Nitric oxide controls proliferation of Leishmania major by inhibiting the recruitment of permissive host cells.

Nitric oxide (NO) is an important antimicrobial effector but also prevents unnecessary tissue damage by shutting down the recruitment of monocyte-derived phagocytes. Intracellular pathogens such as Leishmania major can hijack these cells as a niche for replication. Thus, NO might exert containment by restricting the availability of the cellular niche required for efficient pathogen proliferation. However, such indirect modes of action remain to be established. By combining mathematical modeling with intravital 2-photon biosensors of pathogen viability and proliferation, we show that low L. major proliferation results not from direct NO impact on the pathogen but from reduced availability of proliferation-permissive host cells. Although inhibiting NO production increases recruitment of these cells, and thus pathogen proliferation, blocking cell recruitment uncouples the NO effect from pathogen proliferation. Therefore, NO fulfills two distinct functions for L. major containment: permitting direct killing and restricting the supply of proliferation-permissive host cells.

A metal-poor star with abundances from a pair-instability supernova.

The most massive and shortest-lived stars dominate the chemical evolution of the pre-galactic era. On the basis of numerical simulations, it has long been speculated that the mass of such first-generation stars was up to several hundred solar masses1-4. The very massive first-generation stars with a mass range from 140 to 260 solar masses are predicted to enrich the early interstellar medium through pair-instability supernovae (PISNe)5. Decades of observational efforts, however, have not been able to uniquely identify the imprints of such very massive stars on the most metal-poor stars in the Milky Way6,7. Here we report the chemical composition of a very metal-poor (VMP) star with extremely low sodium and cobalt abundances. The sodium with respect to iron in this star is more than two orders of magnitude lower than that of the Sun. This star exhibits very large abundance variance between the odd- and even-charge-number elements, such as sodium/magnesium and cobalt/nickel. Such peculiar odd-even effect, along with deficiencies of sodium and α elements, are consistent with the prediction of primordial pair-instability supernova (PISN) from stars more massive than 140 solar masses. This provides a clear chemical signature indicating the existence of very massive stars in the early universe.

Differential Scaling of Gene Expression with Cell Size May Explain Size Control in Budding Yeast.

Yeast cells must grow to a critical size before committing to division. It is unknown how size is measured. We find that as cells grow, mRNAs for some cell-cycle activators scale faster than size, increasing in concentration, while mRNAs for some inhibitors scale slower than size, decreasing in concentration. Size-scaled gene expression could cause an increasing ratio of activators to inhibitors with size, triggering cell-cycle entry. Consistent with this, expression of the CLN2 activator from the promoter of the WHI5 inhibitor, or vice versa, interfered with cell size homeostasis, yielding a broader distribution of cell sizes. We suggest that size homeostasis comes from differential scaling of gene expression with size. Differential regulation of gene expression as a function of cell size could affect many cellular processes.

Warming may offset impact of precipitation changes on riverine nitrogen loading.

Climate change, especially in the form of precipitation and temperature changes, can alter the transformation and delivery of nitrogen on the land surface and to aquatic systems, impacting the trophic states of downstream water bodies. While the expected impacts of changes in precipitation have been explored, a quantitative understanding of the impact of temperature on nitrogen loading is lacking at landscape scales. Here, using several decades of nitrogen loading observations, we quantify how individual and combined future changes in precipitation and temperature will affect riverine nitrogen loading. We find that, contrary to recent decades, rising temperatures are likely to offset or even reverse previously reported impacts of future increases in total and extreme precipitation on nitrogen runoff across the majority of the contiguous United States. These findings highlight the multifaceted impacts of climate change on the global nitrogen cycle.

Suppression of Overactive Insulin-Like Growth Factor 1 Attenuates Trauma-Induced Heterotopic Ossification in Mice.

Heterotopic ossification (HO) is the ectopic bone formation in soft tissues. Aside from hereditary HO, traumatic HO is common after orthopedic surgery, combat-related injuries, severe burns, or neurologic injuries. Recently, mammalian target of rapamycin (mTOR) was demonstrated to be involved in the chondrogenic and osteogenic processes of HO formation. However, its upstream signaling mechanism remains unknown. The current study used an Achilles tendon puncture-induced HO model to show that overactive insulin-like growth factor 1 (IGF-1) was involved in the progression of HO in mice. Micro-computed tomography imaging showed that IGF-1 not only accelerated the rate of osteogenesis and increased ectopic bone volume but also induced spontaneous ectopic bone formation in undamaged Achilles tendons. Blocking IGF-1 activity with IGF-1 antibody or IGF-1 receptor inhibitor picropodophyllin significantly inhibited HO formation. Mechanistically, IGF-1/IGF-1 receptor activates phosphatidylinositol 3-kinase (PI3K)/Akt signaling to promote the phosphorylation of mTOR, resulting in the chondrogenic and osteogenic differentiation of tendon-derived stem cells into chondrocytes and osteoblasts in vitro and in vivo. Inhibitors of PI3K (LY294002) and mTOR (rapamycin) both suppressed the IGF-1-stimulated mTOR signal and mitigated the formation of ectopic bones significantly. In conclusion, these results indicate that IGF-1 mediated the progression of traumatic HO through PI3K/Akt/mTOR signaling, and suppressing IGF-1 signaling cascades attenuated HO formation, providing a promising therapeutic strategy targeting HO.

Pancreatic Acinar Cells-Derived Sphingosine-1-Phosphate Contributes to Fibrosis of Chronic Pancreatitis via Inducing Autophagy and Activation of Pancreatic Stellate Cells.

BACKGROUND & AIMS: Studies have demonstrated that activated pancreatic stellate cells (PSCs) play a crucial role in pancreatic fibrogenesis in chronic pancreatitis (CP); however, the precise mechanism for PSCs activation has not been fully elucidated. We analyzed the role of injured pancreatic acinar cells (iPACs) in the activation of PSCs of CP. METHODS: Sphingosine kinase 1 (SPHK1)/sphingosine-1-phosphate (S1P) signaling was evaluated in experimental CP induced by cerulein injection or pancreatic duct ligation, as well as in PACs injured by cholecystokinin. The activation of PSCs and pancreatic fibrosis in CP samples was evaluated by immunohistochemical and immunofluorescence analyses. In vitro coculture assay of iPACs and PSCs was created to evaluate the effect of the SPHK1/S1P pathway and S1P receptor 2 (SIPR2) on autophagy and activation of PSCs. The pathogenesis of CP was assessed in SPHK1-/- mice or PACs-specific SPHK1-knockdown mice with recombinant adeno-associated virus serotypes 9-SPHK1-knockdown, as well as in mice treated with inhibitor of SPHK1 and S1P receptor 2 (S1PR2). RESULTS: SPHK1/S1P was remarkably increased in iPACs and acinar cells in pancreatic tissues of CP mice. Meanwhile, the pathogenesis, fibrosis, and PSCs activation of CP was significantly prevented in SPHK1-/- mice and recombinant adeno-associated virus serotypes 9-SPHK1-knockdown mice. Meanwhile, iPACs obviously activated PSCs, which was prevented by SPHK1 knockdown in iPACs. Moreover, iPACs-derived S1P specifically combined to S1PR2 of PSCs, by which modulated 5' adenosine monophosphate-activated protein kinase/mechanistic target of rapamycin pathway and consequently induced autophagy and activation of PSCs. Furthermore, hypoxia-inducible factor 1-α and -2α promoted SPHK1 transcription of PACs under hypoxia conditions, which is a distinct characteristic of the CP microenvironment. Coincidently, inhibition of SPHK1 and S1PR2 activity with inhibitor PF-543 and JTE-013 obviously impeded pancreatic fibrogenesis of CP mice. CONCLUSIONS: The activated SPHK1/S1P pathway in iPACs induces autophagy and activation of PSCs by regulating the S1PR2/5' adenosine monophosphate-activated protein kinase/mammalian target of rapamycin pathway, which promotes fibrogenesis of CP. The hypoxia microenvironment might contribute to the cross talk between PACs and PSCs in pathogenesis of CP.

NADPH mimics the antidepressant effects of exercise in a chronic unpredictable stress rat model.

Exercise is known to be an effective intervention for depression. NADPH has been demonstrated to have neuroprotective effects in our previous studies. This study aimed to investigate if NADPH has antidepressant effects and can mimic the effects of exercise in a chronic unpredictable stress (CUS) rat model. CUS rats underwent an 8-week swimming exercise (30 min/d, 5d/w) or were intraperitoneally administered 4 mg/kg or 8 mg/kg NADPH. The open field test (OFT), sucrose preference test (SPT), novelty-suppressed feeding test (NSFT), and forced swimming test (FST) were used to examine the antidepressant-like behaviors of the rats. Exercise, 4 mg/kg, and 8 mg/kg NADPH similarly reduced anxiety, as demonstrated by the number of fecal pellets. Meanwhile, exercise and 8 mg/kg NADPH significantly increased locomotion activity in the OFT. Exercise, 4 mg/kg, and 8 mg/kg NADPH effectively reversed CUS-induced anhedonia in rats in the SPT. Exercise, 4 mg/kg, and 8 mg/kg NADPH had no impact on appetite of depressed rats; however, 8 mg/kg NADPH increased the rats' exploratory activity in the NSFT. Exercise, 4 mg/kg, and 8 mg/kg NADPH significantly reduced the immobility time of CUS model rats, while exercise and 8 mg/kg NADPH postponed the early CUS-induced "immobility" in the FST. These results demonstrated that NADPH has similar antidepressant-like effects to exercise in CUS-induced depression model rats and is a potential exercise-mimicking antidepressant.

Metagenomic analysis reveals altered gut virome and diagnostic potential in pancreatic cancer.

Pancreatic cancer (PC) is a highly aggressive malignancy with a poor prognosis, making early diagnosis crucial for improving patient outcomes. While the gut microbiome, including bacteria and viruses, is believed to be essential in cancer pathogenicity, the potential contribution of the gut virome to PC remains largely unexplored. In this study, we conducted a comparative analysis of the gut viral compositional and functional profiles between PC patients and healthy controls, based on fecal metagenomes from two publicly available data sets comprising a total of 101 patients and 82 healthy controls. Our results revealed a decreasing trend in the gut virome diversity of PC patients with disease severity. We identified significant alterations in the overall viral structure of PC patients, with a meta-analysis revealing 219 viral operational taxonomic units (vOTUs) showing significant differences in relative abundance between patients and healthy controls. Among these, 65 vOTUs were enriched in PC patients, and 154 were reduced. Host prediction revealed that PC-enriched vOTUs preferentially infected bacterial members of Veillonellaceae, Enterobacteriaceae, Fusobacteriaceae, and Streptococcaceae, while PC-reduced vOTUs were more likely to infect Ruminococcaceae, Lachnospiraceae, Clostridiaceae, Oscillospiraceae, and Peptostreptococcaceae. Furthermore, we constructed random forest models based on the PC-associated vOTUs, achieving an optimal average area under the curve (AUC) of up to 0.879 for distinguishing patients from controls. Through additional 10 public cohorts, we demonstrated the reproducibility and high specificity of these viral signatures. Our study suggests that the gut virome may play a role in PC development and could serve as a promising target for PC diagnosis and therapeutic intervention. Future studies should further explore the underlying mechanisms of gut virus-bacteria interactions and validate the diagnostic models in larger and more diverse populations.

Two-photon absorption flexible photodetector responsive to femtosecond laser.

Integrated on-chip femtosecond (fs) laser optoelectronic system, with photodetector as a critical component for light-electrical signal conversion, is a long-sought-after goal for a wide range of frontier applications. However, the high laser peak intensity and complicated nanophotonic waveguide structure of on-chip fs laser are beyond the detectability and integrability of conventional photodetectors. Therefore, flexible photodetector with the response on intense fs laser is in urgent needs. Herein, we demonstrate the first (to our knowledge) two-photon absorption (TPA) flexible photodetector based on the strong TPA nonlinearity of layered hybrid perovskite (IA)2(MA)2Pb3Br10, exhibiting efficient sub-bandgap response on the infrared fs laser at 700-1000 nm. High saturation intensity up to ∼3.8 MW/cm2 is achieved. The device also shows superior current stability even after bending for 1000 cycles. This work may pave the new way for the application of flexible optoelectronics specialized in integrated fs-laser detection.

Stable Q-switched and femtosecond mode-locked erbium-doped fiber laser based on a CuSe nanosheets saturable absorber.

Stable Q-switched and femtosecond mode-locked erbium-doped fiber laser (EDFL) have been achieved using CuSe nanosheets as novel saturable absorber (SA), where the CuSe nanosheets were prepared by a hydrothermal method. The nonlinear optical properties of CuSe nanosheets were measured using an Z-scan setup, revealing nonlinear absorption coefficients of -3.67 ± 0.22 cm GW-1 at 1560 nm. The prepared CuSe nanosheets were mixed with polyvinyl alcohol (PVA) to obtain a CuSe-PVA SA with a modulation depth of 3.8 ± 0.13%, and it was utilized to realize a Q-switched EDFL, obtaining the narrowest pulse duration of 1.29 µs and the maximum output power of 5.96 mW, which corresponds to a pulse energy of up to 103.7 nJ. In addition, CuSe nanosheets were deposited on a D-shaped fiber (DSF) to fabricate a CuSe-DSF SA with a modulation depth of 5.6 ± 0.17%, and it was utilized to realize a mode-locked EDFL. The mode-locked EDFL demonstrated a low threshold of only 42 mW, a pulse duration of 740 fs, and a maximum output power of 9.7 mW. Meanwhile, it exhibited a high signal-to-noise ratio of 72 dB. To the best of our knowledge, this is the first time of CuSe nanosheets as SA in EDFL. The results demonstrate that CuSe nanosheets are a highly promising nonlinear optical material with great potential for applications in ultrafast photonics.

Optical feedback frequency locking: impact of directly reflected field and responding strategies.

The challenges presented by the directly reflected field in optical feedback cavity-enhanced spectroscopy systems serve as substantial obstacles, introducing additional complexity to existing systems and compromising their sensitivity, as the underlying mechanisms of its adverse effects remain not fully understood. This study aims to address this issue by introducing a comprehensive analytical model. Additionally, frequency locking can be achieved by decreasing the feedback rate, the laser's linewidth enhancement factor, and the directly reflected field, and by increasing the refractive index of the gain medium, the length of the laser's resonant cavity, the electric field reflectivity of the laser's output facet, and the resonant field. These parameters can affect the feedback coupling rate pre-factor, and for a resonant cavity with a length of 0.394 m, optical feedback can only be established when the feedback coupling rate pre-factor is less than 1.05 × 109. Through experimental validation, we successfully confirm the effectiveness of the proposed solution in eliminating the detrimental effects of the directly reflected field. Importantly, this suppression is achieved without compromising other aspects of the system's performance. The research findings not only offer the potential to optimize various cavity-enhanced spectroscopy systems that rely on optical feedback but also show promising applications in advancing the development of high-purity spectrum diode lasers utilizing optical feedback from an external high-finesse cavity.

Improving vitrification efficiency of human in vitro matured oocytes by the addition of LEA proteins.

STUDY QUESTION: Can the addition of late embryogenesis-abundant (LEA) proteins as a cryoprotective agent during the vitrification cryopreservation of in vitro matured oocytes enhance their developmental potential after fertilization? SUMMARY ANSWER: LEA proteins improve the developmental potential of human in vitro matured oocytes following cryopreservation, mostly by downregulating FOS genes, reducing oxidative stress, and inhibiting the formation of ice crystals. WHAT IS KNOWN ALREADY: Various factors in the vitrification process, including cryoprotectant toxicity, osmotic stress, and ice crystal formation during rewarming, can cause fatal damage to oocytes, thereby affecting the oocytes developmental potential and subsequent clinical outcomes. Recent studies have shown that LEA proteins possess high hydrophilicity and inherent stress tolerance, and can reduce low-temperature damage, although the molecular mechanism it exerts protective effects is still unclear. STUDY DESIGN, SIZE, DURATION: Two LEA proteins extracted and purified by us were added to solutions for vitrification-warming of oocytes at concentrations of 10, 100, and 200 µg/mL, to determine the optimal protective concentration for each protein. Individual oocyte samples were collected for transcriptomic analysis, with each group consisting of three sample replicates. PARTICIPANTS/MATERIALS, SETTING, METHODS: Immature oocytes were collected from patients who were undergoing combined in vitro fertilization (IVF) treatment and who had met the designated inclusion and exclusion criteria. These oocytes underwent in vitro maturation (IVM) culture for experimental research. A fluorescence microscope was used to detect the levels of mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and calcium in the mitochondria of vitrified-warmed human oocytes treated with different concentrations of LEA proteins, and the protective effect of the protein on mitochondrial function was assessed. The levels of intracellular ice recrystallization inhibition (IRI) in human oocytes after vitrification-warming were characterized by the cryomicroscope, to determine the LEA proteins inhibitory effect on recrystallization. By analyzing transcriptome sequencing data to investigate the potential mechanism through which LEA proteins exert their cryoprotective effects. MAIN RESULTS AND THE ROLE OF CHANCE: The secondary structures of AfrLEA2 and AfrLEA3m proteins were shown to consist of a large number of α-helices and the proteins were shown to be highly hydrophilic, in agreement with previous reports. Confocal microscopy results showed that the immunofluorescence of AfrLEA2-FITC and AfrLEA3m-FITC-labeled proteins appeared to be extracellular and did not penetrate the cell membrane compared with the fluorescein isothiocyanate (FITC) control group, indicating that both AfrLEA2 and AfrLEA3m proteins were extracellular. The group treated with 100 µg/mL AfrLEA2 or AfrLEA3m protein had more uniform cytoplasmic particles and fewer vacuoles compared to the 10 and 200 µg/mL groups and were closest to the fresh group. In the 100 µg/mL groups, MMPs were significantly higher while ROS and calcium levels were significantly lower than those in the control group and were closer to the levels observed in fresh oocytes. Meanwhile, 100 µg/mL of AfrLEA2 or AfrLEA3m protein caused smaller ice crystal formation in the IRI assay compared to the control group treated with dimethylsulphoxide (DMSO) and ethylene glycol (EG); thus, the recrystallization inhibition was superior to that with the conventional cryoprotectants DMSO and EG. Further results revealed that the proteins improved the developmental potential of human oocytes following cryopreservation, likely by downregulating FOS genes and reducing oxidative stress. LIMITATIONS, REASONS FOR CAUTION: The in vitro-matured metaphase II (IVM-MII) oocytes used in the study, due to ethical constraints, may not accurately reflect the condition of MII oocytes in general. The AfrLEA2 and AfrLEA3m proteins are recombinant proteins and their synthetic stability needs to be further explored. WIDER IMPLICATIONS OF THE FINDINGS: LEA proteins, as a non-toxic and effective cryoprotectant, can reduce the cryoinjury of oocytes during cryopreservation. It provides a new promising method for cryopreservation of various cell types. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the National Key Research and Development Program of China (2022YFC2703000) and the National Natural Science Foundation of China (52206064). The authors declare no competing interest. TRIAL REGISTRATION NUMBER: N/A.

Impact of wheat processing on growth, serum biochemistry, and ruminal microbiota in sheep (Ovis aries).

This study investigated the impact of wheat processing methods (wheat flour vs wheat pellets) on the growth performance, serum biochemical parameters, and rumen microbiome composition in sheep. Results indicated that feeding of wheat flour resulted in significantly higher terminal weight and average daily gain (P < 0.05) and lower cholesterol and ALP04 levels (P < 0.05) in sheep compared to those fed wheat pellets. Analysis of 16s rDNA high-throughput sequencing data revealed significantly higher microbial richness (Chao1 index) in the rumen of sheep fed wheat flour (P < 0.05), even though the phylum-level composition dominated by Firmicutes, Bacteroidetes, and Proteobacteria was similar in both groups of sheep. Notably, sheep fed wheat flour were found to have a significantly higher relative abundance of Bacteroidetes (P < 0.05). At the genus level, Succinivibrionaceae_UCG-001 and Prevotella_1 were significantly more abundant in the rumen of sheep fed wheat flour (P < 0.05). Correlation analysis identified that both terminal weight and average daily gain were positively correlated with ruminal abundance of Bacteroidetes and Prevotella_1, while ALP04 was negatively correlated with the abundance of these taxa. Functional prediction using PICRUSt2 indicated enrichment of pathways related to the ABC-type glycerol-3-phosphate transport system, and periplasmic components in both wheat flour and pellet fed sheep. Overall, these findings suggest that dietary wheat flour modulates rumen microbiota composition, and improves growth performance in sheep.

Continuous-wave operation of a tandem optical parametric oscillator up to 5.19†µm based on periodically poled LiNbO3.

A continuous-wave, tandem optical parametric oscillator (TOPO) based on a MgO-doped periodically poled LiNbO3 (MgO:PPLN) is demonstrated. Because the MgO:PPLN is tandemly pumped by the OPO's signal beam, it outputs simultaneously two groups of signal and idler with a single pump source. The entire range spans from 1398 to 1490 nm, 1914 to 2107 nm, 3720 to 4444 nm, and 4849 to 5190 nm, which is limited by periods of the MgO:PPLN and cavity mirror coatings. The TOPO, whose oscillation threshold of pump power exceeds 7 W, can be easily triggered by marginally increasing the pump power as long as the OPO process occurs. The maximum idler powers are respectively 2.6 W (at 3896 nm) and 34 mW (at 4863 nm), and the corresponding signal powers are both nearly 100 mW.

Optical feedback noise-immune cavity-enhanced optical heterodyne molecular spectrometry for sub-Doppler-broadened detection of C2H2.

A novel, to the best of our knowledge, noise-immune cavity-enhanced optical heterodyne molecular spectrometry (NICE-OHMS) has been developed, utilizing optical feedback for laser-to-cavity locking with a common distributed-feedback diode laser. The system incorporates active control of the feedback phase and feedforward control of the laser current, allowing for consecutive laser frequency detuning by scanning a piezoelectric transducer (PZT) attached to the cavity. To enhance the fidelity of the spectroscopic signal, wavelength-modulated (wm) NICE-OHMS is implemented. Benefiting from the optical feedback, a modulation frequency of 15 kHz is achieved, surpassing the frequencies typically used in traditional NICE-OHMS setups. Then, the sub-Doppler-broadened wm-NICE-OHMS signal of acetylene at 1.53 µm is observed. A seven-fold improvement in signal to noise ratio has been demonstrated compared to NICE-OHMS alone and a limit of detection of 6.1 × 10-10cm-1 is achieved.

Optical feedback noise-immune cavity-enhanced optical heterodyne molecular spectrometry for sub-Doppler-broadened detection of C2H2: publisher's note.

This publisher's note contains a correction to Opt. Lett.49, 202 (2024)10.1364/OL.507004.

Capsaicin combined with cisplatin inhibits TGF-ß1-induced EMT and TSCC cells migration via the Claudin-1/PI3K/AKT/mTOR signaling pathway.

Tongue squamous cell carcinoma (TSCC) is one of the most common malignant tumors among oral cancers, and its treatment is based on radio-chemotherapy and surgery, which always produces more serious side effects and sequelae. Traditional medicine can compensate for the shortcomings of modern medical treatments and play a better therapeutic role. Currently, active ingredients derived from plants are attracting the attention of researchers and clinical professionals. We examined capsaicin (CAP), an active ingredient isolated from Capsicum annuum (family Solanaceae), and explored the effect of CAP combined with cisplatin (DDP) on epithelial-mesenchymal transition (EMT) and TSCC cells migration. Our results demonstrated that Transforming growth factor-ß1(TGF-ß1) induced EMT and promoted cell migration in TSCC cells. CAP combined with DDP inhibits non-TGF-ß1-induced or TGF-ß1-induced EMT and migration. Mechanistically, the inhibition of non-TGF-ß1-induced EMT and migration by CAP combined with DDP was mediated by the AMPK/mTOR pathway, whereas TGF-ß1-induced EMT and migration were regulated by the Claudin-1/PI3K/AKT/mTOR pathway. A nude lung metastasis mouse model was established for in vivo validation. These results support our hypothesis that the combination of CAP and DDP inhibits TSCC metastasis. These data set the stage for further studies aimed at validating CAP as an effective active ingredient for enhancing chemotherapy efficacy and reducing the dosage and toxicity of chemotherapeutic drugs, ultimately paving the way for translational research and clinical trials for TSCC eradication.

ZNF32 prevents the activation of cancer-associated fibroblasts through negative regulation of TGFB1 transcription in breast cancer.

Breast cancer is the most frequently diagnosed malignancy and the leading cause of cancer-related deaths in women worldwide. Cancer-associated fibroblasts (CAFs) are one of the fundamental cellular components of the tumor microenvironment and play a critical role in the initiation, progression, and therapy resistance of breast cancer. However, the detailed molecular mechanisms of CAFs activation from normal fibroblasts (NFs) are still not well understood. In the present study, we reported that ZNF32 expression in breast cancer cells was negatively correlated with CAF-related markers (FSP1, α-SMA, and FAP) in stromal fibroblasts, and loss of ZNF32 promoted the activation of CAFs, as evidenced by the enhanced proliferation and contractility of CAFs. ZNF32 deficiency-mediated fibroblast activation promoted the growth and metastasis of breast cancer cells in vitro and in vivo. Mechanistically, we demonstrated that ZNF32 inhibited TGFB1 transcription by directly binding to the -1968/-1962 region of the TGFB1 promoter, leading to the prevention of fibroblast activation. Altogether, our findings reveal an important mechanism by which ZNF32 suppression increases the transcription of the TGFB1 gene in breast cancer cells, and subsequently, elevated levels of secretory TGF-ß stimulate NFs transformation into CAFs, which in turn facilitates the malignant progression of breast cancer. Our data implicated ZNF32 as a potential therapeutic strategy against breast cancer.

Thermoresponsive Polymeric Hydromorphone Prodrug Provides Sustained Local Analgesia without Apparent Adverse Effects.

The extensive use of opioids for chronic pain management has contributed significantly to the current opioid epidemic. While many alternative nonopioid analgesics are available, opioids remain the most potent analgesics for moderate to severe pain management. In addition to the implementation of multimodal analgesia, there is a pressing need for the development of more effective and safer opioids. In this study, we developed a thermoresponsive N-(2-hydroxypropyl) methacrylamide (HPMA) copolymer-based hydromorphone (HMP) prodrug (ProGel-HMP, HMP content = 16.2 wt %, in base form). The aqueous solution of ProGel-HMP was free-flowing at 4 °C but became a hydrogel when the temperature was raised to ≥37 °C, allowing sustained local retention when administered in vivo. When tested in the destabilization of the medial meniscus (DMM) mouse model of osteoarthritis (OA), ProGel-HMP was retained after intra-articular injection in the OA knee joint for at least 2 weeks postinjection, with low extra-articular distribution. ProGel-HMP was not detected in the central nervous system (CNS). A single dose of ProGel-HMP produced rapid and sustained joint pain resolution for greater than 14 days when compared to saline and dose-equivalent HMP controls, likely mediated through peripheral µ-opioid receptors in the knee joint. Systemic analgesia effect was absent in the DMM mice treated with ProGel-HMP, as evident in the lack of difference in tail flick response between the ProGel-HMP-treated mice and the controls (i.e., Healthy, Saline, and Sham). Repeated dosing of ProGel-HMP did not induce tolerance. Collectively, these data support the further development of ProGel-HMP as a potent, safe, long-acting and nonaddictive analgesic for better clinical pain management.

Pd-Catalyzed Hydroboration of Vinylarenes with B2pin2.

A palladium(II)-catalyzed Markovnikov hydroboration of aryl alkenes with readily available bis(pinacolato)diboron (B2pin2) is reported. The reaction proceeded with low catalyst loading (0.5 mol %) in the absence of N- or P-containing ligands, affording the products in up to 90% yield. Trifluoracetic acid serves as the hydrogen source, enabling the synthesis of benzylic boronic esters under mild ambient conditions.