Dual-ROS Sensitive Moieties Conjugate Inhibits Curcumin Oxidative Degradation for Colitis Precise Therapy.

Curcumin, a natural bioactive polyphenol with diverse molecular targets, is well known for its anti-oxidation and anti-inflammatory potential. However, curcumin exhibits low solubility (<1 µg mL-1), poor tissue-targeting ability, and rapid oxidative degradation, resulting in poor bioavailability and stability for inflammatory therapy. Here, poly(diselenide-oxalate-curcumin) nanoparticle (SeOC-NP) with dual-reactive oxygen species (ROS) sensitive chemical moieties (diselenide and peroxalate ester bonds) is fabricated by a one-step synthetic strategy. The results confirmed that dual-ROS sensitive chemical moieties endowed SeOC-NP with the ability of targeted delivery of curcumin and significantly suppress oxidative degradation of curcumin for high-efficiency inflammatory therapy. In detail, the degradation amount of curcumin for SeOC is about 4-fold lower than that of free curcumin in an oxidative microenvironment. As a result, SeOC-NP significantly enhanced the antioxidant activity and anti-inflammatory efficacy of curcumin in vitro analysis by scavenging intracellular ROS and suppressing the secretion of nitric oxide and pro-inflammatory cytokines. In mouse colitis models, orally administered SeOC-NP can remarkably alleviate the symptoms of IBD and maintain the homeostasis of gut microbiota. This work provided a simple and effective strategy to fabricate ROS-responsive micellar and enhance the oxidation stability of medicine for precise therapeutic inflammation.

The History and Prediction of Prebiotics and Postbiotics: A Patent Analysis.

Prebiotics and postbiotics have gained attention as functional food additives due to their substantial influence on the gut microbiome and potential implications for human health on a broader scale. In addition, the number of patents for these additives has also increased, yet their functional classification has been problematic. In this study, we classified 2215 patents granted from 2001 to 2020 by functionality to enable predictions of future development directions. These patents encompassed subjects as diverse as feed supplementation, regulation of intestinal homeostasis, prevention of gastrointestinal ailments, targeted drug administration and augmentation of drug potency. The progression of patents issued during this time frame could be divided into three phases: occasional accounts prior to 2001, a period from 2001 to 2013 during which an average of 42 patents were issued annually, followed by a surge exceeding 140 patents annually after 2013. The latter increase has indicated that pre- and post-biotics have been recognized as biologically relevant. Patent mining therefore can enable forecasts of the future trajectory of these biologics and provide insights to evaluate their advancement. Moreover, this research is the first attempt to generalize and predict the directions of prebiotics and postbiotics using patent information and offers a comprehensive perspective for the potential utilization of prebiotics and postbiotics across a wide variety of fields.

Improving Time to Antibiotic Administration for Pediatric Oncology Patients With New-Onset Fever.

PURPOSE: Time to antibiotic administration (TTA) in <60 minutes for children with neutropenic fever presenting to an emergency room is associated with reduced incidence of sepsis and intensive care admission. As such, TTA is used as a national quality metric for pediatric oncology patients. At our center, in 2020, 19% of the hospitalized patients with a new fever encounter were receiving antibiotics in <60 minutes, prompting a multidisciplinary approach to reach a goal of >90% in all pediatric patients with cancer with a new fever. METHODS: A multidisciplinary team completed four Plan-Do-Study-Act cycles between March 2021 and September 2023. We implemented education initiatives, an updated handoff smartphrase guiding the on-call team, an antibiotic champion (AC) nursing role, a revised fever plan for handoff, a rapid-response team to address new fevers, and an algorithm for blood culture collection. Data were collected, analyzed, and reported biweekly with feedback sought for delays in TTA. RESULTS: There was a total of 639 new fevers in 329 unique oncology patients. As of September 4, 2023, average TTA decreased from 89 minutes at baseline to 46.4 minutes for more than 12 months. The percentage of patients receiving first dose of antibiotic in <60 minutes also increased from 19% to 93.7%, which was sustained as well. The most effective interventions were creation of the AC role and streamlining the blood culture collection process. CONCLUSION: This project demonstrates the importance of multidisciplinary involvement for providing optimal care. Specific implementation of targeted education, an AC role, and development of an algorithm streamlining the processes led to meaningful targeted improvements. Further analyses will explore the impact of these interventions on patient outcomes.

Self-assembly of H2S-responsive nanoprodrugs based on natural rhein and geraniol for targeted therapy against Salmonella Typhimurium.

Salmonellosis is a globally extensive food-borne disease, which threatens public health and results in huge economic losses in the world annually. The rising prevalence of antibiotic resistance in Salmonella poses a significant global concern, emphasizing an imperative to identify novel therapeutic agents or methodologies to effectively combat this predicament. In this study, self-assembly hydrogen sulfide (H2S)-responsive nanoprodrugs were fabricated with poly(α-lipoic acid)-polyethylene glycol grafted rhein and geraniol (PPRG), self-assembled into core-shell nanoparticles via electrostatic, hydrophilic and hydrophobic interactions, with hydrophilic exterior and hydrophobic interior. The rhein and geraniol are released from self-assembly nanoprodrugs PPRG in response to Salmonella infection, which is known to produce hydrogen sulfide (H2S). PPRG demonstrated stronger antibacterial activity against Salmonella compared with rhein or geraniol alone in vitro and in vivo. Additionally, PPRG was also able to suppress the inflammation and modulate gut microbiota homeostasis. In conclusion, the as-prepared self-assembly nanoprodrug sheds new light on the design of natural product active ingredients and provides new ideas for exploring targeted therapies for specific Enteropathogens. Graphical  illustration for construction of self-assembly nanoprodrugs PPRG and its antibacterial and anti-inflammatory activities on experimental Salmonella infection in mice.

Two-Dimensional Multiferroics with Intrinsic Magnetoelectric Coupling in A-Site Ordered Perovskite Monolayers.

The magnetoelectric coupling effect in multiferroics provides a route to realize the control of magnetism by electric field. Here, we demonstrate the coexistence and coupling of ferroelectricity and ferromagnetism in designed A-site ordered perovskite oxide monolayers by combining symmetry analysis and first-principles calculation. These monolayers all exhibit a layered ordering and tilt distortion, and some of them exhibit rotation or Jahn-Teller distortion simultaneously, leading to the emergence of in-plane ferroelectricity. The Mn-based monolayers exhibit robust ferromagnetism, while some monolayers tend to form E-type spin order due to the splitting of the nearest-neighbor exchange interactions. Whether polarization reversal can lead to magnetization reversal depends on the mode of ferroelectric switching, that is, only the ferroelectric switching that reversing the tilt distortion can lead to magnetization reversal. This work demonstrates the feasibility of controlling the direction of magnetization by electric field in the monolayer limit of perovskites.

Coexistence and Coupling of Spin-Induced Ferroelectricity and Ferromagnetism in Perovskites.

Spin-induced ferroelectricity usually does not occur in perovskites with simple collinear magnetic structures. Here, we demonstrate that in even-layer perovskite systems, some common distortion modes involving octahedral rotation and Jahn-Teller distortion can break the inversion symmetry, allowing the emergence of spin-dependent out-of-plane polarization in a simple magnetic structure. Such spin-induced ferroelectricity is very common in double-perovskite systems and can coexist with ferromagnetism or ferrimagnetism above room temperature. We explain its origin by modifying the spin-dependent p-d hybridization mechanism. Our Letter provides a universal design for two-dimensional multiferroics and enables the control of polarization by means of a magnetic field.

Computational and experimental characterization of isomers of escin-induced renal cytotoxicity by inhibiting heat shock proteins.

Escin is a natural mixture of triterpene saponins, exhibits anti-oedematous properties and promotes venous drainage by oral administration or injection. Upon clinical application of escin, adverse kidney reactions have been reported and the nephrotoxic mechanism responsible for this reaction remains elusive. In the present study, four isomeric escins (ß-form: escin Ia and escin Ib; α-form: isoescin Ia and isoescin Ib) were found severely decreasing the cell viability of human kidney (HK-2) cells. A decline in HK-2 cell viability caused by sodium aescinate (a mixture of four isomers) was reduced after ß-glucuronidase hydrolysis. In addition, sodium aescinate concentration-dependently inhibited the expression level of heat shock proteins (HSPs) in the Madin-Darby Canine Kidney (MDCK) cells. Moreover, with molecular docking and molecular dynamics simulation, these four isomeric escins could directly bind to the ATP-binding domain of HSP70 and HSP90, thus competitively inhibiting the function of HSPs. Escin Ia is bound to HSPs with the lowest binding free energy, which is consistent with the observation that escin Ia most severely decreases HK-2 cell viability. Thus, we demonstrate a heretofore unknown molecular mechanism of escin-induced renal cytotoxicity as well as identify HSPs as potential targets for the renal cytotoxic effect of escin.

Strong and Robust Electrochemical Artificial Muscles by Ionic-Liquid-in-Nanofiber-Sheathed Carbon Nanotube Yarns.

To address the lack of a suitable electrolyte that supports the stable operation of the electrochemical yarn muscles in air, an ionic-liquid-in-nanofibers sheathed carbon nanotube (CNT) yarn muscle is prepared. The nanofibers serve as a separator to avoid the short-circuiting of the yarns and a reservoir for ionic liquid. The ionic-liquid-in-nanofiber-sheathed yarn muscles are strong, providing an isometric stress of 10.8 MPa (about 31 times the skeletal muscles). The yarn muscles are highly robust, which can reversibly contract stably at such conditions as being knotted, wide-range humidity (30 to 90 RH%) and temperature (25 to 70 °C), and long-term cycling and storage in air. By utilizing the accumulated isometric stress, the yarn muscles achieve a high contraction rate of 36.3% s-1 . The yarn muscles are tightly bundled to lift heavy weights and grasp objects. These unique features can make the strong and robust yarn muscles as a desirable actuation component for robotic devices.

Programmable Contractile Actuations of Twisted Spider Dragline Silk Yarns.

The contraction behavior of spider dragline silk upon water exposure has drawn particular interest in developing humidity-responsive smart materials. We report herein that the spider dragline silk yarns with moderate twists can generate much improved lengthwise contraction of 60% or an isometric stress of 11 MPa when wetted by water. Upon the removal of the absorbed water, the dried and contracted spider silk yarns showed programmable contractile actuations. These yarns can be plastically stretched to any specified lengths between the fully contracted state and the state before supercontraction and return to the fully contracted state when wetted. Moreover, the generated isometric stress of these yarns is also programmable, depending on the stretching ratio. The mechanism of the programmable reversible contraction is based on the plastic mechanical property of the dried and contracted spider silk yarns, which can be explained by the variation of the hydrogen bonds and the secondary structures of the proteins in spider dragline silk. Humidity alarm switches, smart doors, and wound healing devices based on the programmable contractile actuations of the spider silk yarns were demonstrated, which provide application scenarios for the supercontraction of spider dragline silk.

Design of Two-Dimensional Multiferroics with Direct Polarization-Magnetization Coupling.

The recent discovery of two-dimensional (2D) ferromagnetism in van der Waals materials has opened the door to the control of 2D magnetism by means of electric field. Here we demonstrate the magnetization reversal through switching polarization in a designed 2D multiferroic oxide by combining group theory analysis and first-principles calculation. We show that ferroelectricity can be induced by a specific octahedral rotation in a perovskite bilayer. Ferromagnetism can be introduced simultaneously by extending the guideline to the B-site ordered double-perovskite bilayer. We have found two coupling mechanisms between polarization and magnetization that enable the reversal of the in-plane magnetization by ferroelectric switching. Our work provides guidelines for the design of 2D multiferroics with intrinsic magnetoelectric coupling and helps to control the 2D magnetism by electric field.

Incerta-thalamic Circuit Controls Nocifensive Behavior via Cannabinoid Type 1 Receptors.

Pain is a source of substantial discomfort. Abnormal activity in both the zona incerta (ZI) and posterior complex of the thalamus (Po) are implicated in neuropathic pain, but their exact roles remain unclear. In particular, the precise cell types and molecular mechanisms of the ZI-Po circuit that regulate nociception are largely uncharacterized. Here, we found that parvalbumin (PV)-positive neuronal projections from the ventral ZI (ZIv) to the Po (ZIv-Po) are critical for promoting nocifensive behaviors, whereas selectively inhibiting ZIv-Po activity reduces nocifensive withdrawal responses. Furthermore, cannabinoid type 1 receptors (CB1Rs) are expressed specifically at ZIv-Po axon terminals in this circuit, and cannabinoids attenuate nocifensive responses through presynaptic inhibition. Selective inhibition of the ZIv-Po circuit or administration of cannabinoids into the Po are sufficient to ameliorate pathological pain. These findings identify the critical role of the ZIv-Po circuit and its modulation by endocannabinoids in controlling nocifensive behaviors.

FondaKIDS III: A long-term retrospective cohort study of fondaparinux for treatment of venous thromboembolism in children.

BACKGROUND: The incidence of venous thromboembolism (VTE) and use of anticoagulation are rising in children, but treatment options remain limited. As a newer anticoagulant, fondaparinux may be a safe and effective alternative with the benefit of once-daily dosing, but there is relatively little data supporting its use. PROCEDURE: This retrospective cohort study describes the long-term dosing, efficacy, and safety of fondaparinux for treatment of VTE in children at a single institution. The study included children <18 years old treated with fondaparinux for VTE between 2008 and 2018. Descriptive statistics were used to present the findings. RESULTS: A total of 277 patients were identified and analyzed in this study. Seventy-six percent of patients reached therapeutic levels with 0 or 1 dose adjustments over a median treatment duration of 93 days. Of the patients included in the efficacy analysis, 91% of patients had improvement in their clot status, including 69% (160/233) with complete resolution and 22% (53/233) with partial resolution. Twenty-six patients (11%) had VTE recurrence, but only seven (3%) of the new thrombi developed while on fondaparinux. Major bleeding occurred in seven patients (2.5%), primarily in patients with underlying medical conditions with increased bleeding risk. Minor bleeding occurred in 53 patients (19%). CONCLUSIONS: This study demonstrates the stable long-term pediatric dosing of fondaparinux with similar efficacy and safety when compared to other anticoagulants. Given its advantages, fondaparinux can be considered a reasonable alternative for treatment of VTE in children.

Luc's Abscess and Temporomandibular Joint Septic Arthritis: Two Rare Sequelae of Acute Otitis Media.

A 5-year-old previously healthy child presented with right-sided otalgia, right facial and temporal swelling, and right jaw pain in the setting of 6 days of low-grade fever. The child had no trauma, vomiting, or prior dental treatments. On physical examination, the patient had facial swelling, erythema, and tenderness over the right temporal region along with trismus, as well as pain on palpation of the right temporomandibular joint (TMJ). A computed tomography scan revealed otitis media, Luc's abscess, and TMJ septic arthritis requiring surgical drainage and intravenous antibiotics. The patient responded well to treatment and recovered without sequelae. Dr. Cardwell Luc first described Luc's abscess in 1913 as a rare complication of middle ear infection leading to an abscess in the infratemporal space. To our knowledge, our case is the first documented case of concurrent Luc's abscess and TMJ septic arthritis in a previously healthy child as complications of acute otitis media. This case highlights 2 rare complications of a common medical condition that pediatric emergency care providers should recognize due to the need for surgical intervention, without which there may be longstanding sequelae.

A novel cortico-intrathalamic circuit for flight behavior.

Flight, an active fear response to imminent threat, is dependent on the rapid risk assessment of sensory information processed by the cortex. The thalamic reticular nucleus (TRN) filters information between the cortex and the thalamus, but whether it participates in the regulation of flight behavior remains largely unknown. Here, we report that activation of parvalbumin-expressing neurons in the limbic TRN, but not those in the sensory TRN, mediates flight. Glutamatergic inputs from the cingulate cortex (Cg) selectively activate the limbic TRN, which in turn inhibits the intermediodorsal thalamic nucleus (IMD). Activation of this Cg→limbic TRN→IMD circuit results in inhibition of the IMD and produces flight behavior. Conversely, removal of inhibition onto the IMD results in more freezing and less flight, suggesting that the IMD may function as a pro-freeze center. Overall, these findings reveal a novel corticothalamic circuit through the TRN that controls the flight response.

A 3D porous polymer monolith-based platform integrated in poly(dimethylsiloxane) microchips for immunoassay.

In this work, we demonstrate the immunocapture and on-line fluorescence immunoassay of protein and virus based on porous polymer monoliths (PPM) in microfluidic devices. Poly(glycidyl methacrylate-co-ethylene glycol dimethacrylate) [poly(GMA-co-EGDMA)] monoliths were successfully synthesized in the polydimethylsiloxane (PDMS) microfluidic channels by in situ UV-initiated free radical polymerization. After surface modification, PPM provides a high-surface area and specific affinity 3D substrate for immunoassays. Combining with well controlled microfluidic devices, the direct immunoassay of IgG and sandwich immunoassay of inactivated H1N1 influenza virus using 5 µL sample has been accomplished, with detection limits of 4 ng mL(-1) and less than 10 pg mL(-1), respectively. The enhanced detection sensitivity is due to both high surface area of PPM and flow-through design. The detection time was obviously decreased mainly due to the shortened diffusion distance and improved convective mass transfer inside the monolith, which accelerates the reaction kinetics between antigen and antibody. This work provides a novel microfluidic immunoassay platform with high efficiency thereby enabling fast and sensitive immunoassay.

Differential cytotoxic effects of denitroaristolochic acid II and aristolochic acids on renal epithelial cells.

Aristolochic acids (AAs), naturally occurring nephrotoxins and rodent carcinogens, are commonly found in medicinal plants such as Radix aristolochiae. The toxicity of AAs is believed to be associated with the formation of promutagenic AA-DNA adducts, and it has also been suggested that the nitro group in AAs might be important in the process. In order to investigate the role of the nitro group in AA-mediated cytotoxicity, the effects of denitroaristolochic acid II (dN-AAII), aristolochic acid II (AAII) and aristolochic acid I (AAI) on renal tubular epithelial Madin-Darby canine kidney (MDCK) cells were examined and compared. The cytotoxicity of AAI, AAII and dN-AAII was found to be time- and concentration-dependent. As determined by MTT assay, AAI was found to be most toxic in MDCK cells upon exposure for 24, 48 and 72h, followed by AAII, and dN-AAII showed the least cytotoxicity. The effect of AAI and AAII on the integrity of cell membrane was found to be similar and appeared to be more prominent than that of dN-AAII. Based on the results obtained from the flow cytometric analysis, significant apoptosis in MDCK cells was observed with AAI and AAII at as low as 25micromol/L following exposure for 24h, whereas significant apoptosis was induced by dN-AAII at a much higher concentration, 300micromol/L, suggesting that both AAI and AAII were significantly more cytotoxic than dN-AAII. In addition, the levels of reactive oxygen species (ROS) were increased following treatment with AAI, AAII and dN-AAII at concentrations of 5, 25 and 25micromol/L, respectively, for 4h. The results suggest that the nitro group plays an important role in AA-mediated cytotoxicity in MDCK cells and increased intracellular ROS levels may be associated, at least in part, with the cell injury observed in MDCK cells.

Development of aptamers specific for potential diagnostic targets in Burkholderia pseudomallei.

Improved diagnostic reagents would be of considerable benefit in enhancing the specificity and sensitivity of rapid assays for Burkholderia pseudomallei, the causative agent of melioidosis. The purpose of this work is to develop aptamers, high affinity RNA-based molecular recognition molecules, which could be used as reagents for identification of the whole organism in assays of biological samples. Data are presented demonstrating the purification of recombinant B. pseudomallei secreted or surface-exposed macromolecules, which have been expressed in Escherichia coli, and the initial stages of aptamer generation using these recombinant proteins. Future studies will focus upon the expansion of this methodology to include other target macromolecules located on or near the outer membrane of this organism.