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BK polyomavirus (BKPyV) is an opportunistic infectious pathogen that is associated with hemorrhagic cystitis and nephropathy, mainly in transplant recipients and human immunodeficiency virus 1 (HIV-1) infected patients. However, molecular characterization studies of BKPyV in China are rare. This study was designed to elucidate the prevalence and to determine the main subtypes of BKPyV among HIV-1-infected patients in southeastern China. In addition, the increased incidences for BKPyV reactivation were analyzed. The isolated BKPyV DNA was amplified by polymerase chain reaction (PCR) and the specimen sequences were aligned with the reference sequences for phylogenetic analysis. In this study, BKPyV viruria was detected in 64.2% (88/137) of HIV-1-infected patients. Patients in the BKPyV-positive group were more diverse with respect to gender (P = 0.039) and age (P = 0.023) than their counterparts in the BKPyV-negative group, and they had a higher rate of co-infection with tuberculosis (TB) (P = 0.026). Viruria was more commonly found in patients with CD4 counts <200 cells/mm (72.7%) than in those with CD4 counts ≥200 cells/mm (58.5%) (not significant). All sequenced BKPyV isolates belonged to subtype I (13/32) and IV (19/32). A high prevalence of BKPyV reactivation was discovered in patients with HIV-1 infection. Females and elderly individuals, as well as those with a TB co-infection, appeared more susceptible to BKPyV reactivation in this study. BKPyV viruria was found more often and was associated with lower CD4 counts. [ABSTRACT FROM AUTHOR]

An active absorptive frequency selective surface (AFSS) is proposed in this paper, which is comprised of a switchable bandpass screen and a periodic resistive surface separated by a foam layer. The switchable bandpass screen embedded with PIN diodes achieves the shift of transmission and reflection in the operating band by controlling the bias voltage. The resistive surface consists of several resonance loops inserted with lumped resistors. At the both sides of the operating band, the entire AFSS performs as an absorber with the switchable bandpass screen playing the role of ground plane. The absorption bands range from 1.3 to 6 GHz and 9.5 to 12.5 GHz with a transmission window at 8.2 GHz, which can be removed with little impact on the absorbing properties. A prototype of the structure is fabricated to verify the numerical simulation. Moreover, the simulated results also show that the proposed AFSS exhibits stable performance for different polarized waves due to the symmetric structure. [ABSTRACT FROM AUTHOR]

In this paper, a controllable terahertz (THz) metamaterial absorber (MA) is designed with the circuit analog method. Taking advantage of the patterned graphene on SiO 2 /doped Si/polyimide substrates with a gold reflector, the controllable MA achieves perfect absorption at 0.75 THz. The chemical potential of graphene is regulated by controlling the voltage between graphene and doped Si layers. As the chemical potential varies from 0 eV to 0.5 eV, the MA is changed from reflection (<0.37) to absorption (>0.99). The distributions of surface current and electric field are illustrated to analyze the resonant characteristic of patterned graphene. According to the resonant characteristic, we introduce patterned graphene elements with different dimension in a unit cell, which effectively extends the effective absorption bandwidth ( absorption > 0 . 9 ) from 0.67–0.93 THz to 0.52–0.95 THz. Moreover, replacing part of the graphene structure with gold, the switchable MA is turned into a frequency tunable MA. The absorption peak moves from 0.62 THz to 0.92 THz as the chemical potential increases from 0.1 eV to 0.5 eV. These designs overcome limitation of traditional absorbers and exhibit great potentials in many practical applications. [ABSTRACT FROM AUTHOR]

Translation of the expanded (ggggcc) repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA) conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients. [ABSTRACT FROM AUTHOR]

Cell-to-cell transmission of protein aggregates is an emerging theme in neurodegenerative disease. Here, we analyze the dipeptide repeat ( DPR) proteins that form neuronal inclusions in patients with hexanucleotide repeat expansion C9orf72, the most common known cause of amyotrophic lateral sclerosis ( ALS) and frontotemporal lobar degeneration ( FTLD). Sense and antisense transcripts of the (G4C2)n repeat are translated by repeat-associated non- ATG ( RAN) translation in all reading frames into five aggregating DPR proteins. We show that the hydrophobic DPR proteins poly- GA, poly- GP, and poly- PA are transmitted between cells using co-culture assays and cell extracts. Moreover, uptake or expression of poly- GA induces nuclear RNA foci in (G4C2)80-expressing cells and patient fibroblasts, suggesting an unexpected positive feedback loop. Exposure to recombinant poly- GA and cerebellar extracts of C9orf72 patients increases repeat RNA levels and seeds aggregation of all DPR proteins in receiver cells expressing (G4C2)80. Treatment with anti- GA antibodies inhibits intracellular poly- GA aggregation and blocks the seeding activity of C9orf72 brain extracts. Poly- GA-directed immunotherapy may thus reduce DPR aggregation and disease progression in C9orf72 ALS/ FTD. [ABSTRACT FROM AUTHOR]

Intronic hexanucleotide (G4C2) repeat expansions in C9orf72 are genetically associated with frontotemporal lobar degeneration ( FTLD) and amyotrophic lateral sclerosis ( ALS). The repeat RNA accumulates within RNA foci but is also translated into disease characterizing dipeptide repeat proteins ( DPR). Repeat-dependent toxicity may affect nuclear import. hn RNPA3 is a heterogeneous nuclear ribonucleoprotein, which specifically binds to the G4C2 repeat RNA. We now report that a reduction of nuclear hn RNPA3 leads to an increase of the repeat RNA as well as DPR production and deposition in primary neurons and a novel tissue culture model that reproduces features of the C9orf72 pathology. In fibroblasts derived from patients carrying extended C9orf72 repeats, nuclear RNA foci accumulated upon reduction of hn RNPA3. Neurons in the hippocampus of C9orf72 patients are frequently devoid of hn RNPA3. Reduced nuclear hn RNPA3 in the hippocampus of patients with extended C9orf72 repeats correlates with increased DPR deposition. Thus, reduced hn RNPA3 expression in C9orf72 cases leads to increased levels of the repeat RNA as well as enhanced production and deposition of DPR proteins and RNA foci. [ABSTRACT FROM AUTHOR]

An intronic (G 4 C 2) n expansion in C9orf72 causes amyotrophic lateral sclerosis and frontotemporal dementia primarily through gain-of-function mechanisms: the accumulation of sense and antisense repeat RNA foci and dipeptide repeat (DPR) proteins (poly-GA/GP/GR/PA/PR) translated from repeat RNA. To therapeutically block this pathway, we screen a library of 1,430 approved drugs and known bioactive compounds in patient-derived induced pluripotent stem cell-derived neurons (iPSC-Neurons) for inhibitors of DPR expression. The clinically used guanosine/cytidine analogs decitabine, entecavir, and nelarabine reduce poly-GA/GP expression, with decitabine being the most potent. Hit compounds nearly abolish sense and antisense RNA foci and reduce expression of the repeat-containing nascent C9orf72 RNA transcript and its mature mRNA with minimal effects on global gene expression, suggesting that they specifically act on repeat transcription. Importantly, decitabine treatment reduces (G 4 C 2) n foci and DPRs in C9orf72 BAC transgenic mice. Our findings suggest that nucleoside analogs are a promising compound class for therapeutic development in C9orf72 repeat-expansion-associated disorders. [Display omitted] • Screen for DPR modifiers in C9orf72 iPSC-Neurons yields guanosine/cytidine analogs • Decitabine, entecavir, and nelarabine reduce expression of repeat RNA and DPR levels • Decitabine does not act via DNMT and has minimal effects on transcriptome • Decitabine is most potent in vitro and reduces pathology in a C9orf72 mouse model Screening 1,430 approved drugs in patient-derived iPSC-Neurons for inhibitors of dipeptide repeat (DPR) expression in C9orf72 ALS/FTD, Czuppa et al. identify three nucleoside analogs: decitabine, nelarabine, and entecavir. The compounds nearly abolish foci of the (G 4 C 2) n repeat RNA without affecting global gene expression. The findings are validated in transgenic mice. [ABSTRACT FROM AUTHOR]

Minimally invasiveimplants and/or scaffolds integrated with multiplefunctionalities are of interest in the clinical settings. In thispaper, chitosan (CTS) functionalized poly(lactic-co-glycolic acid) (PLGA) microspheres containing a model payload, lysozyme(Lyz), were prepared by a water-in-oil-in-water emulsion method, fromwhich cylindrical shaped rod (5 mm in diameter) was fabricated bysintering the composite microspheres in a mold. High-intensity focusedultrasound (HIFU) was then employed as a unique technique to enableshape memory and payload release effects of the three-dimensional(3-D) structure. It was found that incorporation of CTS into PLGAmicrospheres could regulate the transition temperature Ttransof the microsphere from 45 to 50 °C and affectshape memory ratio of the fabricated cylindrical rod to some extent.Shape memory test and drug release assay proved that HIFU could modulatethe shape recovery process and synchronize the release kinetics ofthe encapsulated Lyz in the rod in a switchable manner. Moreover,the two processes could be manipulated by varying the acoustic powerand insonation duration. Mechanical tests of the microspheres-basedrod before and after ultrasound irradiation revealed its compressiveproperties in the range of trabecular bone. Examination of the degradationbehavior indicated that the introduction of CTS into the PLGA microspheresalso alleviated acidic degradation characteristic of the PLGA-dominantcylindrical rod. With HIFU, this study thus demonstrated the desiredcapabilities of shape recovery and payload release effects integratedin one microspheres-based biodegradable cylindrical structure. [ABSTRACT FROM AUTHOR]

Severe resistance of doxorubicin (DOX) caused by drug efflux and immunosuppression has led to a high treatment failure risk of breast cancer (BC). Compared with the single atom nanozymes, the bi‐single‐atomic nanozymes obtained through sequential single‐atom synthesis strategy in different spaces of the same nanomaterial, can significantly improve the space utilization efficiency and catalytic capacity. In this study, bi‐single‐atom nanozymes (Zn/Cu‐BSAN‐DOX NPs) are designed to reverse BC DOX resistance by causing damage to mitochondria of mesenchymal stem cells (MSCs) and 4T1 cells through reactive oxygen species (ROS) amplification. In situ H2O2 self‐supply is improved by releasing DOX through activating the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs). ROS amplification is triggered by enhanced chemodynamic therapy (CDT) and sonodynamic therapy (SDT) of Zn/Cu‐BSAN, which efficiently reverses the DOX resistance by breaking the hyaluronic acid (HA) barrier and DOX efflux. Furthermore, ROS amplification significantly promotes the immune improvement including DCs maturation, T cell activation, and the polarization of M1 macrophage. In summary, as “hexagonal” anti‐tumor warrior, Zn/Cu‐BSAN‐DOX NPs show great potential for multimodal DOX‐resistant BC therapy, which further expands the new preparation strategy and the clinical anti‐tumor application paradigm of single‐atom nanozymes. [ABSTRACT FROM AUTHOR]

Ion interference including copper (Cu+)/calcium (Ca2+) overload activate cell‐specific death channels, damage mitochondria and disrupt cellular homeostasis, showing great potential in anti‐tumor therapy. However, the complex metabolic environment and the powerful self‐protection of tumors cause clinical failure of ion interference. Thus, metabolic disruption is expected an innovative strategy for the enhancement of ion interference. Herein, CuS‐α‐CHCA&penthiopyrad@CaCO3‐RGD nanoparticles (CCPCR NPs) are prepared to provide a Cu+/Ca2+ dual‐overload anti‐tumor therapy assisted by metabolic‐symbiosis‐destruction strategy, realizing the collapse of tumor self‐protection. Specifically, precise CuS and CaCO3 delivery triggered irreversible Cu+/Ca2+ dual‐overload and reactive oxygen species (ROS) attack toward 4T1 cells. Meanwhile, α‐CHCA and penthiopyrad disturbed the metabolic symbiotic environment by disrupting the TCA cycle and preventing lactate efflux to aggravate intracellular acidosis and promote Fenton‐like reaction of Cu+, enhancing the sensitivity of tumor cells to copper death and Ca2+ overload. Further, aided by the metabolism of symbiosis, the destroyed tumor cells further activate the polarization of M1 macrophages and the maturation and antigen cross‐presentation of dendritic cells (DCs), which further eliminate tumor cells. In summary, an amplified anti‐tumor dual‐ion interference strategy assisted by metabolic symbiotic destruction is established, which is of great significance in improving the clinical effect of ion therapy for tumors. [ABSTRACT FROM AUTHOR]

Pathological scars (PS) are involved in the excessive response of inflammation and overactivation of myofibroblasts. Herein, a novel microneedle (MN) patch based on the adipose‐derived stem cell concentrated conditioned medium (ADSCC‐CM) cross‐linked keratin hydrogel is developed to load triamcinolone acetonide (TA), thereby achieving the dual‐drug delivery of ADSCC‐CM and TA to simultaneously reduce the inflammation and guide myofibroblast behaviors. Results not only confirm the ability of ADSCC‐CM to drive the formation of keratin‐based hydrogel, but also verify the dual‐drug release capacities of the hydrogel‐developed MNs (TA@AC‐MN). Using human hyperplastic scar fibroblast (HSF), the combination of ADSCC‐CM and TA demonstrates a pronounced synergistic effect in mitigating the detrimental effects of the inflammatory microenvironment on HSFs, including suppressing the production of reactive oxygen species and attenuating the expression of inflammatory factors. Compared with the clinically used TA, TA@AC‐MN promotes scar biomimetic repair (i.e., optimizing the proportion of collagen and increasing the tissue tensile strength). This study demonstrates that TA@AC‐MN has the capacity to provide a self‐managing and minimally invasive therapeutic strategy for PS. [ABSTRACT FROM AUTHOR]

• Dox:CS/CMCS-NPs had good physicochemical properties and cytocompatibility. • Dox:CS/CMCS-NPs inhibited the growth of Porphyromonas gingivalis. • Dox:CS/CMCS-NPs inhibited the activation of NLRP3 inflammasome in HGFs. • Dox:CS/CMCS-NPs reduced the expression of IL-1β by inhibiting the NLRP3 inflammasome. A polyelectrolyte complex nanoparticle comprising chitosan (CS) and carboxymethyl chitosan (CMCS) was prepared (CS/CMCS-NPs) by ionic gelation, which was then used as a doxycycline carrier (Dox:CS/CMCS-NPs). The obtained CS/CMCS-NPs and Dox:CS/CMCS-NPs were characterized for various parameters and bacteriostatic ability against Porphyromonas gingivalis. The regulation of related genes and proteins of NLRP3 inflammasome and IL-1β in human gingival fibroblasts (HGFs) was characterized by qRT-PCR, western blotting and ELISA. The results showed that Dox:CS/CMCS-NPs had an orderly morphology and an excellent cytocompatibility. P. gingivalis was strongly inhibited by Dox:CS/CMCS-NPs contrasted with control group. Dox:CS/CMCS-NPs effectively down-regulated both gene and protein levels of NLRP3 inflammasome and IL-1β in HGFs. This study provides a new method for rational application of Dox in the clinical treatment of periodontal disease and a new direction for explaining the mechanism of action of Dox:CS/CMCS-NPs and more drug-carrying nanoparticles. [ABSTRACT FROM AUTHOR]

The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non‐canonical translation of the expanded repeat results in abundant poly‐GA inclusion pathology throughout the CNS. (GA)149‐CFP expression in mice triggers motor deficits and neuroinflammation. Since poly‐GA is transmitted between cells, we investigated the therapeutic potential of anti‐GA antibodies by vaccinating (GA)149‐CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin‐(GA)10 conjugates and pre‐aggregated carrier‐free (GA)15. Only ovalbumin‐(GA)10 immunization induced a strong anti‐GA response. The resulting antisera detected poly‐GA aggregates in cell culture and patient tissue. Ovalbumin‐(GA)10 immunization largely rescued the motor function in (GA)149‐CFP transgenic mice and reduced poly‐GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin‐(GA)10‐immunized poly‐GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/macrophages. Moreover, cytoplasmic TDP‐43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers. Synopsis: The study proposes active immunization targeting poly‐GA as a prevention approach for pre‐symptomatic C9orf72 mutation carriers at risk of developping ALS/FTD. Immunization using Ovalbumin‐(GA)10 largely rescued motor deficits in a poly‐GA mouse model. Ovalbumin‐(GA)10 immunization drives strong anti‐GA response without apparent side effects.Ovalbumin‐(GA)10 immunization reduces motor deficits and poly‐GA inclusions.Ovalbumin‐(GA)10 immunization attenuates neuroinflammation, neuroaxonal damage and reduces cytoplasmic TDP‐43 mislocalization. [ABSTRACT FROM AUTHOR]

New high‐throughput technologies for cell–material interaction studies provide researchers with powerful tools to speed up research in the field of biomaterial–cell interactions. However, sharing technologies is often difficult due to the necessity of specific knowledge and experiences. Engineered surfaces can elucidate effects of surface topography on cell behavior, which is of critical value for gaining control over cellular processes. Here, the translation of a gradient‐based high‐throughput cell screening approach for aligned nano/micro topographies interacting with cells is presented. An aligned topography 96‐well plate is created by upscaling of highly specific gradient technology. The resulting cell culture dishes are compatible with general laboratory and imaging equipment, and the platform allows for studying cell behavior with regard to adhesion and alignment. The challenge lies in increasing the dimensions of the previous 1 × 1 cm gradient topography substrate, to be able to cover the span of a 96‐well plate and translate it into a standardized cell‐screening tool. Adhesion experiments of human bone marrow derived mesenchymal stem cells confirm the standardization, compatibility, and usability of the technology. In the process of using multi‐system imaging and analysis, it becomes apparent that future challenges need to include universally applied data analysis approaches. [ABSTRACT FROM AUTHOR]

Immune activation has been widely recognized to promote anti‐tumor effects in vivo. However, in previous anti‐tumor studies of combined photo/immunotherapy, the tumor apoptosis pathway is widely regarded as an independent process, which led to an incomplete understanding of the anti‐tumor mechanisms of the immune system during phototherapy. Herein, the decisive role of immune activation for the anti‐tumor effect of phototherapy and its specific mechanism, are investigated by preparing a melanin@chlorin e6@hyaluronic acid and oxidized Bletilla striata polysaccharide@NO‐donor (MCH‐OBN) nanoplatform, which integrated significant immune activation by phototherapy. The comparison of anti‐tumor effects between wild‐type mice and immunodeficient mice showed that effective phototherapy provided by the MCH‐OBN can not independently kill tumor cells in vivo, as it significantly depends on the immune activation. Furthermore, the activated immune system is demonstrated to destroy the tumor cell "barrier protection" by inhibiting the growth of cancer‐associated fibroblasts (CAFs), thereby ensuring the damage of heat, reactive oxygen species (ROS), and other components of phototherapy to the tumor. Thus, this work reveals for the first time the biological consequences of immune activation that determine the anti‐tumor effect of phototherapy by regulating CAF proliferation, which is of great significance for optimizing anti‐tumor clinical treatments through phototherapy. [ABSTRACT FROM AUTHOR]

Background: Indoleamine 2, 3-dioxygenase (IDO) is a key enzyme in the degradation of tryptophan (Trp) to kynurenine (Kyn). We measured IDO activity as the Kyn to Trp ratio, and investigated whether IDO could be used to assess prognosis of acquired immune deficiency Sydrome (AIDS) patients with pneumocystis pneumonia (PCP).Methods: The Kyn and Trp concentration were measured by UPLC-MS/MS in plasma samples. A total of 49 AIDS-PCP patients were included in the analysis. Clinical characteristics and Kyn/Trp ratio were compared between survivors and non-survivors.Results: Kyn/Trp ratio was significantly lower after anti-PCP treatment in AIDS patients with PCP (P < 0.0001). Plasma Kyn/Trp ratio was higher in patients with PaO2/FiO2 ≤ 300 mmHg than in those with PaO2/FiO2 > 300 mmHg (P = 0.007). Kyn/Trp ratio, D-dimer and CRP showed much higher AUC for predicting death of AIDS-PCP patients. Kyn/Trp ratio was useful for predicting the mortality of AIDS-PCP due to a significantly higher Kyn/Trp ratio in the non-survivors (P = 0.002). And the high Kyn/Trp ratio group had higher mortality rate than low Kyn/Trp group (32.1% vs. 9.1%, respectively, p = 0.024).Conclusion: Activation of the kynurenine pathway is associated with the severity and fatal outcomes of AIDS patients with pneumocystis pneumonia. [ABSTRACT FROM AUTHOR]

Third-party IME (Input Method Editor) apps are often the preference means of interaction for Android users' input. In this paper, we first discuss the insecurity of IME apps, including the Potentially Harmful Apps (PHAs) and malicious IME apps, which may leak users' sensitive keystrokes. The current defense system, such as I-BOX, is vulnerable to the prefix substitution attack and the colluding attack due to the post-IME nature. We provide a deeper understanding that all the designs with the post-IME nature are subject to the prefix-substitution and colluding attacks. To remedy the above post-IME system's flaws, we propose a new idea, pre-IME, which guarantees that "Is this touch event a sensitive keystroke?" analysis will always access user touch events prior to the execution of any IME app code. We design an innovative TrustZone-based framework named IM-Visor which has the pre-IME nature. Specifically, IM-Visor creates the isolation environment named STIE as soon as a user intends to type on a soft keyboard, then the STIE intercepts,Android event sub translates and analyzes the user's touch input. If the input is sensitive, the translation of keystrokes will be delivered to user apps through a trusted path. Otherwise, IM-Visor replays non-sensitive keystroke touch events for IME apps or replays non-keystroke touch events for other apps. A prototype of IM-Visor has been implemented and tested with several most popular IMEs. The experimental results show that IM-Visor has small runtime overheads. [ABSTRACT FROM AUTHOR]