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Background Diet may influence biological aging and the discrepancy (∆age) between a subject’s biological age (BA) and chronological age (CA). We aimed to investigate the correlation of dietary flavonoids with the ∆age of organs (heart, kidney, liver) and the whole body. Method A total of 3193 United States adults were extracted from the National Health and Nutrition Examination Survey (NHANES) in 2007–2008 and 2017–2018. Dietary flavonoids intake was assessed using 24-h dietary recall method. Multiple linear regression analysis was performed to evaluate the association of dietary flavonoids intake with the ∆age of organs (heart, kidney, liver) and the whole body. BA was computed based on circulating biomarkers, and the resulting ∆age was tested as an outcome in linear regression analysis. Results The ∆age of the whole body, heart, and liver was inversely associated with higher flavonoids intake (the whole body ∆age β = − 0.58, cardiovascular ∆age β = − 0.96, liver ∆age β = − 3.19) after adjustment for variables. However, higher flavonoids intake positively related to renal ∆age (β = 0.40) in participants with chronic kidney disease (CKD). Associations were influenced by population characteristics, such as age, health behavior, or chronic diseases. Anthocyanidins, isoflavones and flavones had the strongest inverse associations between the whole body ∆age and cardiovascular ∆age among all the flavonoids subclasses. Conclusion Flavonoids intake positively contributes to delaying the biological aging process, especially in the heart, and liver organ, which may be beneficial for reducing the long-term risk of cardiovascular or liver disease.

Mycoplasma pneumoniae is an important pathogen causing upper and lower respiratory tract infections in children and other age groups. Macrolides are the recommended treatments of choice for M. pneumoniae infections. However, macrolide resistance in M. pneumoniae is increasing worldwide, which complicates the treatment strategies. The mechanisms of macrolide resistance have been extensively studied focusing on the mutations in 23S rRNA and ribosomal proteins. Since the secondary treatment choice for pediatric patients is very limited, we decided to look for potential new treatment strategies in macrolide drugs and investigate possible new mechanisms of resistance. We performed an in vitro selection of mutants resistant to five macrolides (erythromycin, roxithromycin, azithromycin, josamycin, and midecamycin) by inducing the parent M. pneumoniae strain M129 with increasing concentrations of the drugs. The evolving cultures in every passage were tested for their antimicrobial susceptibilities to eight drugs and mutations known to be associated with macrolide resistance by PCR and sequencing. The final selected mutants were also analyzed by whole-genome sequencing. Results showed that roxithromycin is the drug that most easily induces resistance (at 0.25 mg/L, with two passages, 23 days), while with midecamycin it is most difficult (at 5.12 mg/L, with seven passages, 87 days). Point mutations C2617A/T, A2063G, or A2064C in domain V of 23S rRNA were detected in mutants resistant to the 14- and 15-membered macrolides, while A2067G/C was selected for the 16-membered macrolides. Single amino acid changes (G72R, G72V) in ribosomal protein L4 emerged during the induction by midecamycin. Genome sequencing identified sequence variations in dnaK , rpoC , glpK , MPN449 , and in one of the hsdS ( MPN365 ) genes in the mutants. Mutants induced by the 14- or 15-membered macrolides were resistant to all macrolides, while those induced by the 16-membered macrolides (midecamycin and josamycin) remained susceptible to the 14- and 15-membered macrolides. In summary, these data demonstrated that midecamycin is less potent in inducing resistance than other macrolides, and the induced resistance is restrained to the 16-membered macrolides, suggesting a potential benefit of using midecamycin as a first treatment choice if the strain is susceptible.

Background Group B streptococcus is a leading cause of neonatal invasive diseases. ST12/serotype Ib GBS isolate, the second most prevalent lineage in East Asia, has aroused increasing attention, as a growing body of reports suggests they may be more virulent and fatal than the ST17/serotype III strain. Results Sag37, an ST12/serotype Ib isolate, was recovered from a fatal neonatal case and exhibited features suggestive of hypervirulence. To define this lineage’s prevalence and virulence, we analyzed 432 non-duplicate GBS isolates collected in Shanghai (2016 ~ 2022), and subtyped them by multilocus sequence typing (MLST) and capsular serotyping via a multiplex polymerase chain reaction. MLST revealed 50 sequence types, with ST10 and ST19 being most common. Nine clonal complexes were identified using the eBURST program, dominated by CC12 and CC19. Among seven serotypes identified, Ib was most prevalent, followed by III, V and Ia. Guided by the epidemiological data, additional clinical ST12/serotype Ib isolates, along with representative strains from other STs/serotypes, were selected for virulence assessment. For survival, 8-week-old CD1 mice were challenged subcutaneously with 1 × 10 8 CFU and monitored for 7 days. ST12/serotype Ib isolates caused 100% mortality within 48 h, whereas other GBS subtypes resulted in delayed or no mortality. For the median lethal dose (LD 50 ), mice received intraperitoneal doses from 10 3 to 10 8 CFU; logistic regression estimated LD 50 values ranging from ≤ 10 3 to ≥ 10 8 CFU within ST12/serotype Ib, indicating marked intra-lineage heterogeneity. To further investigate the molecular mechanisms underlying the hypervirulence, whole-genome sequencing was conducted on 33 ST12/serotype Ib GBS strains identified herein. A pyseer-based genome-wide association study was performed using LD 50 as a quantitative trait. Multiple genetic variations potentially related to virulence were identified, providing insights into the molecular basis of hypervirulence of ST12/serotype Ib GBS. Conclusions This study underscored the correlation between ST12/serotype Ib GBS isolates and hypervirulence, and further and revealed multiple candidate loci potentially associated with this phenotype. These findings highlighted the need for ongoing surveillance and functional investigation of emerging GBS lineages. Clinical trial number Not applicable.

Background Carbapenem-resistant Klebsiella pneumoniae (CRKP) has emerged as a critical global health threat, often causing life-threatening infections with limited therapeutic options. Polymyxins are often used as the last-line agent, but its efficacy is limited by heteroresistance-where resistant subpopulations emerge during treatment. To combat this, we evaluated the synergistic activity of colistin combined with nitroxoline against polymyxin heteroresistant (PHR) CRKP subpopulations. Results The prevalence of PHR was 90.9% (10/11 isolates). While colistin or nitroxoline monotherapy failed to eradicate PHR subpopulations, the combination of colistin and nitroxoline achieved complete clearance at reduced concentrations in 3 out of 4 tested isolates. In adaptive laboratory evolution experiments, colistin monotherapy rapidly selected for resistant mutants, with MIC increasing 256-fold by the second passage. In contrast, the combination maintained stable susceptibility over 20 passages, with no detectable MIC increase. N-phenyl-1-naphthylamine and propidium iodide staining, along with scanning electron microscopy, revealed that the combination induced markedly enhanced membrane damage and cellular disruption compared to monotherapies. In a murine peritoneal infection model, combination therapy reduced mortality to 10% versus 30% with colistin monotherapy, although the difference was not statistically significant ( p  = 0.30). Conclusions PHR is highly prevalent in CRKP and undermines colistin monotherapy. Colistin-nitroxoline combination exhibits potent synergy, suppresses resistance emergence, and shows promise for treating refractory CRKP infections.

This paper focuses on the automatic target recognition (ATR) method based on ship-radiated noise and proposes an underwater acoustic target recognition (UATR) method based on ResNet. In the proposed method, a multi-window spectral analysis (MWSA) method is used to solve the difficulty that the traditional time–frequency (T–F) analysis method has in extracting multiple signal characteristics simultaneously. MWSA generates spectrograms with different T–F resolutions through multiple window processing to provide input for the classifier. Because of the insufficient number of ship-radiated noise samples, a conditional deep convolutional generative adversarial network (cDCGAN) model was designed for high-quality data augmentation. Experimental results on real ship-radiated noise show that the proposed UATR method has good classification performance.

Objective Healthcare-associated Gram-negative bacterial meningitis is a substantial clinical issue with poor outcomes, especially for neurosurgical patients. Here, we aimed to study the characteristics and treatment options of patients with healthcare-associated carbapenem-non-susceptible (Carba-NS) Gram-negative bacterial meningitis. Methods This observational cohort study was conducted at a teaching hospital from 2004 to 2019. The clinical characteristics of patients with meningitis with Carba-NS and carbapenem-susceptible (Carba-S) bacilli were compared, and the antimicrobial chemotherapy regimens and outcomes for Carba-NS Gram-negative bacterial meningitis were analyzed. Results A total of 505 patients were included, of whom 83.8% were post-neurosurgical patients. The most common isolates were Acinetobacter spp. and Klebsiella spp., which had meropenem-resistance rates of 50.6% and 42.5%, respectively, and showed a markedly growing carbapenem-resistance trend. Kaplan–Meier curve analysis revealed that Carba-NS Gram-negative bacilli were associated with a significantly higher in-hospital mortality rate (18.8%, 35/186) compared to the Carba-S group (7.4%, 9/122; P  = 0.001). For Carba-NS Enterobacterales meningitis, aminoglycoside-based and trimethoprim-sulfamethoxazole-based regimens yielded significantly higher clinical efficacy rates than non-aminoglycoside-based and non-trimethoprim-sulfamethoxazole-based regimens (69.0% vs. 38.7%, P  = 0.019 and 81.8% vs. 46.9%, P  = 0.036, respectively). For Carba-NS A. baumannii complex meningitis, tetracycline-based (including doxycycline, minocycline, or tigecycline) therapy achieved a significantly higher clinical efficacy rate (62.9%, 22/35) than the non-tetracycline-based therapy group (40.4%, 19/47; P  = 0.044). Conclusions Our findings revealed that Carba-NS Gram-negative bacilli are associated with higher in-hospital mortality in patients with healthcare-associated meningitis. The combination therapies involving particular old antibiotics may improve patients’ outcome. Trial registration This study was registered on the Chinese Clinical Trial Register under ChiCTR2000036572 (08/2020).

Background Neurite dystrophy is a pathologic hallmark of Alzheimer’s disease (AD). However, drug discovery targeting neurite protection in AD remains largely unexplored. Methods Aβ-induced neurite and mitochondrial damage assays were used to evaluate Aβ toxicity and the neuroprotective efficacy of a natural compound salidroside (SAL). The 5×FAD transgenic mouse model of AD was used to study the neuroprotective function of SAL. To verify the direct target of SAL, we used surface plasmon resonance and cellular thermal shift assays to analyze the drug-protein interaction. Results SAL ameliorates Aβ-mediated neurite damage in cell culture. We further reveal that SAL represses mitochondrial damage in neurites by promoting mitophagy and maintaining mitochondrial homeostasis, dependent on an NAD-dependent deacetylase SIRT3. In AD mice, SAL protects neurite morphology, mitigates Aβ pathology, and improves cognitive function, which are all SIRT3-dependent. Notably, SAL directly binds to transcription factor NRF2, inhibits its degradation by blocking its interaction with KEAP1 ubiquitin ligase, and then advances NRF2-mediated SIRT3 transcription. Conclusions Overall, we demonstrate that SAL, a potential anti-aging drug candidate, attenuates AD pathology by targeting NRF2/SIRT3 pathway for mitochondrial and neurite protection. Drug discovery strategies focusing on SAL may thus provide promising therapeutics for AD.

Antimicrobial resistance (AMR) is a critical global health challenge, demanding rapid and accurate diagnostics to guide timely antimicrobial therapy. Current diagnosis is hindered by prolonged culturing and difficulties detecting low pathogen loads. Here, we present a culture-free diagnostic platform that integrates microfluidics, Raman micro-spectroscopy, and deep learning to deliver “sample-to-report” testing within 20 min. The microfluidic enrichment system employs dialysis-dielectrophoresis (DEP) technology to rapidly isolate pathogens directly from clinical samples with a detection limit as low as <2 colony forming unit (CFU)/ml. Combining a single-cell Raman fingerprint database of 342 clinical isolates from 29 bacterial and 7 fungal species with a 1D ResNet deep learning model, our approach achieved 95.1% accuracy in lab settings. Validated in a 305-patient clinical study involving primary urine and other clinical samples, it demonstrated 95.4% agreement with traditional culture methods and 98.5% sensitivity in diagnosing infections. While broader validation is needed for clinical implementation, the integrated, rapid diagnosis pipeline, as well as broad-spectrum detection, offer a promising solution for next-generation diagnostics for combating AMR. Antimicrobial resistance poses a significant global health threat, necessitating swift and precise diagnostic solutions. Here, the authors introduce a culture-free diagnostic platform integrating microfluidic cell enrichment, single-cell Raman spectroscopy, and deep learning, that identifies bacterial and fungal infections directly from clinical samples within 20 minutes.

It is well known that as the generalized case for Fourier transform (FT) and fractional Fourier transform (FrFT), the linear canonical transform (LCT) has attracted more and more attention in signal processing and optics and so on due to more freedoms. On the other hand, as the tool of turning the real signals into the complex ones, the Hilbert transform (HT) is of much signification to information science. Since the complex signals through HT have the characteristic of the absence in negative frequency, HT plays an important role in communication. In the present paper, first, the generalized HT (GHT) in terms of LCT is given. Then, five types of generalized Uncertainty relations with novel uncertainty bounds of the complex signals in terms of generalized HT (GHT) in terms of LCT are demonstrated. These newly refined uncertainty bounds proved to be different from and much lower or sharper in many cases than that of the traditional complex and real signals. Finally, the examples are given to show the efficiency of the proposed uncertainty relations in this paper.