In vivo efficacy of phage cocktails against carbapenem resistance Acinetobacter baumannii in the rat pneumonia model.

Acinetobacter baumannii, an opportunistic pathogen, poses a significant threat in intensive care units, leading to severe nosocomial infections. The rise of multi-drug-resistant strains, particularly carbapenem-resistant A. baumannii, has created formidable challenges for effective treatment. Given the prolonged development cycle and high costs associated with antibiotics, phages have garnered clinical attention as an alternative for combating infections caused by drug-resistant bacteria. However, the utilization of phage therapy encounters notable challenges, including the narrow host spectrum, where each phage targets a limited subset of bacteria, increasing the risk of phage resistance development. Additionally, uncertainties in immune system dynamics during treatment hinder tailoring symptomatic interventions based on patient-specific states. In this study, we isolated two A. baumannii phages from wastewater and conducted a comprehensive assessment of their potential applications. This evaluation included sequencing analysis, genome classification, pH and temperature stability assessments, and in vitro bacterial inhibition assays. Further investigations involved analyzing histological and cytokine alterations in rats undergoing phage cocktail treatment for pneumonia. The therapeutic efficacy of the phages was validated, and transcriptomic studies of rat lung tissue during phage treatment revealed crucial changes in the immune system. The findings from our study underscore the potential of phages for future development as a treatment strategy and offer compelling evidence regarding immune system dynamics throughout the treatment process.IMPORTANCEDue to the growing problem of multi-drug-resistant bacteria, the use of phages is being considered as an alternative to antibiotics, and the genetic safety and application stability of phages determine the potential of phage application. The absence of drug resistance genes and virulence genes in the phage genome can ensure the safety of phage application, and the fact that phage can remain active in a wide range of temperatures and pH is also necessary for application. In addition, the effect evaluation of preclinical studies is especially important for clinical application. By simulating the immune response situation during the treatment process through mammalian models, the changes in animal immunity can be observed, and the effect of phage therapy can be further evaluated. Our study provides compelling evidence that phages hold promise for further development as therapeutic agents for Acinetobacter baumannii infections.

Ammonium Additive Engineering in Antisolvents for Improving Perovskite/Charge-Transport-Layer Interfaces toward Efficient Lead-Tin Alloyed Perovskite Solar Cells.

Although significant advancements have been achieved in lead-tin (Pb-Sn) alloyed perovskite solar cells (PSCs), their power conversion efficiency (PCE) remains inferior to that of their Pb-based counterparts, primarily due to higher open-circuit voltage (Voc) losses and lower fill factors (FFs). Herein, we report both perovskite top and bottom interfacial improvements by incorporating a facile fluorophenylethylammonium iodide (p-FPEAI)/ethyl acetate (EA) solution during the film crystal growth. Based on the analysis of perovskite crystallization, film growth, and strain relaxation, the mechanisms behind these interfacial improvements have been well understood. Furthermore, p-FPEAI could reduce the defect density and nonradiative recombination losses, thus attributing to the improved Voc and FF. Finally, the treated device achieved a PCE of 20.14% with a Voc of up to 0.84 V, which is among the highest reported values so far for Pb-Sn alloyed PSCs without additional precursor additives. In addition, the unencapsulated p-FPEAI-treated device maintained its initial efficiency of approximately 92% after being kept in a nitrogen atmosphere for 1 month, in contrast to the control device which retained only 30% of its initial value. Our findings provide a comprehension for understanding the effect of bulky cations as antisolvents on fabricating highly efficient Pb-Sn alloyed perovskite solar cells.

Brain glucose induces tolerance of Cryptococcus neoformans to amphotericin B during meningitis.

Antibiotic tolerance is the ability of a susceptible population to survive high doses of cidal drugs and has been shown to compromise therapeutic outcomes in bacterial infections. In comparison, whether fungicide tolerance can be induced by host-derived factors during fungal diseases remains largely unknown. Here, through a systematic evaluation of metabolite-drug-fungal interactions in the leading fungal meningitis pathogen, Cryptococcus neoformans, we found that brain glucose induces fungal tolerance to amphotericin B (AmB) in mouse brain tissue and patient cerebrospinal fluid via the fungal glucose repression activator Mig1. Mig1-mediated tolerance limits treatment efficacy for cryptococcal meningitis in mice via inhibiting the synthesis of ergosterol, the target of AmB, and promoting the production of inositolphosphorylceramide, which competes with AmB for ergosterol. Furthermore, AmB combined with an inhibitor of fungal-specific inositolphosphorylceramide synthase, aureobasidin A, shows better efficacy against cryptococcal meningitis in mice than do clinically recommended therapies.

Over 19% Efficiency Perovskite Solar Modules by Simultaneously Suppressing Cation Deprotonation and Iodide Oxidation.

Perovskite solar cells (PSCs) based on sputtered nickel oxide (NiOx) hole transport layer have emerged as promising configuration due to their good stability, cost-effectiveness, and scalability. However, the adverse chemical redox reaction at the NiOx/perovskite interface remains an ever-present problem that has not yet been well solved. To address this issue before, the problems that cation deprotonation and iodide oxidation that occurred in precursor solution easily result in the interfacial chemical reaction should be prevented. Hence, we report an efficient strategy to simultaneously suppress the interfacial reaction and stabilize the precursor solution by incorporating a reducing and weakly acidic stabilizer, l-ascorbic acid (l-AA). l-AA can reduce I2 generated in the precursor solution and during the interfacial reaction to I-. Furthermore, the protons ionized by adjacent enol hydroxyl groups in l-AA effectively impede the deprotonation of organic cations in the precursor solution as well as at the NiOx/perovskite interface resulting from the chemical reaction. Attributing to the improved crystallization of the perovskite film and the suppression of the interfacial reaction by l-AA, the inverted PSC based on such good light absorber achieves an impressive power conversion efficiency (PCE) of 22.72% along with a high open-circuit voltage of 1.19 V. Notably, further introducing l-AA into the large-area solar modules by the slot-die coating method in air enables a remarkable PCE of 19.17%, which reaches one of the highest PCEs reported for inverted perovskite solar modules (PSMs) (active area >50 cm2) to date. l-AA located at the buried interface also forms a barrier layer that can prevent undesirable chemical reactions at the NiOx/perovskite interface, significantly enhancing the device stability of solar cells and PSMs. These findings in our work provide important guidance for improving the NiOx/perovskite interface and the fabrication of highly efficient, low-cost, and large-area PSMs.

Highly Efficient and Stable ITO-Free Organic Solar Cells Based on Squaraine N-Doped Quaternary Bulk Heterojunction.

Simultaneously achieving high efficiency and robust device stability remains a significant challenge for organic solar cells (OSCs). Solving this challenge is highly dependent on the film morphology of the bulk heterojunction (BHJ) photoactive blends; however, there is a lack of rational control strategy. Herein, it is shown that the molecular crystallinity and nanomorphology of nonfullerene-based BHJ can be effectively controlled by a squaraine-based doping strategy, leading to an increase in device efficiency from 17.26% to 18.5% when doping 2 wt% squaraine into the PBDB-TF:BTP-eC9:PC71 BM ternary BHJ. The efficiency is further improved to 19.11% (certified 19.06%) using an indium-tin-oxide-free column-patterned microcavity (CPM) architecture. Combined with interfacial modification, CPM quaternary OSC excitingly shows an extrapolated lifetime of ≈23 years based on accelerated aging test, with the mechanism behind enhanced stability well studied. Furthermore, a flexible OSC module with a high and stable efficiency of 15.2% and an overall area of 5 cm2 is successfully fabricated, exhibiting a high average output power for wearable electronics. This work demonstrates that OSCs with new design of BHJ and device architecture are highly promising to be practical relevance with excellent performance and stability.

Optogenetic and pharmacological interventions link hypocretin neurons to impulsivity in mice.

Neurons in the lateral hypothalamus expressing the neuropeptide Hypocretin, also known as orexin, are known critical modulators of arousal stability. However, their role in the different components of the arousal construct such as attention and decision making is poorly understood. Here we study Hypocretin neuronal circuit dynamics during stop action impulsivity in a Go/NoGo task in mice. We show that Hypocretin neuronal activity correlates with anticipation of reward. We then assessed the causal role of Hypocretin neuronal activity using optogenetics in a Go/NoGo task. We show that stimulation of Hypocretin neurons during the cue period dramatically increases the number of premature responses. These effects are mimicked by amphetamine, reduced by atomoxetine, a norepinephrine uptake inhibitor, and blocked by a Hypocretin receptor 1 selective antagonist. We conclude that Hypocretin neurons have a key role in the integration of salient stimuli during wakefulness to produce appropriate and timely responses to rewarding and aversive cues.

Effect of combination drug therapy during cesarean section in preventing postpartum hemorrhage for women with hypertensive disorder complicating pregnancy.

The study was carried out to observe the effect of combination drug therapy during cesarean section in preventing postpartum hemorrhage for women with hypertensive disorder complicating pregnancy (HDCP). The 180 women who had been treated in our hospital for HDCP were enrolled and randomly divided into observation group (sublingual administration of carboprost combined with oxytocin treatment (20IU oxytocin and small pot drip of 10IU oxytocin after delivery) and control group (1mg of carboprost when the fetal head came out and then applied with intramuscular injection of 20IU oxytocin), each containing 90. The comparison of postpartum hemorrhage situation between two groups was carried out. Compared with control group, the observation group had significantly lower intraoperative blood loss and postoperative 1h blood loss, p<0.0, but similar postoperative 2-24h blood loss, p>0.05; in observation, there were 6 cases of postpartum hemorrhage, while the number in control group was 20 cases. The two groups had no difference in blood pressure after treatment, p>0.05.The combination drug therapy during cesarean section is effective and reliable in preventing postpartum hemorrhage for women with HDCP.

Natural and anthropogenic factors and their interactions drive stream community integrity in a North American river basin at a large spatial scale.

Urbanization, agriculture, and other human activities can exert considerable influence on the health and integrity of stream ecosystems. These influences vary greatly over space, time, and scale. We investigated trends in stream biotic integrity over 19 years (1997-2016) in relation to natural and anthropogenic factors in their spatial context using data from a stream biomonitoring program in a region dominated by agricultural land use. Macroinvertebrate and fish diversity and abundance data were used to calculate four multimetric indices (MMIs) that described biotic integrity of streams from 1997 to 2016. Boosted regression trees (BRT), a machine learning technique, were used to model how stream integrity responded to catchment-level natural and anthropogenic drivers including land use, human population density, road density, runoff potential, and natural factors such as latitude and elevation. Neither natural nor anthropogenic factors were consistently more influential on the MMIs. Macroinvertebrate indices were most responsive to time, latitude, elevation, and road density. Fish indices were driven mostly by latitude and longitude, with agricultural land cover among the most influential anthropogenic factors. We concluded that 1) stream biotic integrity was mostly stable in the study region from 1997 to 2016, although macroinvertebrate MMIs had decreased approximately 10% since 2010; 2) stream biotic integrity was driven by a mix of factors including geography, human activity, and variability over yearly time intervals; 3) MMI responses to environmental drivers were nonlinear and often nonmonotonic; 4) MMI composition could influence causal inferences; and 5) although our findings were mostly consistent with the literature on drivers of stream integrity, some commonly seen patterns were not evident. Our findings highlight the utility of large-scale, publicly available spatial data for understanding drivers of stream biodiversity and illustrate some potential pitfalls of large scale, integrative analyses.

Lateral hypothalamic galanin neurons are activated by stress and blunt anxiety-like behavior in mice.

Despite the prevalence of anxiety disorders, the molecular identity of neural circuits underlying anxiety remains unclear. The lateral hypothalamus (LH) is one brain region implicated in the regulation of anxiety, and our recent data found that chemogenetic activation of LH galanin neurons attenuated the stress response to a novel environment as measured by the marble burying test. Thus, we hypothesize that LH galanin neurons may contribute to anxiety-related behavior. We used chemogenetics and fiber photometry to test the ability of LH galanin neurons to influence anxiety and stress-related behavior. Chemogenetic activation of LH galanin neurons significantly decreased anxiety-like behavior in the elevated plus maze, open field test, and light dark test. However, LH galanin activation did not alter restraint stress induced HPA activation or freezing behavior in the fear conditioning paradigm. In vivo calcium monitoring by fiber photometry indicated that LH galanin neurons were activated by anxiogenic and/or stressful stimuli including tail suspension, novel mouse interaction, and predator odor. Further, in a fear conditioning task, calcium transients strongly increased during foot shock, but were not affected by the unconditioned stimulus tone. These data indicate that LH galanin neurons both respond to and modulate anxiety, with no influence on stress induced HPA activation or fear behaviors. Further investigation of LH galanin circuitry and functional mediators of behavioral output may offer a more refined pharmacological target as an alternative to first-line broad pharmacotherapies such as benzodiazepines.

Hyperexcitable arousal circuits drive sleep instability during aging.

Sleep quality declines with age; however, the underlying mechanisms remain elusive. We found that hyperexcitable hypocretin/orexin (Hcrt/OX) neurons drive sleep fragmentation during aging. In aged mice, Hcrt neurons exhibited more frequent neuronal activity epochs driving wake bouts, and optogenetic activation of Hcrt neurons elicited more prolonged wakefulness. Aged Hcrt neurons showed hyperexcitability with lower KCNQ2 expression and impaired M-current, mediated by KCNQ2/3 channels. Single-nucleus RNA-sequencing revealed adaptive changes to Hcrt neuron loss in the aging brain. Disruption of Kcnq2/3 genes in Hcrt neurons of young mice destabilized sleep, mimicking aging-associated sleep fragmentation, whereas the KCNQ-selective activator flupirtine hyperpolarized Hcrt neurons and rejuvenated sleep architecture in aged mice. Our findings demonstrate a mechanism underlying sleep instability during aging and a strategy to improve sleep continuity.

Regulating crystallization dynamics and crystal orientation of methylammonium tin iodide enables high-efficiency lead-free perovskite solar cells.

Tin (Sn)-based perovskite solar cells (PSCs) have attracted much attention because they are more environmentally friendly than lead-based PSCs. However, the fast crystallization of Sn-based perovskite films and the easy oxidation of Sn2+ to Sn4+ hinder the improvement of their efficiency and stability. In this work, ethylammonium bromide (EABr) was added to methylammonium tin iodide (MASnI3) perovskite precursor solution to regulate the crystallization dynamics and improve the film morphology. The results show that the large EA+ ions slow down the crystallization process of Sn-based perovskites and form a smooth perovskite film with high crystallinity, while the added Br- anions further improved the crystallinity and orientation of the perovskite film. Under the combined action of EA+ and Br- ions, the as-produced PSCs achieved a champion power conversion efficiency (PCE) of 9.59%. The EABr additive also retarded the oxidation of Sn2+, and the solar cell device maintained 93% of its initial efficiency after 30 days in a nitrogen-filled glove box without being encapsulated. This work provides a new strategy for the realization of high-efficiency Sn-based PSCs.

Zwitterion-Assisted Crystal Growth of 2D Perovskites with Unfavorable Phase Suppression for High-Performance Solar Cells.

Despite two-dimensional (2D) Ruddlesden-Popper-phase layered perovskites (RPLPs) exhibiting excellent environmental stability, most solar cells based on 2D RPLP films are fabricated in a controlled inert atmosphere. Meanwhile, the poor charge transport of 2D RPLP films owing to the unfavorable phase arrangement and defects limits the efficiency of 2D RPLP solar cells. Here, we fabricate high-efficiency 2D RPLP solar cells in ambient air assisted by a zwitterion (ZW) additive. We show that the ZW additive suppresses the formation of the bottom 2D phases (n ≤ 2) and the top 3D-like phases in 2D RPLP films. These 2D phases usually grow parallel to the substrate and act as trap sites that inhibit charge transport in the vertical direction. The 3D-like phases, on the other hand, aggravate the long-term stability due to the intrinsic instability of MA+ cations. With improved phase distribution, crystal orientation, and reduced trap states in 2D RPLP films, efficient charge transport is obtained. Finally, a record-high open-circuit voltage (Voc) of 1.19 V and a power conversion efficiency of 17.04% with an enhanced stability are achieved for (BA0.9PEA0.1)2MA3Pb4I13-based (n = 4) solar cells fabricated under high humidity (∼65% RH).

Periodic B- and N-doped phenalenyl π-aggregates: unexpected nonlinear optical properties by tuning pancake π-π bonding.

Phenalenyl (PLY) and its derivatives could form one-dimensional π-aggregates through pancake π-π bonding, which would lead to exotic optoelectronic properties. We will highlight the key aspects of the PLY derivatives from the design strategies to exploration of the electronic properties. Here, we primarily construct alternating boron (B)- and nitrogen (N)-doped PLY π-aggregates: dimer[12], trimer[12-1], trimer[12-2], tetramer[12]2, pentamer[12]2-1, pentamer[12]2-2, and hexamer[12]3. The geometric and electronic structures show that the short intermolecular distances of the π-aggregates drive the formation of pancake π-π bonding. Significantly, the molecular structures show periodic changes in the π-aggregates, but the first hyperpolarizabilities (ßtot) present unexpected changes, which are found to increase sharply with increasing even layer thickness due to intermolecular charge transfer. The ßtot value of hexamer[12]3 (5.72 × 104 a.u.) is 6.4 times that of tetramer[12]2 (8.95 × 103 a.u.), and is 22.4 times that of dimer[12] (2.55 × 103 a.u.). Thus, constructing π-aggregates can significantly improve the second-order NLO response, which is mainly due to intermolecular charge transfer through pancake π-π bonding of the interlayers.

Efficient Stabilization and Passivation for Low-Temperature-Processed γ-CsPbI3 Solar Cells.

The inorganic CsPbI3 perovskite has attracted tremendous attention in the photovoltaic fields for its chemical stability and suitable band gap. Generally, CsPbI3 solar cells with decent performances adopted high annealing temperature to form high-quality black-phase perovskite films. The high-temperature process hinders its practical application and further development. Hence, fabricating stable black-phase CsPbI3 at low temperature is imperative and necessary. In this work, a new additive p-xylilenediamine bromide (PhDMADBr) is reported to facilitate the synthesis of solution-processed, high-quality, and stable γ-CsPbI3 films at a surprisingly low temperature of 60 °C. The additive with an appropriate content can effectively improve both the film morphology and crystallinity of γ-CsPbI3 perovskite films. PhDMADBr anchors to the perovskite surface or grain boundaries as a protection through hydrogen bonding between its ammonium cations and CsPbI3. In addition, the Br element introduced by the additive passivates I- vacancies in perovskite films, resulting in the improvement of both phase stability and devices' performance. Finally, the PSCs based on the modified γ-CsPbI3 perovskite film achieve a champion efficiency of 12.71%. Moreover, the device retains 85% of its original efficiency after being kept for 1000 h.

Voltage-independent GluN2A-type NMDA receptor Ca2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in mice.

The NMDA receptor-mediated Ca2+ signaling during simultaneous pre- and postsynaptic activity is critically involved in synaptic plasticity and thus has a key role in the nervous system. In GRIN2-variant patients alterations of this coincidence detection provoked complex clinical phenotypes, ranging from reduced muscle strength to epileptic seizures and intellectual disability. By using our gene-targeted mouse line (Grin2aN615S), we show that voltage-independent glutamate-gated signaling of GluN2A-containing NMDA receptors is associated with NMDAR-dependent audiogenic seizures due to hyperexcitable midbrain circuits. In contrast, the NMDAR antagonist MK-801-induced c-Fos expression is reduced in the hippocampus. Likewise, the synchronization of theta- and gamma oscillatory activity is lowered during exploration, demonstrating reduced hippocampal activity. This is associated with exploratory hyperactivity and aberrantly increased and dysregulated levels of attention that can interfere with associative learning, in particular when relevant cues and reward outcomes are disconnected in space and time. Together, our findings provide (i) experimental evidence that the inherent voltage-dependent Ca2+ signaling of NMDA receptors is essential for maintaining appropriate responses to sensory stimuli and (ii) a mechanistic explanation for the neurological manifestations seen in the NMDAR-related human disorders with GRIN2 variant-meidiated intellectual disability and focal epilepsy.

Self-Powered All-Inorganic Perovskite Photodetectors with Fast Response Speed.

In this manuscript, the inorganic perovskite CsPbI2Br and CsPbIBr2 are investigated as photoactive materials that offer higher stability than the organometal trihalide perovskite materials. The fabrication methods allow anti-solvent processing the CsPbIxBr3-x films, overcoming the poor film quality that always occur in a single-step solution process. The introduced diethyl ether in spin-coating process is demonstrated to be successful, and the effects of the anti-solvent on film quality are studied. The devices fabricated using the methods achieve high-performance, self-powered and the stabilized photodetectors show fast response speed. The results illustrate a great potential of all-inorganic CsPbIxBr3-x perovskites in visible photodetection and provide an effective way to achieve high performance devices with self-powered capability.