothalamus, rendering conventional surgery susceptible to significant complications. We mainly discussed the surgical application value and diagnostic value of diffusion tensor imaging (DTI) in HOCG and CP. METHODS: The retrospective analysis of 13 cases of HOCG and 16 cases of CP was conducted. All patients underwent conventional MRI and DTI prior to surgery, and were pathologically diagnosed postoperatively. RESULTS: Both CP and HOCG appeared as heterogeneous mixed signal masses on conventional MRI. For HOCGs, fiber tractography revealed two different growth patterns of the tumor: infiltrative type and inflated type. The surgical approach and risk levels differ between these growth patterns. Additionally, fiber tractography demonstrates significant differences compared to CPs. The surgical approach and extent of resection for all cases of these two tumors were guided by DTI. CONCLUSION: DTI enhances the accuracy of HOCG and CP differentiation. Furthermore, patterns of tractography described in this study assist neurosurgeons in delineating the surgical pathway and tumor resection range without damaging important fiber bundles, thereby avoiding permanent neurological deficits and improving survival quality for patients.

Weakly Solvating Ether-Based Electrolyte Constructing Anion-Derived Solid Electrolyte Interface in Graphite Anode toward High-Stable Potassium-Ion Batteries.

Low-cost graphite has emerged as the most promising anode material for potassium-ion batteries (PIBs). Constructing the inorganic-rich solid electrolyte interface (SEI) on the surface of graphite anode is crucial for achieving superior electrochemical performance of PIBs. However, the compositions of SEI formed by conventional strongly solvating electrolytes are mainly organic, leading to the SEI structure being thick and causing the co-intercalation behavior of ions with the solvent. Herein, a weakly solvating electrolyte is applied to weaken the cation-solvent interaction and alter the cation solvation sheath structures, conducing to the inorganic composition derived from anions also participating in the formation of SEI, together with forming a uniformly shaped SEI with superior mechanical properties, and thus improving the overall performance of PIBs. The electrolyte solvation structure rich in aggregated ion pairs (AGGs) (69%) enables remarkable potassium-ion intercalation behavior at the graphite anode (reversible capacity of 269 mAh g-1) and highly stable plating/stripping of potassium metal anode (96.5%). As a practical device application, the assembled potassium-ion full-battery (PTCDA//Graphite) displays superior cycle stability. The optimizing strategy of cation solvation sheath structures offers a promising approach for developing high-performance electrolytes and beyond.

Unpredicted protective function of Fc-mediated inhibitory antibodies for HIV and SARS-CoV-2 vaccines.

Developing effective vaccines is necessary in combating new virus pandemics. For HIV and SARS-CoV-2, the induction of neutralizing antibodies (NAb) is important for vaccine protection; however, the exact mechanisms underlying protection require further study. Recent data emphasize that even Abs that do not exhibit neutralizing activity may contribute to immune defense. Abs exhibiting this function may counter virus mutations, which are acquired to escape from NAbs, and therefore, broaden the protective Ab response induced by vaccination. However, the steps leading to Ab Fc-mediated inhibition are complex. How can these functions be measured in vitro? What inhibitory assay is the most physiologically relevant at mimicking effective in vivo protection? This review provides a comprehensive update on the current knowledge gaps on the Ab Fc-mediated functions involved in HIV and SARS-CoV-2 protection. Understanding the inhibitory effects of these Abs is vital for designing the next generation of protective HIV and SARS-CoV-2 vaccines.

A preliminary study of renal function for renal artery stenosis using multiparametric magnetic resonance imaging.

OBJECTIVE: To comprehensively evaluate the renal structure and function of patients with renal artery stenosis (RAS) using multiparametric magnetic resonance imaging (MRI), and analyze the correlation between magnetic resonance (MR) parameters and renal function. MATERIALS AND METHODS: Renal multiparametric MRI was conducted on 62 patients with RAS utilizing a Philips Ingenia CX 3.0 T MRI system. The scanning protocols encompassed arterial spin labeling, phase contrast MRI, diffusion weighted imaging, T1 mapping, and blood oxygen level-dependent MRI. All patients underwent radionuclide renal dynamic imaging to calculate the glomerular filtration rate (GFR) for assessing renal function. RESULTS: Most MR parameters were correlated with GFR: renal parenchymal volume (R = 0.603), whole kidney renal blood flow (RBF) (R = 0.192), renal cortical RBF (R = 0.294), renal artery mean velocity (R = 0.593), stroke volume (R = 0.599), mean flux (R = 0.629), renal cortical apparent diffusion coefficient (ADC) (R = 0.466), medullary ADC (R = 0.332), cortical T1 value (R = - 0.206), corticomedullary T1 difference (R = 0.204), cortical T2* value (R = 0.448), and medullary T2* value (R = 0.272). The best prediction model for GFR using multiparametric MRI was obtained, including renal PV, whole kidney RBF, cortical RBF, mean velocity, mean flux, and CMD T1. CONCLUSION: Multiparametric MRI is a novel noninvasive examination method that can effectively and comprehensively assess the renal structure and function of RAS.

The impact of high-altitude migration on cardiac structure and function: a 1-year prospective study.

Introduction: The trend of human migration to terrestrial high altitudes (HA) has been increasing over the years. However, no published prospective studies exist with follow-up periods exceeding 1 month to investigate the cardiac change. This prospective study aimed to investigate the changes in cardiac structure and function in healthy young male lowlanders following long-term migration to HA. Methods: A total of 122 Chinese healthy young males were divided into 2 groups: those migrating to altitudes between 3600 m and 4000 m (low HA group, n = 65) and those migrating to altitudes between 4000 m and 4700 m (high HA group, n = 57). Traditional echocardiographic parameters were measured at sea level, 1 month and 1 year after migration to HA. Results: All 4 cardiac chamber dimensions, areas, and volumes decreased after both 1 month and 1 year of HA exposure. This reduction was more pronounced in the high HA group than in the low HA group. Bi-ventricular diastolic function decreased after 1 month of HA exposure, while systolic function decreased after 1 year. Notably, these functional changes were not significantly influenced by altitude differences. Dilation of the pulmonary artery and a progressive increase in pulmonary artery systolic pressure were observed with both increasing exposure time and altitude. Additionally, a decreased diameter of the inferior vena cava and reduced bicuspid and tricuspid blood flow velocity indicated reduced blood flow following migration to the HA. Discussion: 1 year of migration to HA is associated with decreased blood volume and enhanced hypoxic pulmonary vasoconstriction. These factors contribute to reduced cardiac chamber size and slight declines in bi-ventricular function.

Comparative analysis of cortical anatomy in male participants with internet gaming disorder or tobacco use disorder: Insights from normative modeling.

Background: Research on individual differences in brain structural features of internet gaming disorder (IGD) and established addictions such as tobacco use disorder (TUD) is currently limited. This study utilized normative modeling to analyze the cortical thickness (CT) development patterns of male patients with IGD and TUD, aiming to provide further insights into whether IGD qualifies as an addiction. Methods: Surface-based brain morphometry (SBM) was used to calculate CT from T1-weighted magnetic resonance imaging data of 804 male participants (665 healthy individuals, 68 IGD and 71 TUD). Gaussian process regression was employed to generate normative models of CT development. Deviation maps were produced to depict deviations of IGD and TUD participants from the typical developmental patterns. Results: Both addiction groups exhibited widespread cortical thinning, particularly in regions such as the bilateral temporal pole and medial orbitofrontal cortex. The TUD group demonstrated a higher degree of individualization and limited spatial overlap compared to the IGD group. Opposite trends in CT changes were observed between the two groups in the bilateral pericalcarine cortex and pars triangularis. Conclusions: These findings regarding the similarities and differences between IGD and TUD provide support for the idea that IGD shares common features with substance-related addictions and contribute to a deeper understanding of the neural mechanisms underlying IGD.

Inhibiting circ_0000673 blocks the progression of colorectal cancer through downregulating CPSF6 via targeting miR-548b-3p.

BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers, and its progression is regulated by several factors, including circular RNA (circRNA). OBJECTIVES: The objective of this study was to determine the role, or roles, of circ_0000673 in CRC. MATERIAL AND METHODS: We used quantitative real-time polymerase chain reaction (qPCR) to detect the expression of circ_0000673, miR-548b-3p and cleavage and polyadenylation specific factor 6 (CPSF6) in DLD-1 and RKO cells. Cell Counting Kit-8 (CCK-8) and 5-ethynyl-2'-deoxyuridine (EdU) assays were used to determine circ_0000673 roles in proliferation. Wound healing and transwell assays were used to detect cell migration and invasion abilities. Expression of CPSF6 protein and stem cell-associated proteins were examined using western blot. The putative relationship between miR-548b-3p and circ_0000673 or CPSF6 was verified with dual-luciferase reporter assay. The role of circ_0000673 in CRC was also investigated in a tumor xenograft assay in nude mice. RESULTS: Circ_0000673 expression was increased in CRC tissues and cancer cells. Silencing circ_0000673 reduced tumor cell proliferation, migration and invasion, while also decreasing cell stemness. MiR-548b-3p was found to be a target of circ_0000673, while CPSF6 was a downstream target of miR-548b-3p. The tumor-regulatory effects of si-circ_0000673, anti-miR-548b-3p and oe-CPSF6 were partially reversed by anti-miR-548b-3p, si-CPSF6 and si-circ_0000673, respectively, in rescue assays. Downregulation of circ_0000673 reduced solid tumor growth in vivo. CONCLUSIONS: Circ_0000673 inhibition reduced CPSF6 expression by targeting miR-548b-3p, thereby blocking proliferation, migration and invasion of CRC tumor cells.

Chemerin 15 peptide reduces neuroinflammation via the ChemR23 receptor after ischemia-reperfusion injury.

Microglia-mediated neuroinflammation plays a crucial role in ischemic stroke; consequently, understanding its regulation could facilitate the development of therapies for ischemic stroke. Chemerin 15, a 15-amino acid peptide derived from chemerin, exerts powerful anti-inflammatory effects through ChemR23, modulates macrophage polarization, and diminishes inflammatory cytokine expression in peripheral inflammation models. However, its effects on microglia and stroke remain unclear. In this study, we used an in vitro oxygen/ glucose deprivation BV2 cell model and a mouse model of ischemia-reperfusion injury to investigate the role of chemerin 15 in stroke and the underlying mechanisms. We co-cultured BV2 microglial cells with HT-22 hippocampal neurons and observed that chemerin 15 reduced apoptosis in HT-22 cells. Furthermore, we found that chemerin 15 binds to the ChemR23 receptor on the cell surface, inducing its internalization. This process regulated the activity of adenosine 5'-monophosphate-activated protein kinase and inhibited its downstream target nuclear factor kappa B. These effects could be reversed by treatment with α-NETA, a ChemR23 inhibitor. In mice with ischemia-reperfusion injury, chemerin 15 modulated microglial polarization, reduced infarct volume and neuronal apoptosis, and facilitated cognitive and neurological function recovery. Our findings suggest that chemerin 15 suppresses the microglia-mediated inflammatory response, decreases neuronal apoptosis, and enhances long-term neurological function recovery by inducing ChemR23 internalization and regulating the adenosine 5'-monophosphate-activated protein kinase/nuclear factor kappa B signaling pathway.

Molecular mechanism of a coastal cyanobacterium Synechococcus sp. PCC 7002 adapting to changing phosphate concentrations.

Phosphorus concentration on the surface of seawater varies greatly with different environments, especially in coastal. The molecular mechanism by which cyanobacteria adapt to fluctuating phosphorus bioavailability is still unclear. In this study, transcriptomes and gene knockouts were used to investigate the adaptive molecular mechanism of a model coastal cyanobacterium Synechococcus sp. PCC 7002 during periods of phosphorus starvation and phosphorus recovery (adding sufficient phosphorus after phosphorus starvation). The findings indicated that phosphorus deficiency affected the photosynthesis, ribosome synthesis, and bacterial motility pathways, which recommenced after phosphorus was resupplied. Even more, most of the metabolic pathways of cyanobacteria were enhanced after phosphorus recovery compared to the control which was kept in continuous phosphorus replete conditions. Based on transcriptome, 54 genes potentially related to phosphorus-deficiency adaptation were selected and knocked out individually or in combination. It was found that five mutants showed weak growth phenotype under phosphorus deficiency, indicating the importance of the genes (A0076, A0549-50, A1094, A1320, A1895) in the adaptation of phosphorus deficiency. Three mutants were found to grow better than the wild type under phosphorus deficiency, suggesting that the products of these genes (A0079, A0340, A2284-86) might influence the adaptation to phosphorus deficiency. Bioinformatics analysis revealed that cyanobacteria exposed to highly fluctuating phosphorus concentrations have more sophisticated phosphorus acquisition strategies. These results elucidated that Synechococcus sp. PCC 7002 have variable phosphorus response mechanisms to adapt to fluctuating phosphorus concentration, providing a novel perspective of how cyanobacteria may respond to the complex and dynamic environments. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-024-00244-y.

Dual-target inhibitors based on acetylcholinesterase: Novel agents for Alzheimer's disease.

Alzheimer's disease (AD) is the most common form of dementia among the elderly, accounting for 60 %-70 % of cases. At present, the pathogenesis of this condition remains unclear, but the hydrolysis of acetylcholine (ACh) is thought to play a role. Acetylcholinesterase (AChE) can break down ACh transmission from the presynaptic membrane and stop neurotransmitters' excitatory effect on the postsynaptic membrane, which plays a key role in nerve conduction. Acetylcholinesterase inhibitors (AChEIs) can delay the hydrolysis of acetylcholine (ACh), which represents a key strategy for treating AD. Due to its complex etiology, AD has proven challenging to treat. Various inhibitors and antagonists targeting key enzymes and proteins implicated in the disease's pathogenesis have been explored as potential therapeutic agents. These include Glycogen Synthase Kinase 3ß (GSK-3ß) inhibitors, ß-site APP Cleaving Enzyme (BACE-1) inhibitors, Monoamine Oxidase (MAO) inhibitors, Phosphodiesterase inhibitors (PDEs), N-methyl--aspartic Acid (NMDA) antagonists, Histamine 3 receptor antagonists (H3R), Serotonin receptor subtype 4 (5-HT4R) antagonists, Sigma1 receptor antagonists (S1R) and soluble Epoxide Hydrolase (sEH) inhibitors. The drug development strategy of multi-target-directed ligands (MTDLs) offers unique advantages in the treatment of complex diseases. On the one hand, it can synergistically enhance the therapeutic efficacy of single-target drugs. On the other hand, it can also reduce the side effects. In this review, we discuss the design strategy of dual inhibitors based on acetylcholinesterase and the structure-activity relationship of these drugs.