Selective enrichment of submicron pathogens (e.g., bacteria, viruses) from complex matrices containing larger interferents remains a fundamental challenge in rapid biosensing. Conventional thermophoresis-based methods suffer from inherent size-dependent limitations and require fluorescent labeling for specificity, compromising clinical utility. Here, we propose a new strategy by exploiting density-manipulated sedimentation to break this limitation, enabling the selective enrichment of 200 nm targets from 1.3 μm interferents within 15 min. Through aptamer-directed in-situ synthesis of plasmonic nanoparticles (AgNPs) on target pathogens, we increase the apparent density of the targets, while simultaneously covering them with surface-enhanced Raman substrates. When coupled with laser-induced convection, the approach enables label-free detection of target bacteria at clinically relevant concentrations in blood serum with coexisting bacteria, as well as in clinical samples. The synergy of density-enhanced sedimentation and convection competition establishes a new microfluidic principle for particle manipulation. This work not only overcomes a critical bottleneck in point-of-care diagnostics but also provides a versatile platform for the rapid biosensing of diverse pathogens.

PurposeVisceral white adipose tissue (vWAT) accumulation causes systemic inflammation, insulin resistance, metabolic syndrome, and senescent cell accumulation that are risk factors for Alzheimer’s disease (AD). Visceral fat removal (VFR) improves metabolism and reduces pro-inflammatory cytokines. We hypothesized that VFR removal in AD mice would improve metabolism and cognition.MethodsMale and female APPNL-F mice underwent sham or vWAT surgical resection (periovarian or epididymal and perirenal) at 4 (pre-symptomatic) and 16 (symptomatic) months of age to understand interventional and therapeutic effects, respectively. At 18 months of age, glucose metabolism and novel object recognition (NOR) memory were assayed followed by assessment of body composition and tissue-specific markers of metabolism, cell senescence, inflammation, or amyloid accumulation.ResultsMale and female APPNL-F mice showed distinct VFR responses. In pre-symptomatic males, increased vWAT lipolysis and hepatic lipogenesis led to ectopic liver lipid accumulation, with reduced adiponectin and leptin, elevated visfatin, and impaired glucose metabolism. Symptomatic males showed reduced vWAT lipogenesis, enhanced hepatic lipolysis, glycolysis, and glycogenesis, lowering liver lipids and improving insulin sensitivity. Only symptomatic males improved NOR, linked to elevated hippocampal learning and memory markers. Female vWAT reaccumulation was due to increased lipogenesis and lower lipolysis. Pre-symptomatic females had lower hepatic lipogenesis, while glycolysis and glycogenesis declined with disease progression. Hippocampal senescence and inflammation were elevated early in the disease that persisted symptomatically.DiscussionSex-specific differences in glucose and lipid metabolism and lipid accumulation underlie the divergent responses to VFR in APPNL-F mice, with symptomatic males showing the only beneficial outcomes in metabolism and cognition.

The urgent need for rapid, low-cost pathogen diagnostics in resource-limited settings drives the development of point-of-care technologies that balance sensitivity, specificity, simplicity, and cost. Here, we present a biosensing platform by integrating an aptamer-poly-T DNA strand for rapidly loading copper nanoclusters (Cu NCs) on the target pathogen and size-exclusion filtration to concentrate the pathogen onto a membrane, enabling ultrasensitive visual detection of low-abundance pathogens within 20 min by naked eyes. The aptamer domain enables the pathogen-specific recognition (validated by Salmonella and SARS-CoV-2 pseudovirus), while the poly-T template facilitates the rapid (<5 min) loading of Cu NCs to the target. The Cu NC-labeled target pathogens were then concentrated on the membrane, while the matrix interferents (salts, proteins), as well as the unbound Cu NCs can be washed away from the membrane due to their relatively small sizes. The efficient release of thousands of Cu2+ from the Cu NCs enables the sensitive coloration of the membrane in the presence of TEA, yielding a 10,000-fold sensitivity gain over colloidal gold assays. This cascaded mechanism achieves a detection limit of 10 particles/μL in undiluted serum. The sensing platform is applicable to other biological particles such as exosomes (cancer biomarkers) with low cost (a per-test cost < $1). By merging molecular specificity with field-deployable robustness, this technology redefines decentralized diagnostics for emerging bacterial or viral threats, offering transformative potential for epidemic surveillance and precision public health interventions.

Alzheimer's disease (AD) disproportionately affects women, yet most preclinical research studies are male-centric. We performed lifespan analyses of male and female AD mouse models (APP/PS1 and APP NL-F/NL-F ) and their shared genetic background control (C57BL/6). Survival curves support significant sex differences between genotypes. Minimal longevity revealed increased age in male APP/PS1, and decreased age in male APP NL-F/NL-F mice. Maximal longevity revealed an increased average age in males. Furthermore, median lifespan differed between sex and genotype. This study supports dimorphic survival in two mouse models of AD, emphasizing the need to examine mechanisms and treatments in both sexes.

Label-free optical imaging of the morphology of single nanoparticles under native conditions remains a challenging task despite its importance in the synthesis, properties, and applications of nanomaterials. Here, we developed an angular scanning dark-field scattering microscopy (ASDFSM) that can identify the particle morphologies by the features of their angle-dependent scattering intensities without increasing spatial resolution. ASDFSM can unambiguously resolve the morphology of single nanoparticles with sizes down to 1/5 wavelength of the incident light in a large field of view, facilitating the simultaneous imaging of a large number of nanoparticles with statistical significance. Coupling with a random forest machine learning algorithm, their morphologies can be well-identified with an average accuracy of 96%, facilitating in situ monitoring of the corrosion and growth kinetics of single nanoparticles in a high-temperature solution. The ASDFSM possesses the advantages of high-throughput, noninvasiveness, dynamic traceability, and simplicity over the present methods, promising its wide applications in nanoscience.

Nanozymes possess multi-enzyme activities over the natural enzymes, which produce multi-pathway synergistic effects for varies of biomedical applications. Unfortunately, their multi-enzyme activities are in fighting, significantly reducing the synergistic effects. Dynamic regulation of their multi-enzyme activities is the bottleneck for intelligent therapies. Herein, we construct a novel oxygen-nitrogen functionalized carbon quantum dots (O/N-CQDs) with peroxidase-like (Reactive oxygen species (ROS) producer) activity. Interestingly, the peroxidase-like activity can be reversibly converted to catalase-like (ROS scavenger) activity under visible light irradiation. It is found that both the peroxidase/catalase-like activity of O/N-CQDs can be precisely manipulated by the light intensity. The mechanism of switchable enzyme activities is attributed to the polarization of quinoid nitrogen in polyaniline (PANI) precursor retained on O/N-CQDs under visible light, which consumes the ROS to produce O2 and H2O. As a proof-of-concept demonstration, we are able to non-intrusively up and down regulate the ROS level in cells successfully by simply switching off and on the light respectively, potentially facilitating the precise medicine based on the development of the disease. Indeed, the photo-switchable peroxidase/catalase-like activity of O/N-CQDs opens a non-invasive strategy for better manipulations of the multi-activity of nanozymes, promising their wider and more intelligent biomedical applications.

Recent studies have demonstrated the remarkable potential of early life intervention strategies at influencing the course of postnatal development, thereby offering exciting possibilities for enhancing longevity and improving overall health. Metformin (MF), an FDA-approved medication for type II diabetes mellitus, has recently gained attention for its promising anti-aging properties, acting as a calorie restriction mimetic, and delaying precocious puberty. Additionally, trodusquemine (MSI-1436), an investigational drug, has been shown to combat obesity and metabolic disorders by inhibiting the enzyme protein tyrosine phosphatase 1b (Ptp1b), consequently reducing hepatic lipogenesis and counteracting insulin and leptin resistance. In this study, we aimed to further explore the effects of these compounds on young, developing mice to uncover biomolecular signatures that are central to liver metabolic processes. We found that MSI-1436 more potently alters mRNA and miRNA expression in the liver compared with MF, with bioinformatic analysis suggesting that cohorts of differentially expressed miRNAs inhibit the action of phosphoinositide 3-kinase (Pi3k), protein kinase B (Akt), and mammalian target of rapamycin (Mtor) to regulate the downstream processes of de novo lipogenesis, fatty acid oxidation, very-low-density lipoprotein transport, and cholesterol biosynthesis and efflux. In summary, our study demonstrates that administering these compounds during the postnatal window metabolically reprograms the liver through induction of potent epigenetic changes in the transcriptome, potentially forestalling the onset of age-related diseases and enhancing longevity. Future studies are necessary to determine the impacts on lifespan and overall quality of life.

Senescent cells accumulate throughout the body and brain contributing to unhealthy aging and Alzheimer’s disease (AD). The APPNL−F/NL−F amyloidogenic AD mouse model exhibits increased markers of senescent cells and the senescence-associated secretory phenotype (SASP) in visceral white adipose tissue and the hippocampus before plaque accumulation and cognitive decline. We hypothesized that senolytic intervention would alleviate cellular senescence thereby improving spatial memory in APPNL−F/NL−F mice. Thus, 4-month-old male and female APPNL−F/NL−F mice were treated monthly with vehicle, 5 mg/kg dasatinib + 50 mg/kg quercetin, or 100 mg/kg fisetin. Blood glucose levels, energy metabolism, spatial memory, amyloid burden, and senescent cell markers were assayed. Dasatinib + quercetin treatment in female APPNL−F/NL−F mice increased oxygen consumption and energy expenditure resulting in decreased body mass. White adipose tissue mass was decreased along with senescence markers, SASP, blood glucose, and plasma insulin and triglycerides. Hippocampal senescence markers and SASP were reduced along with soluble and insoluble amyloid-β (Aβ)42 and senescence-associated-β-gal activity leading to improved spatial memory. Fisetin had negligible effects on these measures in female APPNL−F/NL−F mice while neither senolytic intervention altered these parameters in the male mice. Considering women have a greater risk of dementia, identifying senotherapeutics appropriate for sex and disease stage is necessary for personalized medicine.

A thermoregulatory decline occurs with age due to changes in muscle mass, vasoconstriction, and metabolism that lowers core body temperature (Tc). Although lower Tc is a biomarker of successful aging, we have previously shown this worsens cognitive performance in the APP/PS1 mouse model of Alzheimer's disease (AD) [1]. We hypothesized that elevating Tc with thermotherapy would improve metabolism and cognition in APP/PS1 mice. From 6-12 months of age, male and female APP/PS1 and C57BL/6 mice were chronically housed at 23 or 30°C. At 12 months of age, mice were assayed for insulin sensitivity, glucose tolerance, and spatial cognition. Plasma, hippocampal, and peripheral (adipose, hepatic, and skeletal muscle) samples were procured postmortem and tissue-specific markers of amyloid accumulation, metabolism, and inflammation were assayed. Chronic 30°C exposure increased Tc in all groups except female APP/PS1 mice. All mice receiving thermotherapy had either improved glucose tolerance or insulin sensitivity, but the underlying processes responsible for these effects varied across sexes. In males, glucose regulation was influenced predominantly by hormonal signaling in plasma and skeletal muscle glucose transporter 4 expression, whereas in females, this was modulated at the tissue level. Thermotherapy improved spatial navigation in male C57BL/6 and APP/PS1 mice, with the later attributed to reduced hippocampal soluble amyloid-β (Aβ)42. Female APP/PS1 mice exhibited worse spatial memory recall after chronic thermotherapy. Together, the data highlights the metabolic benefits of passive thermotherapy, but future studies are needed to determine therapeutic benefits for those with AD.

Senolytic treatment in aged mice clears senescent cell burden leading to functional improvements. However, less is known regarding the effects of these compounds when administered prior to significant senescent cell accumulation. From 4–13 months of age, C57BL/6 male and female mice received monthly oral dosing of either 100 mg/kg Fisetin or a 5 mg/kg Dasatinib (D) plus 50 mg/kg Quercetin (Q) cocktail. During treatment, several aspects of healthy aging were assayed including glucose metabolism using an insulin and glucose tolerance test, cognitive performance using Morris water maze and novel object recognition, and energy metabolism using indirect calorimetry. Afterwards, mice were euthanized for plasma, tissue specific markers of senescence-associated secretory phenotype (SASP), and white adipose tissue accumulation (WAT). Sexually dimorphic treatment effects were observed. Fisetin treated male mice had reduced SASP, enhanced glucose and energy metabolism, improved cognitive performance, and increased mRNA expression of adiponectin receptor 1 and glucose transporter 4. D + Q treatment had minimal effects in male C57BL/6 mice, but was detrimental to females causing increased SASP expression along with accumulation of WAT depots. Reduced energy metabolism and cognitive performance were also noted. Fisetin treatment had no effect in female C57BL/6 mice potentially due to a slower rate of biological aging. In summary, the senolytic treatment in young adulthood, has beneficial, negligible, or detrimental effects in C57BL/6 mice dependent upon sex and treatment. These observations should serve as a note of caution in this rapidly evolving and expanding field of investigation. Male and female C57BL/6 mice were treated with once monthly oral doses of either Dasatinib (D) + Quercetin (Q) or Fisetin from 4–13 months of age. Males treated with Fisetin had reduced SASP markers (blue spheres) as well as improved metabolism (red flame) and cognition. Females treated with D + Q had increased adiposity and SASP markers (red spheres) along with decreased metabolism (blue flame) and cognitive performance. No effects were observed in females treated with Fisetin or males treated with D + Q.

Cd2+ is one of the most toxic heavy metal ions that can be easily accumulated in human body via food chain. Thus, the onsite detection of Cd2+ in food is very important. However, present methods for Cd2+ detection either require the use of large equipment, or suffer from the severe interference from other analogical metal ions. This work establishes a facile Cd2+ mediated turn-on ECL method for highly selective detection of Cd2+ via cation exchanging with the nontoxic ZnS nanoparticles, owing to the unique surface-state ECL properties of CdS nanomaterials. The linear range of the calibration curve is from 7.0 x 10-8 to 1.0 x 10-6 M, while other analogical metal ions do not interfere, facilitating the selective detection of Cd2+ in oyster samples. The result agrees well with that obtained using atomic emission spectroscopy, indicating the potential for wider application of this approach.

The excessive use of nitrate fertilizer in agriculture has been a serious problem causing giant economic loss and environment pollution. Therefore, nitrate sensing in soil is very important for environment and agriculture. In this work, we develop a rapid sensing platform for on-site nitrate detection, which is composed of an easily conducted extraction filter (ECEF) and a sensing element based on cadmium sulfide nanorods (CdS NRs) modified screen printed electrode (CdS NRs-SPE). Nitrate extraction from soil can be easily conducted by ECEF in 3 min using a syringe coupled with a filter. The extracted solution is subsequently injected onto the CdS NRs-SPE, which can directly detect nitrate in neutral media within 10 min. The detection limit of nitrate is 2.3 mu M (S/N = 3) and a linear range from 0.05 to 5 mM. Moreover, the CdS NRs-SPEs are portable, low cost (3 dollars), and can be reused for over one month without significant loss of the performance, implying its promising application for intelligent nitrogen-management and developing precise fertilization in modern agriculture.

Rapid detection of ammonium nitrogen(NH4+) in soil is quit important for precise agriculture as it can significantly increase the utilization of soil fertility and reduce the environmental pollution. Compared with the traditional detection methods for NH4+ which are time-consuming and expensive, here we developed a rapid and sensitive electrochemical sensor by platinum deposited screen printed electrodes(Pt-SPEs) as sensing components. Owing to the specific catalysis to NH4+ , using the carbonate to precipitate the metal ions, coupling with the ammonium extraction syringe, NH4+ in soil can be detected in 5 min for the first time, with a detection range of 0.1-5 mmol/L(R2=0.997)and a detection limit of 13 mu mol/L(S/N=3). This sensors can be applied for on-site detection of NH4+ in soil due to its rapidity, simplicity, high selectivity and stability without large equipment, providing an important data support for precise agriculture.

目的 观察阿米卡星配合鞘内注药治疗强化期结核性脑膜炎(TBM)的临床效果.方法 回顾性选取2018年4月—2021年5月广州市胸科医院收治的强化期TBM患者89例,根据治疗方案不同分为研究组45例和对照组44例.对照组患者予以2HRZE/10HR治疗方案,研究组则在对照组基础上加用阿米卡星治疗,2组均治疗8周.比较2组患者治疗效果,治疗前后脑脊液(CSF)指标(白细胞计数、脑蛋白、葡萄糖比值、氯化物)变化及不良反应.结果 研究组患者治疗总有效率为64.44％,高于对照组的40.91％(χ2=4.945,P=0.026);治疗8周后,2组患者CSF中白细胞计数、脑蛋白水平较治疗前下降,葡萄糖比值及氯化物水平较治疗前升高(P均<0.01),且研究组变化幅度较对照组更大(P<0.05或P<0.01),但2组治疗后氯化物水平比较差异无统计学意义(P>0.05);2组不良反应总发生率比较差异无统计学意义(18.18％vs.22.22％,χ2=0.225,P=0.635),不良反应经过药物调整后均好转,无严重不良反应发生.结论 在2HRZE/10HR治疗方案基础上采用阿米卡星配合鞘内注药治疗强化期TBM患者的效果良好,可有效改善患者CSF指标,且不会明显增加不良反应.

Rapid detection of pathogenic bacteria within a few minutes is the key to control infec-tious disease. However, rapid detection of pathogenic bacteria in clinical samples is quite a challenging task due to the complex matrix, as well as the low abundance of bacteria in real samples. Herein, we employ a label-free single-particle imaging approach to address this challenge. By tracking the scattering intensity variation of single particles in free solu-tion, the morphological heterogeneity can be well identified with particle size smaller than the diffraction limit, facilitating the morphological identification of single bacteria from a complex matrix in a label-free manner. Furthermore, the manipulation of convec-tion in free solution enables the rapid screening of low-abundance bacteria in a small field of view, which significantly improves the sensitivity of single-particle detection. As a proof of concept demonstration, we are able to differentiate the group B streptococci (GBS)-positive samples within 10 min from vaginal swabs without using any biological reagents. This is the most rapid and low-cost method to the best of our knowledge. We believe that such a single-particle imaging approach will find wider applications in clinical diagnosis and disease control due to its high sensitivity, rapidity, simplicity, and low cost.

目的:分析喹诺酮类药物联合HRZE方案对肺结核的治疗效果.方法:选取100例肺结核患者为研究对象,应用随机数表法分为两组,对照组(50例)给予HRZE方案治疗,研究组(50例)在对照组基础上另加用喹诺酮类药物治疗.观察两组治疗2个月、4个月、6个月后痰菌转阴率及治疗后肺部病灶总吸收率、不良反应发生情况.结果:研究组治疗2个月后的痰菌转阴率(100％)高于对照组(70％),差异有统计学意义(P<0.05),两组4个月、6个月后痰菌转阴率比较,差异无统计学意义(P>0.05);研究组治疗2个月、4个月、6个月后肺部病灶总吸收率均高于对照组,差异有统计学意义(P<0.05);研究组毒副反应发生率为4％,对照组为8％,两组比较差异无统计学意义(P>0.05).结论:肺结核应用喹诺酮类药物联合HRZE方案治疗可显著提高患者病灶吸收情况,提升痰菌转阴率,并不增加毒副反应.

Adapting to stress, including cold environmental temperature (eT), is crucial for the survival of mammals, especially small rodents. Long-lived mutant mice have enhanced stress resistance against oxidative and non-oxidative challenges. However, much less is known about the response of those long-lived mice to cold stress. Growth hormone receptor knockout (GHR-KO) mice are long-lived with reduced growth hormone signaling. We wanted to test whether GHR-KO mice have enhanced resistance to cold stress. To examine the response of GHR-KO mice to cold eT, GHR-KO mice were housed at mild cold eT (16 °C) immediately following weaning. Longevity results showed that female GHR-KO and wild-type (WT) mice retained similar lifespan, while both male GHR-KO and WT mice had shortened lifespan compared to the mice housed at 23 °C eT. Female GHR-KO and WT mice housed at 16 °C had upregulated fibroblast growth factor 21 (FGF21), enhanced energy metabolism, reduced plasma triglycerides, and increased mRNA expression of some xenobiotic enzymes compared to females housed at 23 °C and male GHR-KO and WT mice housed under the same condition. In contrast, male GHR-KO and WT mice housed at 16 °C showed deleterious effects in parameters which might be associated with their shortened longevity compared to male GHR-KO and WT mice housed at 23 °C. Together, this study suggests that in response to mild cold stress, sex plays a pivotal role in the regulation of longevity, and female GHR-KO and WT mice are more resistant to this challenge than the males.

Growth hormone (GH) exerts major actions in cardiac growth and metabolism. Considering the important role of insulin in the heart and the well-established anti-insulin effects of GH, cardiac insulin resistance may play a role in the cardiopathology observed in acromegalic patients. As conditions of prolonged exposure to GH are associated with a concomitant increase of circulating GH, IGF1 and insulin levels, to dissect the direct effects of GH, in this study, we evaluated the activation of insulin signaling in the heart using four different models: (i) transgenic mice overexpressing GH, with chronically elevated GH, IGF1 and insulin circulating levels; (ii) liver IGF1-deficient mice, with chronically elevated GH and insulin but decreased IGF1 circulating levels; (iii) mice treated with GH for a short period of time; (iv) primary culture of rat cardiomyocytes incubated with GH. Despite the differences in the development of cardiomegaly and in the metabolic alterations among the three experimental mouse models analyzed, exposure to GH was consistently associated with a decreased response to acute insulin stimulation in the heart at the receptor level and through the PI3K/AKT pathway. Moreover, a blunted response to insulin stimulation of this signaling pathway was also observed in cultured cardiomyocytes of neonatal rats incubated with GH. Therefore, the key novel finding of this work is that impairment of insulin signaling in the heart is a direct and early event observed as a consequence of exposure to GH, which may play a major role in the development of cardiac pathology.

Growth hormone receptor knockout (GHRKO) mice are smaller, long living, and have an increased metabolic rate compared with normal (N) littermates. However, it is known that thermoneutral conditions (30-32°C) elicit metabolic adaptations in mice, increasing the metabolic rate. Therefore, we hypothesized that environmental temperature would affect the expression profile of different adipose tissue depots in GHRKO mice. For this, N (n = 12) and GHRKO (n = 11) male mice were maintained at 23 or 30°C from weaning until 11 months of age. RNA sequencing from adipose tissue depots (epididymal-eWAT, perirenal-pWAT, subcutaneous-sWAT, and brown fat-BAT) was performed. Thermoneutrality increased body weight gain in GHRKO mice, but not in N mice. Only a few genes were commonly regulated by temperature in N and GHRKO mice. The BAT was the most responsive to changes in temperature in both N and GHRKO mice. BAT Ucp1 and Ucp3 expression were decreased to a similar extent in both N and GHRKO mice under thermoneutrality. In contrast, eWAT was mostly unresponsive to changes in temperature. The response to thermoneutrality in GHRKO mice was most divergent from N mice in sWAT. Relative weight of sWAT was almost 4 times greater in GHRKO mice. Very few genes were regulated in N mice sWAT when compared with GHRKO mice. This suggests that this WAT depot has a central role in the adaptation of GHRKO mice to changes in temperature.

Plastic pollution in water is of increasing scientific and public concern due to the increasing plastic production, slow degradation rate and low recycling efficiency. However, the present methods for the removal of plastic particles in water are either inefficient or expensive, which limit their wide application. In this work, we propose a new strategy for the efficient removal of plastic particles in water that is driven by solar energy. Sunlight was focused through a glass ball with high power density, which could induce convection and form a microbubble at the interface. The plastic particles were driven into the bubble by convection and subsequently fused in the microbubble, as the temperature in the bubble was much higher than that in the solution due to the significantly different densities. Such a hot microbubble acts as a 'furnace', which can collect and fuse plastic particles into large bulks in the microbubble, facilitating the sustainable removal of plastic particles in water without the use of any chemical or biological reagents or filters. Moreover, this method is quite simple and can effectively utilize free sunlight without requiring extra energy or causing secondary pollution, implying its promising application in dealing with plastic pollution in aquatic ecosystems.