PLASMODESMATA-LOCATED PROTEIN 6 regulates plasmodesmal function in Arabidopsis vasculature.

Plasmodesmata connect adjoining plant cells, allowing molecules to move between the connected cells for communication and sharing resources. It has been well established that the plant polysaccharide callose is deposited at plasmodesmata, regulating their aperture and function. Among proteins involved in maintaining callose homeostasis, PLASMODESMATA-LOCATED PROTEINSs (PDLPs) promote callose deposition at plasmodesmata. This study explored the function of PDLP5 and PDLP6 in different cell types. We discovered that PDLP5 and PDLP6 are expressed in nonoverlapping cell types in Arabidopsis (Arabidopsis thaliana). The overexpression of PDLP5 and PDLP6 results in the overaccumulation of plasmodesmal callose at different cell interfaces, indicating that PDLP5 and PDLP6 are active in different cell types. We also observed 2 distinct patterns of starch accumulation in mature leaves of PDLP5 and PDLP6 overexpressors. An enzyme-catalyzed proximity labeling approach was used to identify putative functional partners of the PDLPs. We identified SUCROSE SYNTHASE 6 (SUS6) as a functional partner of PDLP6 in the vasculature. We further demonstrated that PDLP6 physically and genetically interacts with SUS6. In addition, CALLOSE SYNTHASE 7 (CALS7) physically interacts with SUS6 and PDLP6. Genetic interaction studies showed that CALS7 is required for PDLP6 function. We propose that PDLP6 functions with SUS6 and CALS7 in the vasculature to regulate plasmodesmal function.

Caloric restriction disrupts the microbiota and colonization resistance.

Diet is a major factor that shapes the gut microbiome1, but the consequences of diet-induced changes in the microbiome for host pathophysiology remain poorly understood. We conducted a randomized human intervention study using a very-low-calorie diet (NCT01105143). Although metabolic health was improved, severe calorie restriction led to a decrease in bacterial abundance and restructuring of the gut microbiome. Transplantation of post-diet microbiota to mice decreased their body weight and adiposity relative to mice that received pre-diet microbiota. Weight loss was associated with impaired nutrient absorption and enrichment in Clostridioides difficile, which was consistent with a decrease in bile acids and was sufficient to replicate metabolic phenotypes in mice in a toxin-dependent manner. These results emphasize the importance of diet-microbiome interactions in modulating host energy balance and the need to understand the role of diet in the interplay between pathogenic and beneficial symbionts.

Integrative splicing-quantitative-trait-locus analysis reveals risk loci for non-small-cell lung cancer.

Splicing quantitative trait loci (sQTLs) have been demonstrated to contribute to disease etiology by affecting alternative splicing. However, the role of sQTLs in the development of non-small-cell lung cancer (NSCLC) remains unknown. Thus, we performed a genome-wide sQTL study to identify genetic variants that affect alternative splicing in lung tissues from 116 individuals of Chinese ancestry, which resulted in the identification of 1,385 sQTL-harboring genes (sGenes) containing 378,210 significant variant-intron pairs. A comprehensive characterization of these sQTLs showed that they were enriched in actively transcribed regions, genetic regulatory elements, and splicing-factor-binding sites. Moreover, sQTLs were largely distinct from expression quantitative trait loci (eQTLs) and showed significant enrichment in potential risk loci of NSCLC. We also integrated sQTLs into NSCLC GWAS datasets (13,327 affected individuals and 13,328 control individuals) by using splice-transcriptome-wide association study (spTWAS) and identified alternative splicing events in 19 genes that were significantly associated with NSCLC risk. By using functional annotation and experiments, we confirmed an sQTL variant, rs35861926, that reduced the risk of lung adenocarcinoma (rs35861926-T, OR = 0.88, 95% confidence interval [CI]: 0.82-0.93, p = 1.87 × 10-5) by promoting FARP1 exon 20 skipping to downregulate the expression level of the long transcript FARP1-011. Transcript FARP1-011 promoted the migration and proliferation of lung adenocarcinoma cells. Overall, our study provided informative lung sQTL resources and insights into the molecular mechanisms linking sQTL variants to NSCLC risk.

A conserved protein inhibitor brings under check the activity of RNase E in cyanobacteria.

The bacterial ribonuclease RNase E plays a key role in RNA metabolism. Yet, with a large substrate spectrum and poor substrate specificity, its activity must be well controlled under different conditions. Only a few regulators of RNase E are known, limiting our understanding on posttranscriptional regulatory mechanisms in bacteria. Here we show that, RebA, a protein universally present in cyanobacteria, interacts with RNase E in the cyanobacterium Anabaena PCC 7120. Distinct from those known regulators of RNase E, RebA interacts with the catalytic region of RNase E, and suppresses the cleavage activities of RNase E for all tested substrates. Consistent with the inhibitory function of RebA on RNase E, depletion of RNase E and overproduction of RebA caused formation of elongated cells, whereas the absence of RebA and overproduction of RNase E resulted in a shorter-cell phenotype. We further showed that the morphological changes caused by altered levels of RNase E or RebA are dependent on their physical interaction. The action of RebA represents a new mechanism, potentially conserved in cyanobacteria, for RNase E regulation. Our findings provide insights into the regulation and the function of RNase E, and demonstrate the importance of balanced RNA metabolism in bacteria.

Both Las17-binding sites on Arp2/3 complex are important for branching nucleation and assembly of functional endocytic actin networks in S. cerevisiae.

Arp2/3 complex nucleates branched actin filaments that drive membrane invagination during endocytosis and leading-edge protrusion in lamellipodia. Arp2/3 complex is maximally activated in vitro by binding of a WASP family protein to two sites-one on the Arp3 subunit and one spanning Arp2 and ARPC1-but the importance of each site in the regulation of force-producing actin networks is unclear. Here, we identify mutations in budding yeast Arp2/3 complex that decrease or block engagement of Las17, the budding yeast WASP, at each site. As in the mammalian system, both sites are required for maximal activation in vitro. Dimerization of Las17 partially restores activity of mutations at both CA-binding sites. Arp2/3 complexes defective at either site assemble force-producing actin networks in a bead motility assay, but their reduced activity hinders motility by decreasing actin assembly near the bead surface and by failing to suppress actin filament bundling within the networks. While even the most defective Las17-binding site mutants assembled actin filaments at endocytic sites, they showed significant internalization defects, potentially because they lack the proper architecture to drive plasma membrane remodeling. Together, our data indicate that both Las17-binding sites are important to assemble functional endocytic actin networks in budding yeast, but Arp2/3 complex retains some activity in vitro and in vivo even with a severe defect at either Las17-binding site.

Nutrition-dependent juvenile hormone sensitivity promotes flight-muscle degeneration during the aphid dispersal-reproduction transition.

In insects, the loss of flight typically involves a dispersal-reproduction transition, but the underlying molecular mechanisms remain poorly understood. In the parthenogenetic pea aphid Acyrthosiphon pisum, winged females undergo flight-muscle degeneration after flight and feeding on new host plants. Similarly, topical application of a juvenile hormone (JH) mimic to starved aphids also induces flight-muscle degeneration. We found that feeding preferentially upregulated the expression of the JH receptor gene Met and a JH-inducible gene, Kr-h1, in the flight muscles, and, thus, enhanced tissue-specific JH sensitivity and signaling. RNAi-mediated knockdown of Kr-h1 prevented flight-muscle degeneration. Likewise, blocking nutritional signals by pharmacological inhibition of the target of rapamycin complex 1 (TORC1) impaired JH sensitivity of the flight muscles in feeding aphids and subsequently delayed muscle degeneration. RNA-sequencing analysis revealed that enhanced JH signaling inhibited the transcription of genes involved in the tricarboxylic acid cycle, likely resulting in reduction of the energy supply, mitochondrial dysfunction and muscle-fiber breakdown. This study shows that nutrient-dependent hormone sensitivity regulates developmental plasticity in a tissue-specific manner, emphasizing a relatively underappreciated mechanism of hormone sensitivity in modulating hormone signaling.

Reducing false positive rate of docking-based virtual screening by active learning.

Machine learning-based scoring functions (MLSFs) have become a very favorable alternative to classical scoring functions because of their potential superior screening performance. However, the information of negative data used to construct MLSFs was rarely reported in the literature, and meanwhile the putative inactive molecules recorded in existing databases usually have obvious bias from active molecules. Here we proposed an easy-to-use method named AMLSF that combines active learning using negative molecular selection strategies with MLSF, which can iteratively improve the quality of inactive sets and thus reduce the false positive rate of virtual screening. We chose energy auxiliary terms learning as the MLSF and validated our method on eight targets in the diverse subset of DUD-E. For each target, we screened the IterBioScreen database by AMLSF and compared the screening results with those of the four control models. The results illustrate that the number of active molecules in the top 1000 molecules identified by AMLSF was significantly higher than those identified by the control models. In addition, the free energy calculation results for the top 10 molecules screened out by the AMLSF, null model and control models based on DUD-E also proved that more active molecules can be identified, and the false positive rate can be reduced by AMLSF.

Decreased AMPK/SIRT1/PDK4 induced by androgen excess inhibits human endometrial stromal cell decidualization in PCOS.

Polycystic ovary syndrome (PCOS) is a complex common endocrine disorder affecting women of reproductive age. Ovulatory dysfunction is recognized as a primary infertile factor, however, even when ovulation is medically induced and restored, PCOS patients continue to experience reduced cumulative pregnancy rates and a higher spontaneous miscarriage rate. Hyperandrogenism, a hallmark feature of PCOS, affects ovarian folliculogenesis, endometrial receptivity, and the establishment and maintenance of pregnancy. Decidualization denotes the transformation that the stromal compart of the endometrium must undergo to accommodate pregnancy, driven by the rising progesterone levels and local cAMP production. However, studies on the impact of hyperandrogenism on decidualization are limited. In this study, we observed that primary endometrial stromal cells from women with PCOS exhibit abnormal responses to progesterone during in vitro decidualization. A high concentration of testosterone inhibits human endometrial stromal cells (HESCs) decidualization. RNA-Seq analysis demonstrated that pyruvate dehydrogenase kinase 4 (PDK4) expression was significantly lower in the endometrium of PCOS patients with hyperandrogenism compared to those without hyperandrogenism. We also characterized that the expression of PDK4 is elevated in the endometrium stroma at the mid-secretory phase. Artificial decidualization could enhance PDK4 expression, while downregulation of PDK4 leads to abnormal decidualization both in vivo and in vitro. Mechanistically, testosterone excess inhibits IGFBP1 and PRL expression, followed by phosphorylating of AMPK that stimulates PDK4 expression. Based on co-immunoprecipitation analysis, we observed an interaction between SIRT1 and PDK4, promoting glycolysis to facilitate decidualization. Restrain of AR activation resumes the AMPK/SIRT1/PDK4 pathway suppressed by testosterone excess, indicating that testosterone primarily acts on decidualization through AR stimulation. Androgen excess in the endometrium inhibits decidualization by disrupting the AMPK/SIRT1/PDK4 signaling pathway. These data demonstrate the critical roles of endometrial PDK4 in regulating decidualization and provide valuable information for understanding the underlying mechanism during decidualization.

Large Polarization Near 50 µC/cm2 in a Single Unit Cell Layer SrTiO3.

The generally nonpolar SrTiO3 has attracted more attention recently because of its possibly induced novel polar states and related paraelectric-ferroelectric phase transitions. By using controlled pulsed laser deposition, high-quality, ultrathin, and strained SrTiO3 layers were obtained. Here, transmission electron microscopy and theoretical simulations have unveiled highly polar states in SrTiO3 films even down to one unit cell at room temperature, which were stabilized in the PbTiO3/SrTiO3/PbTiO3 sandwich structures by in-plane tensile strain and interfacial coupling, as evidenced by large tetragonality (∼1.05), notable polar ion displacement (0.019 nm), and thus ultrahigh spontaneous polarization (up to ∼50 µC/cm2). These values are nearly comparable to those of the strong ferroelectrics as the PbZrxTi1-xO3 family. Our findings provide an effective and practical approach for integrating large strain states into oxide films and inducing polarization in nonpolar materials, which may broaden the functionality of nonpolar oxides and pave the way for the discovery of new electronic materials.

A Roadmap for Ferroelectric-Antiferroelectric Phase Transition.

Antiferroelectric materials have shown great potential in electronic devices benefiting from the reversible phase transition between ferroelectric and antiferroelectric phases. Understanding the dipole arrangements and clear phase transition pathways is crucial for design of antiferroelectric materials-based energy storage and conversion devices. However, the specific phase transition details remain largely unclear and even controversial to date. Here, we have grown a series of PbZrO3 on SrTiO3 substrates and elucidated the fine atom structures and phase transition pathways using atomic-resolution transmission electron microscopy. Specifically, a roadmap for ferroelectric to antiferroelectric phase transitions, here with increasing film thickness, is determined as ferroelectric rhombohedral (R3c)-ferroelectric monoclinic (Pc)-ferrielectric orthorhombic (Ima2)-antiferroelectric orthorhombic (Pbam), where Pc and Ima2 phases act as structural bridges. Moreover, the phase transition pathway is strongly related to the synergistic effect of oxygen octahedral tilting and cation displacement. These findings provide an insightful understanding for the theories and related properties of antiferroelectrics.

Rapid discrimination of four Salmonella enterica serovars: A performance comparison between benchtop and handheld Raman spectrometers.

Foodborne illnesses, particularly those caused by Salmonella enterica with its extensive array of over 2600 serovars, present a significant public health challenge. Therefore, prompt and precise identification of S. enterica serovars is essential for clinical relevance, which facilitates the understanding of S. enterica transmission routes and the determination of outbreak sources. Classical serotyping methods via molecular subtyping and genomic markers currently suffer from various limitations, such as labour intensiveness, time consumption, etc. Therefore, there is a pressing need to develop new diagnostic techniques. Surface-enhanced Raman spectroscopy (SERS) is a non-invasive diagnostic technique that can generate Raman spectra, based on which rapid and accurate discrimination of bacterial pathogens could be achieved. To generate SERS spectra, a Raman spectrometer is needed to detect and collect signals, which are divided into two types: the expensive benchtop spectrometer and the inexpensive handheld spectrometer. In this study, we compared the performance of two Raman spectrometers to discriminate four closely associated S. enterica serovars, that is, S. enterica subsp. enterica serovar dublin, enteritidis, typhi and typhimurium. Six machine learning algorithms were applied to analyse these SERS spectra. The support vector machine (SVM) model showed the highest accuracy for both handheld (99.97%) and benchtop (99.38%) Raman spectrometers. This study demonstrated that handheld Raman spectrometers achieved similar prediction accuracy as benchtop spectrometers when combined with machine learning models, providing an effective solution for rapid, accurate and cost-effective identification of closely associated S. enterica serovars.

Mitochondria-derived peptide is an effective target for treating streptozotocin induced painful diabetic neuropathy through induction of activated protein kinase/peroxisome proliferator-activated receptor gamma coactivator 1alpha -mediated mitochondrial biogenesis.

Painful Diabetic Neuropathy (PDN) is a common diabetes complication that frequently causes severe hyperalgesia and allodynia and presents treatment challenges. Mitochondrial-derived peptide (MOTS-c), a novel mitochondrial-derived peptide, has been shown to regulate glucose metabolism, insulin sensitivity, and inflammatory responses. This study aimed to evaluate the effects of MOTS-c in streptozocin (STZ)-induced PDN model and investigate the putative underlying mechanisms. We found that endogenous MOTS-c levels in plasma and spinal dorsal horn were significantly lower in STZ-treated mice than in control animals. Accordingly, MOTS-c treatment significantly improves STZ-induced weight loss, elevation of blood glucose, mechanical allodynia, and thermal hyperalgesia; however, these effects were blocked by dorsomorphin, an adenosine monophosphate-activated protein kinase (AMPK) inhibitor. In addition, MOTS-c treatment significantly enhanced AMPKα1/2 phosphorylation and PGC-1α expression in the lumbar spinal cord of PDN mice. Mechanistic studies indicated that MOTS-c significantly restored mitochondrial biogenesis, inhibited microglia activation, and decreased the production of pro-inflammatory factors, which contributed to the alleviation of pain. Moreover, MOTS-c decreased STZ-induced pain hypersensitivity in PDN mice by activating AMPK/PGC-1α signaling pathway. This provides the pharmacological and biological evidence for developing mitochondrial peptide-based therapeutic agents for PDN.

Integrative analyses of N6-methyladenosine-associated single-nucleotide polymorphisms (m6A-SNPs) identify tumor suppressor gene AK9 in lung cancer.

N6 -methyladenosine (m6 A) modification has been identified as one of the most important epigenetic regulation mechanisms in the development of human cancers. However, the association between m6 A-associated single-nucleotide polymorphisms (m6 A-SNPs) and lung cancer risk remains largely unknown. Here, we identified m6 A-SNPs and examined the association of these m6 A-SNPs with lung cancer risk in 13,793 lung cancer cases and 14,027 controls. In silico functional annotation was used to identify causal m6 A-SNPs and target genes. Furthermore, methylated RNA immunoprecipitation and quantitative real-time polymerase chain reaction (MeRIP-qPCR) assay was performed to assess the m6 A modification level of different genotypes of the causal SNP. In vitro assays were performed to validate the potential role of the target gene in lung cancer. A total of 8794 m6 A-SNPs were detected, among which 397 SNPs in nine susceptibility loci were associated with lung cancer risk, including six novel loci. Bioinformatics analyses indicated that rs1321328 in 6q21 was located around the m6 A modification site of AK9 and significantly reduced AK9 expression (ß = -0.15, p = 2.78 × 10-8 ). Moreover, AK9 was significantly downregulated in lung cancer tissues than that in adjacent normal tissues of samples from the Cancer Genome Atlas and Nanjing Lung Cancer Cohort. MeRIP-qPCR assay suggested that C allele of rs1321328 could significantly decrease the m6 A modification level of AK9 compared with G allele. In vitro assays verified the tumor-suppressing role of AK9 in lung cancer. These findings shed light on the pathogenic mechanism of lung cancer susceptibility loci linked with m6 A modification.

Low Intake of Total Antioxidant Nutrients as a Risk Factor for Incident Dementia in Older Adults: The Shanghai Aging Study.

INTRODUCTION: Previous longitudinal studies reported the impact of antioxidant nutrients (ANs) on cognitive impairment in the older population, but the conclusions were inconsistent. This study aimed to verify the hypothesis that dietary intake of total AN was associated with incident dementia among older individuals. METHODS: Community residents without dementia aged ≥60 years were prospectively followed up for an average of 5.2 years in the Shanghai Aging Study. At baseline, daily intakes of total dietary AN (the sum of carotene, vitamin C, vitamin E, lutein, and flavonoids) and energy were calculated based on an interviewer-administered food frequency questionnaire measuring the dietary intake over the past 1 year for each participant. A battery of neuropsychological tests was used to evaluate cognitive function, and a consensus diagnosis of dementia was made according to the DSM-IV criteria at baseline and follow-up. RESULTS: Among 1,550 dementia-free participants, 135 (8.7%) incident dementia cases were identified during the average of 5.2 years of follow-up. Participants with low AN intake (<112 mg/day) had a significantly higher risk of incident dementia than those with high AN intake (≥112 mg/day) (hazard ratio 1.87, 95% confidence interval 1.26-2.77) after adjusting for age, gender, education, obesity, APOE-ε4, hypertension, diabetes, depression, baseline Mini-Mental State Examination score, and total energy intake. The significant association of total AN intake with incident dementia was only found in individuals ≥70 years. CONCLUSION: Low total AN intake may be a risk factor for incident dementia among older adults. Maintaining sufficient AN intake may be beneficial against age-related cognitive decline.

A Time-Interval Strategy to Prepare Porous SiO2 Spheres with Adjustable Core-Shell Ratio for Multiple Guest Loading.

Porous microspheres with desired pore size and distribution are in high demand for loading various guest materials, especially various pollutants that are several nanometers in size or stably suspended in liquid. Herein, multilevel porous SiO2 microspheres with arbitrarily adjustable core-shell ratios are prepared by solely regulating the time interval between the start of the hydrolysis reaction and the addition of organic solvent. The core-shell ratio of the SiO2 microspheres increases gradually with prolongation of the addition time interval; meanwhile, the specific surface area can be adjusted from 543.2 m2 g-1 to 992.9 m2 g-1, and the average pore diameter varies from 2.3 to 5.7 nm together with a high pore volume reaching 0.91 cm3 g-1. Moreover, the hierarchical core-shell SiO2 microspheres with an adjustable core-shell ratio, a large specific surface area, and a multilevel pore size could be obtained on a large scale. These SiO2 microspheres demonstrate excellent performance in coloading platinum nanoparticles and various dye molecules, suggesting their great potential in treating various pollutants in printing and dyeing wastewater.

Photothermal Conversion Perylene-Based Metal-Organic Framework with Panchromatic Absorption Bandwidth across the Visible to Near-Infrared.

Recently, facilely designable metal-organic frameworks have gained attention in the construction of photothermal conversion materials. Nonetheless, most of the previously reported photothermal conversion metal-organic frameworks exhibit limited light absorption capabilities. In this work, a distinctive metal-organic framework with heterogeneous periodic alternate spatial arrangements of metal-oxygen clusters and perylene-based derivative molecules was prepared by in situ synthesis. The building blocks in this inimitable structure behave as both electron donors and electron acceptors, giving rise to the significant inherent charge transfer in this crystalline material, resulting in a narrow band gap with excellent panchromatic absorption, with the ground state being the charge transfer state. Moreover, it can retain excellent air-, photo-, and water-stability in the solid state. The excellent stability and broad light absorption characteristics enable the effective realization of near-infrared (NIR) photothermal conversion, including infrequent NIR-II photothermal conversion, in this perylene-based metal-organic framework.

Mechanical Grinding-Induced Intermolecular Charge Transfer for Near-Infrared Photothermal Conversion.

In this study, charge-transfer-type compounds comprising synthesized naphthalenediimide derivative (H4NDISA) or its Pb-based coordination polymer (Pb-NDISA) and suitable primary or secondary amine organic molecules were prepared by the solvent-free mechanical grinding method. The coloration phenomenon arising from charge transfer during grinding serves as a discriminative tool for distinguishing various organic guest molecules. The porous structure of Pb-NDISA crystals facilitates the infiltration of guest molecules and contributes to the preservation of the intermolecular charge transfer state. Moreover, the intermolecular charge transfer induced by grinding exhibits remarkable stability in an ambient atmosphere, underscoring the pivotal role of well-ordered molecules in the mechanical grinding procedure. This mechanochromic phenomenon holds promise for the detection and sensing of organic molecules, while the exceptional charge-transfer absorption characteristics offer the potential for efficient near-infrared photothermal conversion.

MXene-Coated Ion-Selective Electrode Sensors for Highly Stable and Selective Lithium Dynamics Monitoring.

Lithium holds immense significance in propelling sustainable energy and environmental systems forward. However, existing sensors used for lithium monitoring encounter issues concerning their selectivity and long-term durability. Addressing these challenges is crucial to ensure accurate and reliable lithium measurements during the lithium recovery processes. In response to these concerns, this study proposes a novel approach involving the use of an MXene composite membrane with incorporated poly(sodium 4-styrenesulfonate) (PSS) as an antibiofouling layer on the Li+ ion selective electrode (ISE) sensors. The resulting MXene-PSS Li+ ISE sensor demonstrates exceptional electrochemical performance, showcasing a superior slope (59.42 mV/dec), lower detection limit (10-7.2 M), quicker response time (∼10 s), higher selectivity to Na+ (-2.37) and K+ (-2.54), and reduced impedance (106.9 kΩ) when compared to conventional Li+ ISE sensors. These improvements are attributed to the unique electronic conductivity and layered structure of the MXene-PSS nanosheet coating layer. In addition, the study exhibits the long-term accuracy and durability of the MXene-PSS Li+ ISE sensor by subjecting it to real wastewater testing for 14 days, resulting in sensor reading errors of less than 10% when compared to laboratory validation results. This research highlights the great potential of MXene nanosheet coatings in advancing sensor technology, particularly in challenging applications, such as detecting emerging contaminants and developing implantable biosensors. The findings offer promising prospects for future advancements in sensor technology, particularly in the context of sustainable energy and environmental monitoring.

α4 nicotinic receptors on GABAergic neurons mediate a cholinergic analgesic circuit in the substantia nigra pars reticulata.

Nicotinic acetylcholine receptors (nAChRs) regulate pain pathways with various outcomes depending on receptor subtypes, neuron types, and locations. But it remains unknown whether α4ß2 nAChRs abundantly expressed in the substantia nigra pars reticulata (SNr) have potential to mitigate hyperalgesia in pain states. We observed that injection of nAChR antagonists into the SNr reduced pain thresholds in naïve mice, whereas injection of nAChR agonists into the SNr relieved hyperalgesia in mice, subjected to capsaicin injection into the lower hind leg, spinal nerve injury, chronic constriction injury, or chronic nicotine exposure. The analgesic effects of nAChR agonists were mimicked by optogenetic stimulation of cholinergic inputs from the pedunculopontine nucleus (PPN) to the SNr, but attenuated upon downregulation of α4 nAChRs on SNr GABAergic neurons and injection of dihydro-ß-erythroidine into the SNr. Chronic nicotine-induced hyperalgesia depended on α4 nAChRs in SNr GABAergic neurons and was associated with the reduction of ACh release in the SNr. Either activation of α4 nAChRs in the SNr or optogenetic stimulation of the PPN-SNr cholinergic projection mitigated chronic nicotine-induced hyperalgesia. Interestingly, mechanical stimulation-induced ACh release was significantly attenuated in mice subjected to either capsaicin injection into the lower hind leg or SNI. These results suggest that α4 nAChRs on GABAergic neurons mediate a cholinergic analgesic circuit in the SNr, and these receptors may be effective therapeutic targets to relieve hyperalgesia in acute and chronic pain, and chronic nicotine exposure.

Face-down positioning or posturing after pars plana vitrectomy for macula-involving rhegmatogenous retinal detachments.

BACKGROUND: A macula-involving rhegmatogenous retinal detachment (RRD) is one of the most common ophthalmic surgical emergencies and causes significant visual morbidity. Pars plana vitrectomy (PPV) with gas tamponade is often performed to repair primary macula-involving RRDs with a high rate of anatomical retinal reattachment. It has been advocated by some ophthalmologists that face-down positioning after PPV and gas tamponade helps reduce postoperative retinal displacement. Retinal displacement can cause metamorphopsia and binocular diplopia. OBJECTIVES: The primary objective of this review is to determine whether face-down positioning reduces the risk of retinal displacement following PPV and gas tamponade for primary macula-involving RRDs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (which contains the Cochrane Eyes and Vision Trials Register) (2022, Issue 11), MEDLINE (January 1946 to 28 November 2022), Embase.com (January 1947 to 28 November 2022), PubMed (1948 to 28 November 2022), Latin American and Caribbean Health Sciences Literature database (1982 to 28 November 2022), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We did not use any date or language restrictions in the electronic search. We last searched the electronic databases on 28 November 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which face-down positioning was compared with no positioning or another form of positioning following PPV and gas tamponade for primary macula-involving RRDs. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and assessed the certainty of the body of evidence for the prespecified outcomes using the GRADE approach. MAIN RESULTS: We identified three RCTs (369 eyes of 368 participants) that met the eligibility criteria. Two RCTs provided data on postoperative retinal displacement, one reported on postoperative distortion and quality of life outcomes, two on postoperative best-corrected visual acuity (BCVA) in logMAR, and two on postoperative ocular adverse events such as outer retinal folds. Study characteristics and risk of bias All the trials involved predominantly male participants (range: 68% to 72%). Only one trial provided race and ethnicity information, was registered on a trial registry, and reported funding sources. Using the RoB 2 tool, we assessed the risk of bias for proportion of eyes with retinal displacement, mean change in visual acuity, objective distortion scores, quality of life assessments, and ocular adverse events, with most domains judged to be at low risk of bias. Findings Immediate face-down positioning may result in a lower proportion of participants with postoperative retinal displacement compared with support-the-break positioning at six months (risk ratio [RR] 0.73, 95% confidence interval [CI] 0.54 to 0.99; 1 RCT; 239 eyes of 239 participants; very low certainty evidence). One study found no evidence of a difference in BCVA at three months when comparing postoperative face-up with face-down positioning with or without perfluorocarbon liquid (mean difference [MD] -0.03, 95% CI -0.09 to 0.02; I2 = 0; 56 eyes of 56 participants; very low certainty evidence). Immediate face-down positioning appears to have little to no effect on postoperative distortion scores at week 26 (MD 1.80, 95% CI -1.92 to 5.52; 1 RCT; 219 eyes of 219 participants; very low certainty evidence) and postoperative quality of life assessment scores at week 26 (MD -1.80, 95% CI -5.52 to 1.92; 1 RCT; 217 eyes of 217 participants; very low certainty evidence). Adverse events One study that enrolled 262 participants with macula-involving RRDs suggested that immediate face-down positioning after PPV and gas tamponade may reduce the ocular adverse event of postoperative outer retinal folds at six months (RR 0.39, 95% CI 0.17 to 0.90; 1 RCT; 262 eyes of 262 participants; very low certainty evidence) and binocular diplopia (RR 0.20, 95% CI 0.04 to 0.90; 1 RCT; 262 eyes of 262 participants; very low certainty evidence) compared with support-the-break positioning. Immediate face-down positioning may increase the ocular adverse event of elevated intraocular pressure compared with support-the-break positioning (RR 1.74, 95% CI 1.11 to 2.73; 1 RCT; 262 eyes of 262 participants; very low certainty evidence). Another study found no evidence of a difference in postoperative outer retinal folds when comparing face-down versus face-up positioning at one and three months (RR 1.00, 95% CI 0.50 to 2.02; RR 1.00, 95% CI 0.28 to 3.61; 1 RCT; 56 eyes of 56 participants; very low certainty evidence). No studies reported non-ocular adverse events. AUTHORS' CONCLUSIONS: Very low certainty evidence suggests that immediate face-down positioning after PPV and gas tamponade may result in a reduction in postoperative retinal displacement, outer retinal folds, and binocular diplopia, but may increase the chance of postoperative raised intraocular pressure compared with support-the-break positioning at six months. We identified two ongoing trials that compare face-down positioning with face-up positioning following PPV and gas tamponade in participants with primary macula-involving RRDs, whose results may provide relevant evidence for our stated objectives. Future trials should be rigorously designed, and investigators should analyze outcome data appropriately and report adequate information to provide evidence of high certainty. Quality of life and patient preferences should be examined in addition to clinical and adverse event outcomes.