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Bloodstream infection is a major health problem worldwide, with extremely high mortality. Detecting infection in the early stage is challenging due to the extremely low concentration of bacteria in the blood. Digital PCR provides unparalleled sensitivity and can achieve absolute quantification, but it is time-consuming. Moreover, the presence of unavoidable background signals in negative controls poses a significant challenge for single-molecule detection. Here, we propose a novel strategy called "Ultrafast flexible thin tube-based droplet digital PCR (utPCR)" that can shorten the digital PCR process from 2 h to only 5 min, with primer annealing/extension time reduced from minutes to only 5 s. Importantly, the ultrafast PCR eliminates nonspecific amplification and thus enables single-molecule detection. The utPCR enabled the sensitive detection and digital quantification of E. coli O157 in the high background of a 106-fold excess of E. coli K12 cells. Moreover, this method also displayed the potential to detect rare pathogens in blood samples, and the limit of detection (LOD) could be as low as 10 CFU per mL of blood without false positive results. Considered ultrafast (<5 min) and highly sensitive (single-molecule detection), the utPCR holds excellent prospects in the next generation of molecular diagnosis. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is characterized with senile plaques formed by Aβ deposition, and neurofibrillary tangles composed of hyperphosphorylated tau protein, which ultimately lead to cognitive impairment. Despite the heavy economic and life burdens faced by the patients with AD, effective treatments are still lacking. Previous studies have reported the neuroprotective effects of FGF10 in CNS diseases, but its role in AD remains unclear. In this study, we demonstrated that FGF10 levels were reduced in the serum of AD patients, as well as in the brains of 3xTg‐AD mice and APPswe‐transfected HT22 cells, suggesting a close relationship between FGF10 and AD. Further investigations revealed that intranasal delivery of FGF10 improved cognitive functions in 3xTg‐AD mice. Additionally, FGF10 treatment reduced tau hyperphosphorylation and neuronal apoptosis, thereby mitigating neuronal cell damage and synaptic deficits in the cortex and hippocampus of 3xTg‐AD mice, as well as APPswe‐transfected HT22 cells. Furthermore, we evaluated the therapeutic potential of FGF10 gene delivery for treating AD symptoms and pathologies. Tail vein delivery of the FGF10 gene using AAV9 improved cognitive and neuronal functions in 3xTg‐AD mice. Similarly, endogenous FGF10 overexpression ameliorated tau hyperphosphorylation and neuronal apoptosis in the cortex and hippocampus of 3xTg‐AD mice. Importantly, we confirmed that the FGFR2/PI3K/AKT signaling pathway was activated following intranasal FGF10 delivery and AAV9‐mediated FGF10 gene delivery in 3xTg‐AD mice and APPswe‐transfected HT22 cells. Knockdown of FGFR2 attenuated the protective effect of FGF10. Collectively, these findings suggest that intranasal delivery of FGF10 and AAV9‐mediated FGF10 gene delivery could be a promising disease‐modifying therapy for AD. [ABSTRACT FROM AUTHOR]

Iron group metal phosphides (IMPs) are one of the most promising substitutes for non‐noble electrocatalysts in overall water splitting. In this work, an electrocatalyst system consisting of different vertically aligned heteroatom‐doped graphene arrays (X‐rGO, X = N, P, B, O, S) integrated with FeCoNiP nanoparticles (FeCoNiP@X‐rGO, X = N, P, B, O, S) is prepared for overall water splitting. The unique vertical structure and the synergistic effect between the P in P‐rGO and the P in FeCoNiP leads to the excellent electrocatalytic performance of FeCoNiP@P‐rGO by exhibiting low overpotentials (121 and 216 mV) at a current density of 10 mA cm−2 for hydrogen evolution reaction in 1 m KOH and 0.5 m H2SO4, respectively. As well as a low overpotential (354 mV) at a current density of 10 mA cm−2 for the oxygen evolution reaction in 1.0 m KOH. The FeCoNiP@P‐rGO electrocatalyst exhibits an outstanding durability toward overall water splitting in alkaline electrolytes, and excellent Faraday efficiency (about 92%) as well. This work provides an insight in proper tuning and the development of appropriate substrates for IMPs and other transition metal compounds toward cost‐effective and high efficiency electrocatalysts for water splitting reactions. [ABSTRACT FROM AUTHOR]

On‐treatment EPID images are contaminated with patient‐generated scattered photons. If this component can be accurately estimated, its effect can be removed, and therefore a corresponding in vivo patient dose estimate will be more accurate. Our group previously developed a "tri‐hybrid" (TH) algorithm to provide fast but accurate estimates of patient‐generated photon scatter. The algorithm uses an analytical method to solve for singly‐scattered photon fluence, a modified Monte Carlo hybrid method to solve for multiply‐scattered photon fluence, and a pencil beam scatter kernel method to solve for electron interaction generated scattered photon fluence. However, for efficient clinical implementation, spatial and energy sampling must be optimized for speed while maintaining overall accuracy. In this work, the most significant sampling issues were examined, including spatial sampling settings for the patient voxel size, the number of Monte Carlo histories used in the modified hybrid MC method, scatter order sampling for the hybrid method, and also a range of energy spectrum sampling (i.e., energy bin sizes). The total predicted patient‐scattered photon fluence entering the EPID was compared with full MC simulation (EGSnrc) for validation. Three phantoms were tested with 6 and 18 MV beam energies, field sizes of 4 × 4, 10 × 10, and 20 × 20 cm2, and source‐to‐imager distance of 140 cm to develop a set of optimal sampling settings. With the recommended sampling, accuracy and precision of the total‐scattered energy fluence of the TH patient scatter prediction method are within 0.9% and 1.2%, respectively, for all test cases compared with full MC simulation results. For the mean energy spectrum across the imaging plane, comparison of TH with full MC simulation showed 95% overlap. This study has optimized sampling settings so that they have minimal impact on patient scatter prediction accuracy while maintaining maximum execution speed, a critical step for future clinical implementation. [ABSTRACT FROM AUTHOR]

In vivo dosimetry methods can verify the prescription dose is delivered to the patient during treatment. Unfortunately, in exit dosimetry, the megavoltage image is contaminated with patient-generated scattered photons. However, estimation and removal of the effect of this fluence improves accuracy of in vivo dosimetry methods. This work develops a 'tri-hybrid' algorithm combining analytical, Monte Carlo (MC) and pencil-beam scatter kernel methods to provide accurate estimates of the total patient-generated scattered photon fluence entering the MV imager. For the multiply-scattered photon fluence, a modified MC simulation method was applied, using only a few histories. From each second- and higher-order interaction site in the simulation, energy fluence entering all pixels of the imager was calculated using analytical methods. For photon fluence generated by electron interactions in the patient (i.e. bremsstrahlung and positron annihilation), a convolution/superposition approach was employed using pencil-beam scatter fluence kernels as a function of patient thickness and air gap distance, superposed on the incident fluence distribution. The total patient-scattered photon fluence entering the imager was compared with a corresponding full MC simulation (EGSnrc) for several test cases. These included three geometric phantoms (water, half-water/half-lung, computed tomography thorax) using monoenergetic (1.5, 5.5 and 12.5 MeV) and polyenergetic (6 and 18 MV) photon beams, 10 × 10 cm2 field, source-to-surface distance 100 cm, source-to-imager distance 150 cm and 40 × 40 cm2 imager. The proposed tri-hybrid method is demonstrated to agree well with full MC simulation, with the average fluence differences and standard deviations found to be within 0.5% and 1%, respectively, for test cases examined here. The method, as implemented here with a single CPU (non-parallelized), takes ∼80 s, which is considerably shorter compared to full MC simulation (∼30 h). This is a promising method for fast yet accurate calculation of patient-scattered fluence at the imaging plane for in vivo dosimetry applications. [ABSTRACT FROM AUTHOR]

Scattered radiation unavoidably generated in the patient will negatively impact both kilovoltage (KV) and megavoltage (MV) imaging applications. Recently, 'hybrid' methods (i.e. combining analytical and Monte Carlo (MC) techniques) are being investigated as a solution to accurately yet quickly calculate the scattered contribution for both KV and MV images. We have developed a customized MC simulation user code for investigating the individual components of patient-scattered photon fluence, which serves as a valuable tool in this area of research. The MC tool is based on the EGSnrc/DOSXYZnrc user code. The IAUSFL flag options associated with subroutine AUSGAB, combined with LATCH tracking, are used to classify the various interactions of particles with the media. Photons are grouped into six different categories: primary, 1st Compton scatter, 1st Rayleigh scatter, multiple scatter, bremsstrahlung, and positron annihilation. We take advantage of the geometric boundary check in DOSXYZnrc, to write exiting photon particle information to a phase-space file. The tool is validated using homogeneous and heterogeneous phantom configurations with monoenergetic and polyenergetic beams under parallel and divergent beam geometry, comparing MC-simulated exit primary fluence and singly-scattered fluence to corresponding analytical calculations. This MC tool has been validated to separately score the primary and scatter fluence components of the KV and MV imaging applications in the field of radiation therapy. The results are acceptable for the various configurations and beam energies tested here. Overall, the mean percentage differences are less than 0.2% and standard deviations less than 1.6%. This will be a critical test instrument for research in photon scatter applications and particularly for the development of hybrid methods, and is freely available from the authors for research purposes.5 [ABSTRACT FROM AUTHOR]

Major depressive disorder is a serious neuropsychiatric disorder with high rates of recurrence and mortality. Many studies have supported that inflammatory processes play a central role in the etiology of depression. Fibroblast growth factor 21 (FGF21), a member of the fibroblast growth factors (FGFs) family, regulates a variety of pharmacological activities, including energy metabolism, glucose and lipid metabolism, and insulin sensitivity. In addition, recent studies showed that the administration of FGF21, a regulator of metabolic function, had therapeutic effects on mood stabilizers, indicating that FGF21 could be a common regulator of the mood response. However, few studies have highlighted the antidepressant effects of FGF21 on lipopolysaccharide (LPS)-induced mice, and the anti-inflammatory mechanism of FGF21 in depression has not yet been elucidated. The purpose of the current study was to determine the antidepressant effects of recombinant human FGF21 (rhFGF21). The effects of rhFGF21 on depression-like behaviors and the inflammatory signaling pathway were investigated in both an LPS-induced mouse model and primary microglia in vitro. The current study demonstrated that LPS induced depressive-like behaviors, upregulated proinflammatory cytokines, and activated microglia in the mouse hippocampus and activated the inflammatory response in primary microglia, while pretreatment with rhFGF21 markedly improved depression-like behavior deficits, as shown by an increase in the total distance traveled and number of standing numbers in the open field test (OFT) and a decrease in the duration of immobility in the tail suspension test (TST) and forced swimming test (FST). Furthermore, rhFGF21 obviously suppressed expression levels of the proinflammatory cytokines interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) and inhibited microglial activation and the nuclear factor-κB (NF-κB) signing pathway. Moreover, coadministration of rhFGF21 with the fibroblast growth factor receptor 1 (FGFR1) inhibitor PD173074 significantly reversed these protective effects, indicating that the antidepressant effects of rhFGF21 occur through FGFR1 activation. Taken together, the results of the current study demonstrated for the first time that exogenous rhFGF21 ameliorated LPS-induced depressive-like behavior by inhibiting microglial expression of proinflammatory cytokines through NF-κB suppression. This new discovery suggests rhFGF21 as a new therapeutic candidate for depression treatment. [ABSTRACT FROM AUTHOR]

This paper focuses on explaining the demographic transition and some of the broad patterns that are associated with it. We present an endogenous growth model that incorporates altruism and son preference within the family as well as gender wage gap and gender wage discrimination in the labour market. We show that with the accumulation of physical capital and human capital, the output share of mental labour increases and the gender wage gap narrows. In the early stages of economic development, gender discrimination is becoming prevalent and the substitution effect of capital accumulation, which raises the cost of child rearing, is dominated by the income effect, so the growth rate of population increases with income. When the degree of gender wage discrimination starts to decline, the increased cost of child rearing induces families to invest more in the human capital of children and the growth rate of the population falls. The quantitative analysis shows that gender wage discrimination is indeed an important contributor to the demographic transition. [ABSTRACT FROM AUTHOR]

Thermal treatment of the substituted tetramethylcyclopentadienes [C5Me4HR] [R?=?n-propyl (1),i-propyl (2), cyclopentyl (3), cyclohexyl (4), and 4-NMe2Ph (5)] with Fe(CO)5gave five new substituted tetramethylcyclopentadienyl dinuclear iron carbonyl complexes, [?5-C5Me4CH2CH2CH3]2Fe2(CO)4(6), [?5-C5Me4CH(CH3)2]2Fe2(CO)4(7), [?5-C5Me4CH(CH2)4]2Fe2(CO)4(8), [?5-C5Me4CH(CH2)5]2Fe2(CO)4(9), and [(?5-C5Me4)(4-NMe2Ph)]2Fe2(CO)4(10). The new complexes were characterized by elemental analysis, IR, and1H NMR spectra. The molecular structures of6,8,9,and10were determined by X-ray single crystal diffraction. [ABSTRACT FROM AUTHOR]

Disruption of the blood-brain barrier (BBB) and the cerebral inflammatory response occurring after traumatic brain injury (TBI) facilitate further brain damage, which leads to long-term complications of TBI. Fibroblast growth factor 20 (FGF20), a neurotrophic factor, plays important roles in brain development and neuronal homeostasis. The aim of the current study was to assess the protective effects of FGF20 on TBI via BBB maintenance. In the present study, recombinant human FGF20 (rhFGF20) reduced neurofunctional deficits, brain edema, Evans blue extravasation and neuroinflammation in a TBI mouse model. In an in vitro TNF-α-induced human brain microvascular endothelial cell (HBMEC) model of BBB disruption, rhFGF20 reduced paracellular permeability and increased trans-endothelial electrical resistance (TEER). Both in the TBI mouse model and in vitro , rhFGF20 increased the expression of proteins composing in BBB-associated tight junctions (TJs) and adherens junctions (AJs), and decreased the inflammatory response, which protected the BBB integrity. Notably, rhFGF20 preserved BBB function by activating the AKT/GSK3β pathway and inhibited the inflammatory response by regulating the JNK/NFκB pathway. Thus, FGF20 is a potential candidate treatment for TBI that protects the BBB by upregulating junction protein expression and inhibiting the inflammatory response. [ABSTRACT FROM AUTHOR]

Iron-based metal phosphides (IMPs) have emerged as a new type of bifunctional electrocatalyst for overall water splitting with high efficiency and good stability. We report IMPs nanoparticles' fabrication with different metal element compositions anchored on phosphorus-doped vertically aligned graphene arrays (IMPs/P-VG), which is successfully achieved by tuning the different phosphates in the electroless plating solution. Compared with other metal ratios of electrocatalysts, Fe 0.5 Co 1.5 Ni 0.5 P/P-VG exhibits the best apparent and intrinsic activity in 1 M KOH, and it also shows good stability up to 12 h without any significant degradation. Moreover, benefiting the unique hierarchical vertical arrays nanostructure of the substrate and the trimetallic phosphides' synergetic effects, the Faraday efficiency of the electrolytic cell based on Fe 0.5 Co 1.5 Ni 0.5 P/P-VG double electrode for the overall water-splitting is up to 90%. This study suggests that proper tuning of the composition of metal elements in IMPs and integrated on compatible substrates can effectively improve the electrocatalytic activity of IMPs for water splitting. [Display omitted] • IMPs nanoparticles with different cationic ratios integrated on P-VG are synthesized by electroless plating. • The tuned cationic ratios of IMPs adjust their catalytic activity towards overall water splitting. • Fe 0.5 Co 1.5 Ni 0.5 P/P-VG exhibits excellent electrocatalytic activity for overall water splitting in alkaline conditions. [ABSTRACT FROM AUTHOR]

Perinatal asphyxia often results in neonatal cerebral hypoxia-ischemia (HI), which is associated with high mortality and severe long-term neurological deficits in newborns. Currently, there are no effective drugs to mitigate the functional impairments post-HI. Previous studies have shown that fibroblast growth factor 21 (FGF21) has a potential neuroprotective effect against brain injury. However, the effect of FGF21 on neonatal HI brain injury is unclear. In the present study, both in vivo and in vitro models were used to assess whether recombinant human FGF21 (rhFGF21) could exert a neuroprotective effect after HI and explore the associated mechanism. The results showed that the rhFGF21 treatment remarkably reduced the infarct volume, ameliorated the body weight and improved the tissue structure after HI in neonatal rats. In addition, the rhFGF21 treatment lengthened the running endurance times in the rotarod test and decreased the mean escape latencies and increased the number of platform crossings in the Morris water maze test at 21 d post-HI insult. In contrast, the FGFR1 inhibitor PD173074 and PI3K inhibitor LY294002 partially reversed these therapeutic effects. In isolated primary cortical neurons, the rhFGF21 treatment protected primary neurons from oxygen-glucose deprivation (OGD) insult by inhibiting neuronal apoptosis and promoting neuronal survival. Both our in vivo and in vitro results reveal that rhFGF21 could inhibit neuronal apoptosis by activating the PI3K/Akt signaling pathway via FGF21/FGFR1/β-klotho complex formation. Therefore, rhFGF21 may be a promising therapeutic agent for promoting functional recovery after HI-induced neonatal brain injury. • rhFGF21 reduces the brain infarct volume and ameliorates the histological structure. • rhFGF21 improves motor and learning disabilities in rats after hypoxia-ischemia. • rhFGF21 activates the PI3K/Akt pathway via FGFR1/β-klotho post hypoxia-ischemia. • rhFGF21 attenuates OGD-induced primary cortical neuronal death. • rhFGF21 protects neurons against OGD injury by inhibiting neuronal apoptosis. [ABSTRACT FROM AUTHOR]

How neuromodulatory transmitters diffuse into the extracellular space remains an unsolved fundamental biological question, despite wide acceptance of the volume transmission model. Here, we report development of a method combining genetically encoded fluorescent sensors with high-resolution imaging and analysis algorithms which permits the first direct visualization of neuromodulatory transmitter diffusion at various neuronal and non-neuronal cells. Our analysis reveals that acetylcholine and monoamines diffuse at individual release sites with a spread length constant of ∼0.75 μm. These transmitters employ varied numbers of release sites, and when spatially close-packed release sites coactivate they can spillover into larger subcellular areas. Our data indicate spatially restricted (i.e., nonvolume) neuromodulatory transmission to be a prominent intercellular communication mode, reshaping current thinking of control and precision of neuromodulation crucial for understanding behaviors and diseases.

Wound healing, especially for diabetic wounds, is a lengthy and complicated process involving interactions and responses at the protein, cell, and tissue levels. Loading of growth factors into a hydrogel to construct a sustained-release system is considered a promising approach to improve wound healing. The present study investigates the effect of thermosensitive heparin-poloxamer (HP) hydrogel-encapsulated recombinant human fibroblast growth factor 21 (rhFGF21) on wound healing in mice with streptozotocin-induced diabetes mellitus. First, we studied the in vitro release of rhFGF21 from the rhFGF21-HP coacervate. The results showed that HP might control the release of rhFGF21. Next, we examined the effect of rhFGF21-HP on skin wound healing in diabetic mice. Our data showed that rhFGF21-HP significantly improved wound closure; promoted granulation, collagen deposition, and re-epithelialization; and enhanced the expression of CD31. Moreover, rhFGF21-HP had obvious advantages in diabetic wound healing. Therefore, the results suggest that the rhFGF21-HP hydrogel polymer plays an important role in skin wound healing. This work provides a suitable sustained-release delivery system that can continuously release rhFGF21 and presents a promising therapeutic strategy for wound healing in patients with diabetes.-Liu, H., Zhao, Y., Zou, Y., Huang, W., Zhu, L., Liu, F., Wang, D., Guo, K., Hu, J., Chen, J., Ye, L., Li, X., Lin, L. Heparin-poloxamer hydrogel-encapsulated rhFGF21 enhances wound healing in diabetic mice.

Various techniques of deep inspiration breath hold (DIBH) have been used to mitigate the likelihood and risk of exposing the heart, an organ-at-risk (OAR) for unintended radiation during left breast radiotherapy. However, issues of reproducibility of these techniques warrant further investigation into the feasibility of detecting the intrusion of an OAR into the treatment field during intra-fractional treatment delivery. The increase of high-dose, low-fraction radiotherapy treatments makes it important to immediately adapt treatment once an OAR is detected in the treatment field. This proof-of-concept implementation includes an algorithm that detects and tracks the motion at the edges of a treatment field and a control algorithm that adapts the treatment aperture according to the motion detected. In accordance to the AAPM Task-Group (TG-132) report, image registration techniques should be verified with virtual and physical phantoms prior to clinical application. Since most OARs move as a result of respiration-induced motion, we have used a lung phantom to generate images of a generic OAR intruding into a treatment field with known velocity. The phantom was programmed to move with sinusoidal and lung patient tumor motion patterns and the accuracy of intrusion tracking and MLC adaptation were benchmarked with the ground truth-programmed motion of the OAR. The motions were recorded with an electronic portal imaging device (EPID). An optimal cluster size of 9  ×  9 motion vectors was found to provide the smallest average absolute position error of 0.3 mm. A strong linear correlation between the adapted MLC leaves and the actual OAR position was observed. The algorithm had a mean position tracking error of  -0.4  ±  0.3 mm and a precision of 1.1 mm. It is possible to adapt MLC leaves based on the motion detected at the edges of the irradiated field, and it would be feasible to shield an unplanned intrusion of an OAR into the treatment field.