Afterglow Nanoprobe-Enabled Quantitative Lateral Flow Immunoassay by a Palm-Size Device for Household Healthcare.

Lateral flow immunoassay (LFIA), a classical point-of-care testing (POCT) technique, plays an important role in disease screening and healthcare monitoring. However, traditional LFIA is either designed for qualitative analysis or requires expensive equipment for quantification, limiting its use in household diagnosis. In this study, we proposed a new generation of LFIA for household health monitoring by using ultralong organic phosphorescence (UOP) nanomaterials as afterglow nanoprobes with a self-developed palm-size sensing device. The UOP nanoprobes exhibit a phosphorescence signal with a second-level lifetime, which completely avoids the interference from excitation light and biological background fluorescence. Therefore, an ultraminiaturized and low-cost UOP nanosensor was successfully designed by eliminating the complex optical path and filtering systems. We chose an inflammatory factor, C-reactive protein (CRP), for household POCT validation. The whole analysis was completed within 9 min. A limit of detection (LOD) of 0.54 ng/mL of CRP antigen was achieved with high stability and good specificity, which is comparable to laboratory instruments and fully satisfying the clinical diagnosis requirement.

Characterization of Retinal VIP-Amacrine Cell Development During the Critical Period.

Retinal vasoactive intestinal peptide amacrine cells (VIP-ACs) play an important role in various retinal light-mediated pathological processes related to different developmental ocular diseases and even mental disorders. It is important to characterize the developmental changes in VIP-ACs to further elucidate their mechanisms of circuit function. We bred VIP-Cre mice with Ai14 and Ai32 to specifically label retinal VIP-ACs. The VIP-AC soma and spine density generally increased, from postnatal day (P)0 to P35, reaching adult levels at P14 and P28, respectively. The VIP-AC soma density curve was different with the VIP-AC spine density curve. The total retinal VIP content reached a high level plateau at P14 but was decreased in adults. From P14 to P16, the resting membrane potential (RMP) became more negative, and the input resistance decreased. Cell membrane capacitance (MC) showed three peaks at P7, P12 and P16. The RMP and MC reached a stable level similar to the adult level at P18, whereas input resistance reached a stable level at P21. The percentage of sustained voltage-dependent potassium currents peaked at P16 and remained stable thereafter. The spontaneous excitatory postsynaptic current and spontaneous inhibitory postsynaptic current frequencies and amplitudes, as well as charge transfer, peaked at P12 to P16; however, there were also secondary peaks at different time points. In conclusion, we found that the second, third and fourth weeks after birth were important periods of VIP-AC development. Many developmental changes occurred around eye opening. The development of soma, dendrite and electrophysiological properties showed uneven dynamics of progression. Cell differentiation may contribute to soma development whereas the changes of different ion channels may play important role for spine development.

Crizotinib-based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation.

As one of the common malignant cancer types, gastric cancer (GC) is known for late-stage diagnosis and poor prognosis. Overexpression of the receptor tyrosine kinase MET is associated with poor prognosis among patients with advanced stage GC. However, no MET inhibitor has been used for GC treatment. Like other tyrosine kinase inhibitors that fit the "occupancy-driven" model, current MET inhibitors are prone to acquired resistance. The emerging proteolysis targeting chimera (PROTAC) strategy could overcome such limitations through direct degradation of the target proteins. In this study, we successfully transformed the MET-targeted inhibitor crizotinib into a series of PROTACs, recruiting cereblon/cullin 4A E3 ubiquitin ligase to degrade the MET proteins. The optimized lead PROTAC (PRO-6 E) effectively eliminated MET proteins in vitro and in vivo, inhibiting proliferation and motility of MET-positive GC cells. In the MKN-45 xenograft model, PRO-6 E showed pronounced antitumor efficacy with a well-tolerated dosage regimen. These results validated PRO-6 E as the first oral PROTAC for MET-dependent GC.

Targeted Protein Degradation Technology and Nanomedicine: Powerful Allies against Cancer.

Targeted protein degradation (TPD) is an emerging therapeutic strategy with the potential of targeting undruggable pathogenic proteins. After the first proof-of-concept proteolysis-targeting chimeric (PROTAC) molecule was reported, the TPD field has entered a new era. In addition to PROTAC, numerous novel TPD strategies have emerged to expand the degradation landscape. However, their physicochemical properties and uncontrolled off-target side effects have limited their therapeutic efficacy, raising concerns regarding TPD delivery system. The combination of TPD and nanotechnology offers great promise in improving safety and therapeutic efficacy. This review provides an overview of novel TPD technologies, discusses their clinical applications, and highlights the trends and perspectives in TPD nanomedicine.

A short period of early life oxytocin treatment rescues social behavior dysfunction via suppression of hippocampal hyperactivity in male mice.

Early sensory experiences interact with genes to shape precise neural circuits during development. This process is vital for proper brain function in adulthood. Neurological dysfunctions caused by environmental alterations and/or genetic mutation may share the same molecular or cellular mechanisms. Here, we show that early life bilateral whisker trimming (BWT) subsequently affects social discrimination in adult male mice. Enhanced activation of the hippocampal dorsal CA3 (dCA3) in BWT mice was observed during social preference tests. Optogenetic activation of dCA3 in naive mice impaired social discrimination, whereas chemogenetic silencing of dCA3 rescued social discrimination deficit in BWT mice. Hippocampal oxytocin (OXT) is reduced after whisker trimming. Neonatal intraventricular compensation of OXT relieved dCA3 over-activation and prevented social dysfunction. Neonatal knockdown of OXT receptor in dCA3 mimics the effects of BWT, and cannot be rescued by OXT treatment. Social behavior deficits in a fragile X syndrome mouse model (Fmr1 KO mice) could also be recovered by early life OXT treatment, through negating dCA3 over-activation. Here, a possible avenue to prevent social dysfunction is uncovered.

Neurodevelopmental outcomes of neonatal posthemorrhagic hydrocephalus and psychological effects on the parents.

BACKGROUND: Neonatal posthemorrhagic hydrocephalus remains a common complication in preterm infants, with high rates of mortality and morbidity, placing parents at high risk of anxiety and depression. We sought to investigate the neurodevelopmental outcomes of infants with posthemorrhagic hydrocephalus who underwent surgery and the psychological effect on their parents. METHODS: We retrospectively analysed all infants with posthemorrhagic hydrocephalus born between 2014 and 2020 in the Children's Hospital of Chongqing Medical University, China. The neurodevelopmental outcomes of 28 patients were evaluated by the Pediatric Stroke Outcome Measure score, and the psychological states of the parents of survivors were assessed by the Hospital Anxiety and Depression Scale. RESULTS: The families of the 28 patients were followed up for a median duration of 3 years; 6 (21.4%) patients died within 6 months after discharge, 12 (42.9%) patients had moderate to severe dysfunction, and only 10 (35.7%) patients had good outcomes. Regarding the 22 parents of the survivors, 5 (22.7%) and 4 (18.2%) had borderline anxiety and depression symptoms, respectively. Two (9.1%) caregivers had exact anxiety and depression symptoms. Leukomalacia after intraventricular haemorrhage was associated with adverse neurological outcomes. The infants' histories of epileptic seizures during the neonatal period were associated with the anxiety of their parents. CONCLUSION: The overall outcome of posthemorrhagic hydrocephalus patients is unsatisfactory, and children with leukomalacia after haemorrhage tend to have poor outcomes. A history of epileptic seizures during the course of the disease may exacerbate the anxiety of the caregivers.

Embolization of midbrain arteriovenous malformation fed by the artery of Percheron in a child, the first case report and literature review.

BACKGROUND: Artery of Percheron (AOP) as main feeder artery of arteriovenous malformation (AVM) is extremely rare. Two cases of thalamic AVM fed by AOP have been reported to date and only one AVM been removed by microsurgery when attempt of intervention embolization failed. Midbrain AVM fed by AOP has not been reported yet. CASE PRESENTATION: Here, we presented the first successful embolized case of midbrain AVM supplied by the AOP in a 10-year-old boy, who suffered dual oculomotor nerve palsy and secondary hemorrhage before embolization. During endovascular embolization, selective angiography by 1.2 Fr. Magic microcatheter showed an intranidal aneurysm located on the distal AOP. Two injections of a 1:4 ratio mixture of NBCA-MS completely occlude the nidus and intranidal aneurysm with no complications occurred. The child recovered well and the oculomotor deficits improved. CONCLUSION: This case highlighted that AOP is a clinically significant branch associated with AVM in midbrain and thalamus. Moreover, intervention embolization of midbrain AVM fed by AOP is a considerable therapeutic strategy.

Short-wavelength artificial light affects visual neural pathway development in mice.

Nearly all modern life depends on artificial light; however, it does cause health problems. With certain restrictions of artificial light emitting technology, the influence of the light spectrum is inevitable. The most remarkable problem is its overload in the short wavelength component. Short wavelength artificial light has a wide range of influences from ocular development to mental problems. The visual neuronal pathway, as the primary light-sensing structure, may contain the fundamental mechanism of all light-induced abnormalities. However, how the artificial light spectrum shapes the visual neuronal pathway during development in mammals is poorly understood. We placed C57BL/6 mice in three different spectrum environments (full-spectrum white light: 400-750 nm; violet light: 400 ± 20 nm; green light: 510 ± 20 nm) beginning at eye opening, with a fixed light time of 7:00-19:00. During development, we assessed the ocular axial dimension, visual function and retinal neurons. After two weeks under short wavelength conditions, the ocular axial length (AL), anterior chamber depth (ACD) and length of lens thickness, real vitreous chamber depth and retinal thickness (LLVR) were shorter, visual acuity (VA) decreased, and retinal electrical activity was impaired. The density of S-cones in the dorsal and ventral retinas both decreased after one week under short wavelength conditions. In the ventral retina, it increased after three weeks. Retinal ganglion cell (RGC) density and axon thickness were not influenced; however, the axonal terminals in the lateral geniculate nucleus (LGN) were less clustered and sparse. Amacrine cells (ACs) were significantly more activated. Green light has few effects. The KEGG and GO enrichment analyses showed that many genes related to neural circuitry, synaptic formation and neurotransmitter function were differentially expressed in the short wavelength light group. In conclusion, exposure to short wavelength artificial light in the early stage of vision-dependent development in mice delayed the development of the visual pathway. The axon terminus structure and neurotransmitter function may be the major suffering.

Baseline Pydiflumetofen Sensitivity of Fusarium pseudograminearum Isolates Collected from Henan, China, and Potential Resistance Mechanisms.

Fusarium crown rot (FCR), caused by Fusarium pseudograminearum, is one of the most important diseases impacting wheat production in the Huanghuai region, the most important wheat-growing region of China. The current study found that the SDHI fungicide pydiflumetofen, which was recently developed by Syngenta Crop Protection, provided effective control of 67 wild-type F. pseudograminearum isolates in potato dextrose agar, with an average EC50 value of 0.060 ± 0.0098 µg/ml (SE). Further investigation revealed that the risk of fungicide resistance in pydiflumetofen was medium to high. Four F. pseudograminearum mutants generated by repeated exposure to pydiflumetofen under laboratory conditions indicated that pydiflumetofen resistance was associated with fitness penalties. Mutants exhibited significantly (P < 0.05) reduced sporulation in mung bean broth and significantly (P < 0.05) reduced pathogenicity in wheat seedlings. Sequence analysis indicated that the observed pydiflumetofen resistance of the mutants was likely associated with amino acid changes in the different subunits of the succinate dehydrogenase target protein, including R18L and V160M substitutions in the FpSdhA sequence; D69V, D147G, and C257R in FpSdhB; and W78R in FpSdhC. This study found no evidence of cross-resistance between pydiflumetofen and the alternative fungicides tebuconazole, fludioxonil, carbendazim, or fluazinam, which all have distinct modes of action and could therefore be used in combination or rotation with pydiflumetofen to reduce the risk of resistance emerging in the field. Taken together, these results indicate that pydiflumetofen has potential as a novel fungicide for the control of FCR caused by F. pseudograminearum and could therefore be of great significance in ensuring high and stable wheat yields in China.

Increasing astrogenesis in the developing hippocampus induces autistic-like behavior in mice via enhancing inhibitory synaptic transmission.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder characterized primarily by impaired social communication and rigid, repetitive, and stereotyped behaviors. Many studies implicate abnormal synapse development and the resultant abnormalities in synaptic excitatory-inhibitory (E/I) balance may underlie many features of the disease, suggesting aberrant neuronal connections and networks are prone to occur in the developing autistic brain. Astrocytes are crucial for synaptic formation and function, and defects in astrocytic activation and function during a critical developmental period may also contribute to the pathogenesis of ASD. Here, we report that increasing hippocampal astrogenesis during development induces autistic-like behavior in mice and a concurrent decreased E/I ratio in the hippocampus that results from enhanced GABAergic transmission in CA1 pyramidal neurons. Suppressing the aberrantly elevated GABAergic synaptic transmission in hippocampal CA1 area rescues autistic-like behavior and restores the E/I balance. Thus, we provide direct evidence for a developmental role of astrocytes in driving the behavioral phenotypes of ASD, and our results support that targeting the altered GABAergic neurotransmission may represent a promising therapeutic strategy for ASD.

Confining isolated chromophores for highly efficient blue phosphorescence.

High-efficiency blue phosphorescence emission is essential for organic optoelectronic applications. However, synthesizing heavy-atom-free organic systems having high triplet energy levels and suppressed non-radiative transitions-key requirements for efficient blue phosphorescence-has proved difficult. Here we demonstrate a simple chemical strategy for achieving high-performance blue phosphors, based on confining isolated chromophores in ionic crystals. Formation of high-density ionic bonds between the cations of ionic crystals and the carboxylic acid groups of the chromophores leads to a segregated molecular arrangement with negligible inter-chromophore interactions. We show that tunable phosphorescence from blue to deep blue with a maximum phosphorescence efficiency of 96.5% can be achieved by varying the charged chromophores and their counterions. Moreover, these phosphorescent materials enable rapid, high-throughput data encryption, fingerprint identification and afterglow display. This work will facilitate the design of high-efficiency blue organic phosphors and extend the domain of organic phosphorescence to new applications.

Baseline Sensitivity and Potential Resistance Mechanisms for Fusarium pseudograminearum to Fludioxonil.

Fusarium crown rot (FCR), which is caused by Fusarium pseudograminearum, is one of the most important diseases affecting wheat production in the Huanghuai wheat-growing region of China. Although the phenylpyrrole fungicide fludioxonil is known to have a broad-spectrum activity against a wide range of plant pathogens, including F. pseudograminearum, it has not yet been registered for the control of FCR in China, and further research is needed to assess the biological characteristics and molecular mechanisms associated with fludioxonil resistance, and especially the potential for highly resistant isolates to emerge. The current study demonstrated that the baseline fludioxonil sensitivity of 61 F. pseudograminearum isolates collected from the Henan province of China during the summers of 2019 to 2021 conformed to a unimodal distribution with a mean effective concentration for 50% inhibition (EC50) value of 0.021 ± 0.003 µg/ml, which indicated that none of the isolates exhibited natural resistance to fludioxonil. Nevertheless, four fludioxonil-resistant mutants were attained after repeated exposure to fludioxonil under laboratory conditions. All resistant mutants exhibited significantly lower growth rates on potato dextrose agar (PDA) and lower levels of sporulation and pathogenicity in wheat seedlings. In addition, the resistant mutants also exhibited less growth on PDA amended with either 0.5 M mannitol, 0.5 M glucose, 0.5 M MgCl2, or 0.5 M NaCl, which indicated that they had greater sensitivity to osmotic stress. Molecular analysis of the proposed fludioxonil target protein FpOs1 indicated that the predicted sequences of the resistant mutants contained none of the characteristic amino acid changes previously associated with fludioxonil resistance in other species. Further investigation via quantitative real-time PCR analysis revealed that expression of the FpOs1 gene was significantly altered in the resistant mutants in both the absence and presence of fludioxonil. Meanwhile, plate assays found evidence of cross-resistance between fludioxonil and cyprodinil, as well as with the triazole fungicides tebuconazole and difenoconazole, but not with other commonly used fungicides including prochloraz, fluazinam, and carbendazim. Taken together, these results provide new insights into the mechanism and biological characteristics associated with fludioxonil resistance in F. pseudograminearum and indicate that fludioxonil could provide effective and sustained control of FCR during wheat production.

Cytotoxic and antitumor peptides as novel chemotherapeutics.

Covering: up to 2020Treatment resistance and drug-induced refractory malignancies pose significant challenges for current chemotherapy drugs. There have been increasing research efforts aimed at developing novel chemotherapeutics, especially from natural products and related derivatives. Natural cytotoxic peptides, an emerging source of chemotherapeutics, have exhibited the advantage of overcoming drug resistance and displayed broad-spectrum antitumor activities in the clinic. This highlight examines the increasingly popular cytotoxic peptides from isolated natural products. In-depth review of several peptides provides examples for how this novel strategy can lead to the improved anti-tumor effects. The mechanisms and current application of representative natural cytotoxic peptides (NCPs) have also been discussed, with a particular focus on future directions for interdisciplinary research.

Microscopic Afterglow Bioimaging by Ultralong Organic Phosphorescent Nanoparticles in Living Cells and Zebrafish.

Compared with short-lived emission probes featuring fluorescence imaging , the use of phosphorescent probes imparts the advantage of long-lived signal persistence that distinguishes against background fluorescence interference. However, the realization of ultralong organic phosphorescent (UOP) probes with an ultralong emission lifetime in an aqueous medium is still a challenge. Here, we present a rational strategy for obtaining UOP nanoparticles (NPs) in an air-saturated aqueous medium prepared using an organic phosphor (PDBCz) and a surfactant polymer (PVP), named PDBCz@PVP, showing an ultralong emission lifetime of 284.59 ms and a phosphorescence quantum efficiency of 7.6%. The excellent phosphorescence properties and water solubility of PDBCz@PVP make it a promising candidate for biological imaging. The as-prepared PDBCz@PVP NPs possess excellent luminescence intensity as well as illustrious biocompatibility both in vitro and in vivo. We demonstrate their use as an efficient phosphorescent nanoprobe both in living cells and zebrafish by capturing their afterglow emission signals under microscopy observation for the first time, realizing convenient and fast bioimaging with low cost, which allows for anti-fluorescence interference and shows promise for the future theragnostic applications in nanomedicine.

Subicular pyramidal neurons gate drug resistance in temporal lobe epilepsy.

OBJECTIVE: Drug-resistant epilepsy causes great clinical danger and still lacks effective treatments. METHODS: Here, we used multifaceted approaches combining electrophysiology, optogenetics, and chemogenetics in a classic phenytoin-resistant epilepsy model to reveal the key target of subicular pyramidal neurons in phenytoin resistance. RESULTS: In vivo neural recording showed that the firing rate of pyramidal neurons in the subiculum, but not other hippocampal subregions, could not be inhibited by phenytoin in phenytoin-resistant rats. Selective inhibition of subicular pyramidal neurons by optogenetics or chemogenetics reversed phenytoin resistance, whereas selective activation of subicular pyramidal neurons induced phenytoin resistance. Moreover, long-term low-frequency stimulation at the subiculum, which is clinically feasible, significantly inhibited the subicular pyramidal neurons and reversed phenytoin resistance. Furthermore, in vitro electrophysiology revealed that off-target use of phenytoin on sodium channels of subicular pyramidal neurons was involved in the phenytoin resistance, and clinical neuroimaging data suggested the volume of the subiculum in drug-resistant patients was related to the usage of sodium channel inhibitors. INTERPRETATION: These results highlight that the subicular pyramidal neurons may be a key switch control of drug-resistant epilepsy and represent a new potential target for precise treatments. ANN NEUROL 2019;86:626-640.

Maternal immune activation alters visual acuity and retinogeniculate axon pruning in offspring mice.

Individuals with autism spectrum disorder (ASD) have been found to have a variety of sensory processing deficits. Here we report that maternal immune activation, a known factor for ASD, alters visual acuity in the offspring mice. By intraperitoneally injecting polyinosinic-polycytidylic acid (polyI:C) to induce maternal immune activation during embryonic days 10 to 14, we found that polyI:C treatment impairs visual acuity in young adult offspring mice as examined by their optomotor responses. Concurrently, polyI:C treatment suppresses retinogeniculate axon elimination, resulting in a high fraction of weak optical fibers innervating the relay neurons in the visual thalamus. The results link in-utero maternal inflammation to defective optical fiber pruning and arrested developmental strengthening of single optic fibers which may underlie impaired visual acuity.

Research on an adaptive filter for the Mie lidar signal.

The statistical properties of the noise in the Mie lidar signal are analyzed by the statistical hypotheses testing method. Based on this, an adaptive filter is proposed to eliminate the noise. The least mean square error algorithm is used to achieve optimal filtering, in which the mean square error is minimized by adjusting the filter's weight matrix. The validity of the adaptive filter is verified by numerical simulation and experimental data retrieving. In the numerical simulation, the signal-to-noise ratio of the adaptive filter is larger than that of the wavelet transform filter, and the mean square error of the output of the adaptive filter is less than the wavelet transform filter. In experimental data retrieving, the filtered lidar signals of the adaptive filter and wavelet transform filter are used to retrieve the extinction coefficient respectively in different weather conditions. The amplitude of the ripples in the extinction coefficient profile of the adaptive filter is less than that of the wavelet transform filter. Additionally, the adaptive filter's extinction coefficient profile is smoother than that of the wavelet transform filter. The detail of the extinction coefficient is displayed more clearly in the profile of the adaptive filter. The research result is of great importance for improving the accuracy of lidar data retrieving.

Pharmaco-genetic therapeutics targeting parvalbumin neurons attenuate temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is the most common type of epilepsy and is often medically refractory. Previous studies suggest that selective pharmaco-genetic inhibition of pyramidal neurons has therapeutic value for the treatment of epilepsy, however there is a risk of disrupting normal physical functions. Here, we test whether pharmaco-genetic activation of parvalbumin neurons, which are transgenetically transduced with the modified muscarinic receptor hM3Dq can attenuate TLE. We found that pharmaco-genetic activation of hippocampal parvalbumin neurons in epileptogenic zone not only significantly extends the latency to different seizure stages and attenuates seizure activities in acute seizure model, but also greatly alleviates the severity of seizure onsets in two chronic epilepsy models. This manipulation did not affect the normal physical function evaluated in various cognitive tasks. Further, the activation of parvalbumin neurons produced an inhibition on parts of surrounding pyramidal neurons, and the direct inactivation of pyramidal neurons via the viral expression of a modified muscarinic receptor hM4Di produced a similar anti-ictogenic effect. Interestingly, pharmaco-genetic inactivation of pyramidal neurons was more sensitive to impair cognitive function. Those data demonstrated that pharmaco-genetic seizure attenuation through targeting parvalbumin neurons rather than pyramidal neurons may be a novel and relatively safe approach for treating refractory TLE.

Enabling user mobility for optical camera communication using mobile phone.

We propose and experimentally demonstrate an optical camera communication (OCC) supporting user mobility. A mobile test platform is designed to emulate user mobility. In the mobile scenario, dynamic column matrix selection algorithm is proposed to select an appropriate column matrix with high extinction-ratio (ER) while avoiding the blooming effect. The mobile phone is placed on the moving track to receive the visible light at a vertical distance of 60 cm. By varying the moving speed at 20, 40, 60, 80, and 100 cm/s and lateral distance at 50 and 70 cm respectively, the system performance using the proposed algorithm is investigated. The experimental results show that with the increase of lateral distance (far from the light source) and user moving speed, the system performance gets degraded. Moreover, it demonstrates that the mobile system can achieve a throughput of 4.08 kbps under a low illuminance of 275 lx.

Glial Regulation of Energy Metabolism.

The major function of brain glial cells is to maintain a homeostatic milieu for neurons to work properly in response to a variety of environmental alterations. Recent studies have shown that glial cells in the hypothalamus, a brain center controlling homeostatic physiological functions, are essential for regulating energy metabolism in both physiological and pathological conditions. Astrocytes, tanycytes, and NG2-glia shuttle and/or sense key metabolic factors presented to the hypothalamus either directly, by glial metabolic enzymes, receptors, and transporters, or indirectly, by modulating the sensing ability of other types of hypothalamic cells. Astrocytes, tanycytes, and microglia are critically important in the development and maintenance of hypothalamic circuits regulating energy balance. Hypothalamic inflammation commonly associated with diet-induced obesity is manifested via hypothalamic reactive gliosis involving microglia and astrocytes, contributing to the correlated abnormal energy metabolism. Although many glial functions in energy metabolism remain to be fully elucidated, we are at the dawn of targeting glia-neuron interactions in the hypothalamus for therapeutic applications in metabolic disorders.