Design, synthesis and modelling of photoreactive chemical probes for investigating target engagement of plasmepsin IX and X in Plasmodium falciparum.

The emergence of Plasmodium parasite resistance to current front-line antimalarial treatments poses a serious threat to global malaria control and highlights the necessity for the development of therapeutics with novel targets and mechanisms of action. Plasmepsins IX and X (PMIX/PMX) have been recognised as highly promising targets in Plasmodium due to their contribution to parasite's pathogenicity. Recent research has demonstrated that dual PMIX/PMX inhibition results in the impairment of multiple parasite's life cycle stages, which is an important feature in drug resistance prevention. Herein we report novel hydroxyethylamine photoaffinity labelling (PAL) probes, designed for PMIX/PMX target engagement and proteomics experiments in Plasmodium parasites. The prepared probes have both a photoreactive group (diazirine or benzophenone) for covalent attachment to target proteins, and a terminal alkyne handle allowing their use in bioorthogonal ligation. One of the synthesised benzophenone probes was shown to be highly promising as demonstrated by its outstanding antimalarial potency (IC50 = 15 nM versus D10 P. falciparum) and its inhibitory effect against PfPMX in an enzymatic assay. Molecular docking and molecular dynamics studies show that the inclusion of the benzophenone and alkyne handle does not alter the binding mode compared to the parent compound. The photoaffinity probe can be used in future chemical proteomics studies to allow hydroxyethylamine drug scaffold target identification and validation in Plasmodium. We expect our findings to act as a tool for future investigations on PMIX/PMX inhibition in antimalarial drug discovery.

Study of the optic nerve in patients with type 2 diabetic retinopathy by shear-wave elastography.

AIM: To investigate the clinical value of two-dimensional shear-wave elastography (2D-SWE) in detecting optic nerve elasticity and in-frame adipose tissue elasticity in patients with type 2 diabetic retinopathy (DR). MATERIALS AND METHODS: 2D-SWE was used to detect SWE values of the optic nerve and adipose tissue in adjacent optic nerve frames in 30 healthy participants, 30 patients with diabetic non-retinopathy (NDR), 35 patients with non-proliferative diabetic retinopathy (NPDR), and 30 patients with proliferative diabetic retinopathy (PDR). The correlation between SWE values and blood glucose, blood lipid, age, body mass index (BMI) was analysed. Receiver operating characteristic (ROC) curve analysis was performed for SWE values. RESULTS: The SWE values of the optic nerve and in-frame adipose tissue increased with the progression of DR, and analysis of variance was compared with groups: the SWE values of the optic nerve and in-frame adipose tissue in each group were significantly different (all p<0.001). The SWE values of the optic nerve and in-frame adipose tissue correlated positively with BMI, age, triglyceride, and fasting blood glucose, and correlated negatively with high-density lipoprotein. The SWE values of the optic nerve and in-frame adipose tissue had higher diagnostic efficacy. The combination of the two had higher diagnostic accuracy. CONCLUSION: The elastic modulus of optic nerve and in-frame adipose tissue can effectively predict and grade of DR, that is, 2D-SWE can be used as a non-invasive imaging diagnostic method for DR. The combined diagnostic efficacy of optic nerve SWE value and in-frame adipose tissue SWE value is significantly better than that of single use. This study found that increased BMI, age, triglyceride, and fasting blood glucose, and decreased high-density lipoprotein are risk factors for DR.

Cost-effectiveness of a real-time spatiotemporal mapping surveillance system for meticillin-resistant Staphylococcus aureus prevention.

OBJECTIVES: An infection surveillance system based on a hospital's digital twin [4D-Disease Outbreak Surveillance System (4D-DOSS)] is being developed in Singapore. It offers near-real-time infection surveillance and mapping capabilities. This early economic modelling study was conducted, using meticillin-resistant Staphylococcus aureus (MRSA) as the pathogen of interest, to assess the potential cost-effectiveness of 4D-DOSS. METHODS: A Markov model that simulates the likelihood of MRSA colonization and infection was developed to evaluate the cost-effectiveness of adopting 4D-DOSS for MRSA surveillance from the hospital perspective, compared with current practice. The cycle duration was 1 day, and the model horizon was 30 days. Probabilistic sensitivity analysis was conducted, and the probability of cost-effectiveness was reported. Scenario analyses and a value of information analysis were performed. RESULTS: In the base-case scenario, with 10-year implementation/maintenance costs of 4D-DOSS of $0, there was 68.6% chance that 4D-DOSS would be cost-effective. In a more pessimistic but plausible scenario where the effectiveness of 4D-DOSS in reducing MRSA transmission was one-quarter of the base-case scenario with 10-year implementation/maintenance costs of $1 million, there was 47.7% chance that adoption of 4D-DOSS would be cost-effective. The value of information analysis showed that uncertainty in MRSA costs made the greatest contribution to model uncertainty. CONCLUSIONS: This early-stage modelling study revealed the circumstances for which 4D-DOSS is likely to be cost-effective at the current willingness-to-pay threshold, and identified the parameters for which further research will be worthwhile to reduce model uncertainty. Inclusion of other drug-resistant organisms will provide a more thorough assessment of the cost-effectiveness of 4D-DOSS.

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

[Prevalence of comorbid depression and anxiety and effect of psychological interventions among schistosomiasis patients in China: a meta-analysis].

OBJECTIVE: To investigate the prevalence of comorbid depression and anxiety and to evaluate the effect of psychological interventions among schistosomiasis patients in China, so as to provide insights into improvements of psychological health among schistosomiasis patients. METHODS: Publications pertaining to comorbid depression and anxiety and psychological interventions among Chinese schistosomiasis patients were retrieved in electronic databases, including CNKI, Wanfang Data, PubMed, Web of Science, and Embase. The prevalence of comorbidity, psychological interventions, and scores for the Self-Rating Depression Scale (SDS) and Self-Rating Anxiety Scale (SAS) before and after psychological interventions among Chinese schistosomiasis patients were extracted. The prevalence of comorbid depression and anxiety was investigated among Chinese schistosomiasis patients using a meta-analysis, and the effect of psychological interventions for depression and anxiety was evaluated. RESULTS: A total of 231 publications were retrieved, and 14 publications that met the inclusion and exclusion criteria were included in the final analysis, including 2 English publications and 12 Chinese publications. Meta-analysis showed that the prevalence rates of comorbid depression and anxiety were 61% [95% confidential interval (CI): (48%, 72%)] and 64% [95% CI: (42%, 81%)] among Chinese schistosomiasis patients. Both the SDS [1.45 points, 95% CI: (1.30, 1.60) points] and SAS scores [2.21 points, 95% CI: (2.05, 2.38) points] reduced among Chinese schistosomiasis patients after psychological interventions than before psychological interventions, and the SDS [-0.47 points, 95% CI: (-6.90, -0.25) points] and SAS scores [-1.30 points, 95% CI: (-1.52, -1.09) points] reduced among Chinese schistosomiasis patients in the case group than in the control group. CONCLUSIONS: The comorbid anxiety and depression are common among Chinese schistosomiasis patients, and conventional psychological interventions facilitate the improvements of anxiety and depression among schistosomiasis patients.

An exploration of testicular cancer survivors' experience of ejaculatory dysfunction following retroperitoneal lymph node dissection-a sub-study of the PREPARE clinical trial.

PURPOSE: Ejaculatory dysfunction secondary to retrograde ejaculation or anejaculation is a complication of retroperitoneal lymph node dissection (RPLND) for survivors of testicular cancer. We explored survivors' experiences of ejaculatory dysfunction following RPLND. METHODS: In a sub-study of a single-arm phase 2 clinical trial (ACTRN12622000537752/12622000542796), participants reporting ejaculatory dysfunction ≥ 6 months following RPLND were invited to complete semi-structured interviews. Purposive sampling was used. Interviews continued until thematic saturation occurred, and codebook thematic analysis of interviews was performed. RESULTS: Of 58 individuals recruited to the trial, 33 (57%) reported ejaculatory dysfunction. Of these, 32 (97%) agreed to interview and 15 participated. Participants interviewed had median age 34 years (range 24-66), 12 (80%) in a long-term relationship with median time from surgery 36 months (range 11-112). Three overarching themes were identified. The first reflected the value of RPLND despite ejaculatory dysfunction. The second illuminated the impact(s) of ejaculatory dysfunction closely mapped to life stage, with flow-on impacts to fertility, sex, psychological wellbeing and communication. The third reflected information needs. Fertility was a substantial source of concern for some participants. Ejaculatory dysfunction had no effect on sex for some, whilst for others, sex was less pleasurable. Some reported benefits. Few reported ejaculatory dysfunction challenged masculinity, confidence, or self-esteem. CONCLUSIONS: Future research should examine interventions to reduce distress related to fertility, challenged masculinity and body image. IMPLICATIONS FOR CANCER SURVIVORS: Whilst most participants considered ejaculatory dysfunction to have little impact on their sexual function and relationships, some reported significant difficulties varying by life stage and relationship status.

Effects of oleanolic acid on acute liver injury triggered by lipopolysaccharide in broiler chickens.

1. Infectious injury caused by lipopolysaccharide (LPS), a metabolite of gram-negative bacteria, can induce stress responses in animals and is a significant cause of morbidity and mortality in young birds. The purpose of this study was to investigate the effects of dietary supplementation with oleanolic acid (OA) on acute liver injury in broiler chickens challenged with LPS.2. In total, 120 broiler chickens were randomly divided into six groups and fed a basal diet containing 0, 50, 100, or 200 mg/kg OA or 100 mg/kg aureomycin. On d 15, broiler chickens were injected with either LPS or an equivalent volume of normal saline. Six hours after LPS injection, two broiler chicks were randomly selected for sampling in each replicate.3. The results indicated that dietary aureomycin was ineffective in alleviating LSP-associated liver injury, but protected broiler chickens from LPS-induced liver damage. This promoted a significant reduction in the levels of malondialdehyde and an increase in the levels of superoxide dismutase in liver. In addition, OA was found to cause significant reductions in the relative expression of IL-1ß, IL-6, and TNF-α in broiler liver tissues, whereas the relative expression of IL-10 was significantly increased.4. In conclusion, oleanolic acid can alleviate oxidative stress and injury in the livers of broiler chickens induced by lipopolysaccharide. Consequently, oleanolic acid has potential utility as a novel anti-inflammatory and antioxidant feed additive.

Order-disorder phase transition and elastic-to-plastic vortex creep crossover in a triclinic iron pnictide superconductor (Ca[Formula: see text]La[Formula: see text])[Formula: see text](Pt[Formula: see text]As[Formula: see text])(Fe[Formula: see text]As[Formula: see text])[Formula: see text].

Vortex matter in layered high-[Formula: see text] superconductors, including iron-pnictides, undergo several thermodynamic phase transitions due to the complex interplay of pinning energy, thermal energy and elastic energy. Moreover, the presence of anisotropy makes their vortex physics even more intriguing. Here, we report a detailed vortex dynamics study, using dc magnetization measurements, in a triclinic iron-pnictide superconductor (Ca[Formula: see text]La[Formula: see text])[Formula: see text](Pt[Formula: see text]As[Formula: see text])(Fe[Formula: see text]As[Formula: see text])[Formula: see text], with a superconducting transition temperature, T[Formula: see text] [Formula: see text] 31 K. A second magnetization peak (SMP) feature is observed for magnetic field perpendicular (H[Formula: see text]c) and parallel (H[Formula: see text]ab) to the crystal plane. However, its fundamental origin is quite different in both directions. For H[Formula: see text]c, the SMP can be well explained using an elastic-to-plastic vortex creep crossover, using collective creep theory. In addition, a possible rhombic-to-square vortex lattice phase transition is also observed for fields in between the onset-field and peak-field related to the SMP. On the other hand, for H[Formula: see text]ab, a clear signature of an order-disorder vortex phase transition is observed in the isothermal M(H) measurements at T [Formula: see text] 6 K. The disordered phase exhibits the characteristics of entangled pinned vortex-liquid. We construct a comprehensive vortex phase diagram by displaying characteristic temperatures and magnetic fields for both crystal geometries in this unique superconducting compound. Our study sheds light on the intricate vortex dynamics and pinning in an iron-pnictide superconductor with triclinic symmetry.

Dirofilariasis mouse models for heartworm preclinical research.

Introduction: Dirofilariasis, including heartworm disease, is a major emergent veterinary parasitic infection and a human zoonosis. Currently, experimental infections of cats and dogs are used in veterinary heartworm preclinical drug research. Methods: As a refined alternative in vivo heartworm preventative drug screen, we assessed lymphopenic mouse strains with ablation of the interleukin-2/7 common gamma chain (γc) as susceptible to the larval development phase of Dirofilaria immitis. Results: Non-obese diabetic (NOD) severe combined immunodeficiency (SCID)γc-/- (NSG and NXG) and recombination-activating gene (RAG)2-/-γc-/- mouse strains yielded viable D. immitis larvae at 2-4 weeks post-infection, including the use of different batches of D. immitis infectious larvae, different D. immitis isolates, and at different laboratories. Mice did not display any clinical signs associated with infection for up to 4 weeks. Developing larvae were found in subcutaneous and muscle fascia tissues, which is the natural site of this stage of heartworm in dogs. Compared with in vitro-propagated larvae at day 14, in vivo-derived larvae had completed the L4 molt, were significantly larger, and contained expanded Wolbachia endobacteria titres. We established an ex vivo L4 paralytic screening system whereby assays with moxidectin or levamisole highlighted discrepancies in relative drug sensitivities in comparison with in vitro-reared L4 D. immitis. We demonstrated effective depletion of Wolbachia by 70%-90% in D. immitis L4 following 2- to 7-day oral in vivo exposures of NSG- or NXG-infected mice with doxycycline or the rapid-acting investigational drug, AWZ1066S. We validated NSG and NXG D. immitis mouse models as a filaricide screen by in vivo treatments with single injections of moxidectin, which mediated a 60%-88% reduction in L4 larvae at 14-28 days. Discussion: Future adoption of these mouse models will benefit end-user laboratories conducting research and development of novel heartworm preventatives via increased access, rapid turnaround, and reduced costs and may simultaneously decrease the need for experimental cat or dog use.

Genetic or Pharmacological Ablation of Acid-Sensing Ion Channel 1a (ASIC1a) Is Not Neuroprotective in a Mouse Model of Spinal Cord Injury.

Acid-sensing ion channel 1a (ASIC1a) is a proton-activated channel that is expressed ubiquitously throughout the central nervous system and in various types of immune cells. Its role in spinal cord injury (SCI) is controversial; inhibition of ASIC1a has been reported to improve SCI pathology in vivo, but conversely, gene ablation increased kainite-mediated excitotoxic cell death in vitro. Here, we re-examined the role of ASIC1a in a mouse model of SCI. First, we observed functional outcomes up to 42 days post-operation (DPO) in SCI mice with a selective genetic ablation of ASIC1a. Mice lacking ASIC1a had significantly worsened locomotor ability and increased lesion size compared with mice possessing the ASIC1a gene. Next, we explored pharmacological antagonism of this ion channel by administering the potent ASIC1a inhibitor, Hi1a. Consistent with a role for ASIC1a to attenuate excitotoxicity, accelerated neuronal cell loss was found at the lesion site in SCI mice treated with Hi1a, but there were no differences in locomotor recovery. Moreover, ASIC1a inhibition did not cause significant alterations to neutrophil migration, microglial density, or blood-spinal cord barrier integrity.

Identification of 2-Aryl-Quinolone Inhibitors of Cytochrome bd and Chemical Validation of Combination Strategies for Respiratory Inhibitors against Mycobacterium tuberculosis.

Mycobacterium tuberculosis cytochrome bd quinol oxidase (cyt bd), the alternative terminal oxidase of the respiratory chain, has been identified as playing a key role during chronic infection and presents a putative target for the development of novel antitubercular agents. Here, we report confirmation of successful heterologous expression of M. tuberculosis cytochrome bd. The heterologous M. tuberculosis cytochrome bd expression system was used to identify a chemical series of inhibitors based on the 2-aryl-quinolone pharmacophore. Cytochrome bd inhibitors displayed modest efficacy in M. tuberculosis growth suppression assays together with a bacteriostatic phenotype in time-kill curve assays. Significantly, however, inhibitor combinations containing our front-runner cyt bd inhibitor CK-2-63 with either cyt bcc-aa3 inhibitors (e.g., Q203) and/or adenosine triphosphate (ATP) synthase inhibitors (e.g., bedaquiline) displayed enhanced efficacy with respect to the reduction of mycobacterium oxygen consumption, growth suppression, and in vitro sterilization kinetics. In vivo combinations of Q203 and CK-2-63 resulted in a modest lowering of lung burden compared to treatment with Q203 alone. The reduced efficacy in the in vivo experiments compared to in vitro experiments was shown to be a result of high plasma protein binding and a low unbound drug exposure at the target site. While further development is required to improve the tractability of cyt bd inhibitors for clinical evaluation, these data support the approach of using small-molecule inhibitors to target multiple components of the branched respiratory chain of M. tuberculosis as a combination strategy to improve therapeutic and pharmacokinetic/pharmacodynamic (PK/PD) indices related to efficacy.

Comparative evaluation of biased agonists Sarcosine1 , d-Alanine8 -Angiotensin (Ang) II (SD Ang II) and Sarcosine1 , Isoleucine8 -Ang II (SI Ang II) and their radioiodinated congeners binding to rat liver membrane AT1 receptors.

Angiotensin II analogue and ß-arrestin biased agonist TRV027 (Sarcosine1 , d-Alanine8 -Angiotensin (Ang) II; SD Ang II), developed by Trevena, Inc. in the early 2010s, brought hopes of a novel treatment for cardiovascular diseases, due to its ability to simultaneously cause signaling through the ß-arrestin signaling pathway, while antagonizing the pathophysiological effects of Ang II mediated by the AT1 receptor G protein signaling cascades. However, a phase II clinical trial of this agent revealed no significant benefit compared to placebo treatment. Using 125 I-Sarcosine1 , Isoleucine8 -Ang II (125 I-SI Ang II) radioligand receptor competition binding assays, we assessed the relative affinity of TRV027 compared to SI Ang II for liver AT1 receptors. We also compared radioiodinated TRV027 (125 I-SD Ang II) binding affinity for liver AT1 receptors with 125 I-SI Ang II. We found that despite its anticipated gain in metabolic stability, TRV027 and 125 I-SD Ang II had reduced affinity for the AT1 receptor compared with SI Ang II and 125 I-SI Ang II. Additionally, male-female comparisons showed that females have a higher AT1 receptor density, potentially attributed to tissue-dependent estrogen and progesterone effects. Peptide drugs have become more popular over the years due to their increased bioavailability, fast onset of action, high specificity, and low toxicity. Even though Trevena®'s biased agonist peptide TRV027 offered greater stability and potency compared to earlier AT1 R biased agonists, it failed its phase II clinical trial in 2016. Further refinements to AT1 R biased agonist peptides to improve affinity, as seen with SI Ang II, with better stability and bioavailability, has the potential to achieve the anticipated biased agonism.

IL-37 alleviates intervertebral disc degeneration via the IL-1R8/NF-κB pathway.

OBJECTIVE: Intervertebral disc degeneration (IDD) has been reported to be a major cause of low back pain (LBP). Interleukin (IL)-37 is an anti-inflammatory cytokine of the interleukin-1 family, which exerts salutary physiological effects. In this study, we assessed the protective effect of IL-37 on IDD progression and its underlying mechanisms. METHODS: Immunofluorescence (IF) was conducted to measure IL-37 expression in nucleus pulposus tissues. CCK-8 assay and Edu staining were used to examine the vitality of IL-37-treated nucleus pulposus cells (NPCs). Western blot, qPCR, ELISA as well as immunohistochemistry were used to assess senescence associated secreted phenotype (SASP) factors expression; and NF-κB pathway was evaluated by western blot and IF; while IL-1R8 knock-down by siRNAs was performed to ascertain its significance in the senescence phenotype modulated by IL-37. The therapeutic effect of IL-37 on IDD were evaluated in puncture-induced rat model using X-ray, Hematoxylin-Eosin, Safranin O-Fast Green (SO), and alcian blue staining. RESULTS: We found IL-37 expression decreased in the IDD process. In vitro, IL-37 suppressed SASP factors level and senescence phenotype in IL-1ß treated NPCs. In vivo, IL-37 alleviated the IDD progression in the puncture-induced rat model. Mechanistic studies demonstrated that IL-37 inhibited IDD progression by downregulating NF-κB pathway activation in NPCs by activating IL-1R8. CONCLUSION: The present study suggests that IL-37 delays the IDD development through the IL-1R8/NF-κB pathway, which suggests IL-37 as a promising novel target for IDD therapy.

Functional mapping of the 14-3-3 hub protein as a guide to design 14-3-3 molecular glues.

Molecular glues represent an evolution in drug discovery, however, targeted stabilization of protein complexes remains challenging, owing to a paucity of drug design rules. The functional mapping of hotspots has been critical to protein-protein interaction (PPI) inhibitor research, however, the orthogonal approach to stabilize PPIs has not exploited this information. Utilizing the hub protein 14-3-3 as a case study we demonstrate that functional mapping of hotspots provides a triage map for 14-3-3 molecular glue development. Truncation and mutation studies allowed deconvoluting the energetic contributions of sidechain and backbone interactions of a 14-3-3-binding non-natural peptide. Three central 14-3-3 hotspots were identified and their thermodynamic characteristics profiled. In addition to the phospho-binding pocket; (i) Asn226, (ii) Lys122 and (iii) the hydrophobic patch formed by Leu218, Ile219 and Leu222 were critical for protein complex formation. Exploiting this hotspot information allowed a peptide-based molecular glue that elicits high cooperativity (α = 36) and selectively stabilizes the 14-3-3/ChREBP PPI to be uniquely developed.

Acyl-CoA thioesterase 9 promotes tumour growth and metastasis through reprogramming of fatty acid metabolism in hepatocellular carcinoma.

Acyl-CoA thioesterase 9 (ACOT9) is a critical regulator of cellular utilization of fatty acids by catalysing the hydrolysis of acyl-CoA thioesters to non-esterified fatty acid and coenzyme A (CoA). Recently, ACOT9 was reported to participate in the pathogenesis of non-alcoholic liver disease (NAFLD), which arises from aberrant lipid metabolism and serves as a risk factor for hepatocellular carcinoma (HCC). However, the functions of ACOT9 in carcinogenesis and aberrant lipid metabolism in HCC remain unexplored. Here, we found that ACOT9 expression is significantly elevated in HCC at least partially due to the down-regulation of miR-449c-3p. Upregulation of ACOT9 is closely associated with poor prognosis for patients with HCC. Knockdown of ACOT9 expression in HCC cells significantly decreased cell proliferation, colony formation, migration and invasion, mainly through suppression of G1-to-S cell cycle transition and epithelial-to-mesenchymal transition (EMT). By contrast, forced ACOT9 expression promoted HCC growth and metastasis. In addition, we found that ACOT9 reprogrammed lipid metabolism in HCC cells by increasing de novo lipogenesis. Furthermore, we demonstrated that increased lipogenesis was involved in ACOT9-promoted HCC growth and metastasis. Altogether, we demonstrate that ACOT9 plays a critical oncogenic role in the promotion of tumour growth and metastasis by reprogramming lipid metabolism in HCC, indicating ACOT9 as a potential therapeutic target in treatment of HCC.

Small Peptide Derivatives Within the Carbohydrate Recognition Domain of SP-A2 Modulate Asthma Outcomes in Mouse Models and Human Cells.

Surfactant Protein-A (SP-A) is an innate immune modulator that regulates a variety of pulmonary host defense functions. We have shown that SP-A is dysfunctional in asthma, which could be partly due to genetic heterogeneity. In mouse models and primary bronchial epithelial cells from asthmatic participants, we evaluated the functional significance of a particular single nucleotide polymorphism of SP-A2, which results in an amino acid substitution at position 223 from glutamine (Q) to lysine (K) within the carbohydrate recognition domain (CRD). We found that SP-A 223Q humanized mice had greater protection from inflammation and mucin production after IL-13 exposure as compared to SP-A-2 223K mice. Likewise, asthmatic participants with two copies the major 223Q allele demonstrated better lung function and asthma control as compared to asthmatic participants with two copies of the minor SP-A 223K allele. In primary bronchial epithelial cells from asthmatic participants, full-length recombinant SP-A 223Q was more effective at reducing IL-13-induced MUC5AC gene expression compared to SP-A 223K. Given this activity, we developed 10 and 20 amino acid peptides of SP-A2 spanning position 223Q. We show that the SP-A 223Q peptides reduce eosinophilic inflammation, mucin production and airways hyperresponsiveness in a house dust mite model of asthma, protect from lung function decline during an IL-13 challenge model in mice, and decrease IL-13-induced MUC5AC gene expression in primary airway epithelial cells from asthmatic participants. These results suggest that position 223 within the CRD of SP-A2 may modulate several outcomes relevant to asthma, and that short peptides of SP-A2 retain anti-inflammatory properties similar to that of the endogenous protein.

Targeting the Ubiquinol-Reduction (Qi) Site of the Mitochondrial Cytochrome bc1 Complex for the Development of Next Generation Quinolone Antimalarials.

Antimalarials targeting the ubiquinol-oxidation (Qo) site of the Plasmodium falciparum bc1 complex, such as atovaquone, have become less effective due to the rapid emergence of resistance linked to point mutations in the Qo site. Recent findings showed a series of 2-aryl quinolones mediate inhibitions of this complex by binding to the ubiquinone-reduction (Qi) site, which offers a potential advantage in circumventing drug resistance. Since it is essential to understand how 2-aryl quinolone lead compounds bind within the Qi site, here we describe the co-crystallization and structure elucidation of the bovine cytochrome bc1 complex with three different antimalarial 4(1H)-quinolone sub-types, including two 2-aryl quinolone derivatives and a 3-aryl quinolone analogue for comparison. Currently, no structural information is available for Plasmodial cytochrome bc1. Our crystallographic studies have enabled comparison of an in-silico homology docking model of P. falciparum with the mammalian's equivalent, enabling an examination of how binding compares for the 2- versus 3-aryl analogues. Based on crystallographic and computational modeling, key differences in human and P. falciparum Qi sites have been mapped that provide new insights that can be exploited for the development of next-generation antimalarials with greater selective inhibitory activity against the parasite bc1 with improved antimalarial properties.

[Research progress on the characteristics of immune tolerant phase and antiviral therapy in children with chronic hepatitis B].

Whether or not children with chronic hepatitis B (CHB) in the immune-tolerant phase need to be treated is one of the hot clinical issues that have not yet been clarified. Thus, in order to make clinical antiviral treatment decisions in children with an immune tolerant phase, a comprehensive understanding of the natural history of HBV infection, as well as its relationship with disease progression and whether prompt treatment can alter the natural history and prognosis, is very important. To that end, this article reviews the research progress of clinical antiviral therapy in the immune-tolerant phase for children with chronic hepatitis B over the last decade, while also discussing the treatment's safety, effectiveness, and related immunological mechanisms, so as to clarify the next key step in research orientation, provide direct evidence-based medical evidence for hepatologists to better diagnose and treat, and ultimately improve the clinical cure rate.

[Association of vitamin D nutritional status with calcaneal bone mineral density in school-age children: a prospective cohort study].

Objective: To investigate the relationships between vitamin D nutritional status and the calcaneal bone mineral density (BMD) in children. Methods: Data were obtained from School-based Cardiovascular and Bone Health Promotion Program. In 2017, a total of 15 391 children aged 6-16 years in Beijing selected through stratified cluster sampling were included in the baseline survey. A follow-up investigation was conducted in 2019. The questionnaire survey, detection of serum 25-hydroxyvitamin D [25(OH)D] level and ultrasound measurement of calcaneal BMD were conducted. Multivariable linear and logistic regression models were used to analyze the relationships between baseline vitamin D nutritional status and the follow-up calcaneal BMD. Results: A total of 10 914 children aged (11.5±3.3) years (boys accounting for 49.6%) were included in the analysis. The average 25(OH)D level was (35.4±12.0) nmol/L, and the deficiency rate was 36.1%. After the adjustment for age, gender, body mass index, smoking status, alcohol use status, dairy products intake, vitamin D supplement, calcium supplement, physical activity, pubertal development, and baseline calcaneal BMD Z-score, for per 10 nmol/L increase in 25(OH)D, the follow-up calcaneal BMD Z-score increased by 0.01(P=0.041), and the OR(95%CI) of decreased calcaneal BMD Z-score after 2 years was 0.96 (0.93-1.00)(P=0.030). Compared with vitamin D adequacy, the follow-up calcaneal BMD Z-score of children with vitamin D insufficiency and deficiency decreased by 0.03(P=0.307) and 0.06 (P=0.046), and the risk of decreased calcaneal BMD Z-score after 2 years increased by 15%(P=0.037) and 21%(P=0.006), respectively (P for trend<0.05). Conclusions: Vitamin D nutritional status was closely related to calcaneal BMD, and children with adequate vitamin D nutritional status tended to obtain higher BMD. Children and adolescents are encouraged to maintain sufficient vitamin D levels, strengthen nutrition and exercise to promote bone health.