Dynamics of Formamide-Water Mixtures Investigated by Linear and Nonlinear Infrared Spectroscopy.

Formamide (FA) exhibits complete miscibility with water, offering a simplified model for exploring the solvation dynamics of peptide linkages in biophysical processes. Its liquid state demonstrates a three-dimensional hydrogen bonding network akin to water, reflecting solvent-like behavior. Analyzing the microscopic structure and dynamics of FA-water mixtures is expected to provide crucial insights into hydrogen bonding dynamics─a key aspect of various biophysical phenomena. This study is focused on the dynamics of FA-water mixtures using linear and femtosecond infrared spectroscopies. By using the intrinsic OD stretch and extrinsic probe SCN-, the local vibrational behaviors across various FA-water compositions were systematically investigated. The vibrational relaxation of OD stretch revealed a negligible impact of FA addition on the vibrational lifetime of water molecules, underscoring the mixture's water-like behavior. However, the reorientational dynamics of OD stretch slowed with increasing FA mole fraction (XFA), plateauing beyond XFA > 0.5. This suggests a correlation between OD's reorientational time and the strength of the hydrogen bond network, likely tied to the solution's changing dielectric constant. Conversely, the vibrational relaxation dynamics of SCN- was strongly correlated with XFA, highlighting a competition between water and FA molecules in solvating SCN-. Moreover, a linear relationship between rising viscosity and the prolonged correlation time of SCN-'s slow dynamics indicates that the solution's macroscopic viscosity is dictated by the extended structures formed between FA and water molecules. The relation between the reorientation dynamics of the SCN- and the macroscopic viscosity in aqueous FA-water mixture solutions was analyzed by using the Stokes-Einstein-Debye equations. The direct viscosity-diffusion coupling is observed, which can be attributed to the homogeneous dynamics feature in FA-water mixture solutions. The inclusion of these intrinsic and extrinsic probes not only enhances the comprehensiveness of our analysis but also provides valuable insights into various aspects of the dynamics within the FA-water system. This investigation sheds light on the fundamental dynamics of FA-water mixtures, emphasizing their molecular-level homogeneity in this binary mixture solution.

Monoamine oxidase B activatable red fluorescence probe for bioimaging in cells and zebrafish.

A real-time and specific for the detection of Monoamine Oxidase B (MAO-B) to investigate the MAO-B-relevant disease development and treatment process is urgently desirable. Here, we utilized MAO-B to catalyze the conversion of propylamino groups to aldehyde groups, which was then quickly followed by a ß-elimination process to produce fluorescent probes (FNJP) that may be used to detect MAO-B in vitro and in vivo. The FNJP probe possesses unique properties, including favorable reactivity (Km = 10.8 µM), high cell permeability, and NIR characteristics (λem = 610 nm). Moreover, the FNJP probe showed high selectivity for MAO-B and was able to detect endogenous MAO-B levels from a mixed population of NIH-3 T3 and HepG2 cells. MAO-B expression was found to be increased in cells under lipopolysaccharide-stimulated cellular oxidative stress in neuronal-like SH-SY5Y cells. In addition, the visualization of FNJP for MAO-B activity in zebrafish can be an effective tool for exploring the biofunctions of MAO-B. Considering these excellent properties, the FNJP probe may be a powerful tool for detecting MAO-B levels in living organisms and can be used for accurate clinical diagnoses of related diseases.

Anion Recognition in Solution: Insights from Thermodynamics and Ultrafast Structural Dynamics.

Anion recognition through noncovalent interactions stands as an emerging field in supramolecular chemistry, exerting a profound influence on the regulation of biological functions. Herein, the thermodynamics of complexation between sodium cyanate (NaOCN) and calix[4]pyrrole was systematically investigated by linear and nonlinear IR spectroscopy, highlighting enthalpy changes as the dominant driving force. The overall orientational relaxation of bound anion can be described by an Arrhenius-type activated process, yielding an activation energy of 15.0 ± 1.0 kJ mol-1. The structural dynamics of contact ion pairs (CIPs) formed between Na+ and OCN- in solution showed a negligible temperature effect, suggesting entropy changes as the principal governing factor. Further analysis revealed that anion recognition in solution is mediated by conformational changes of the receptor and collective rearrangement of hydrogen bond dynamics. This study, framed within the paradigms of thermodynamics and ultrafast structural dynamics, substantially advances our comprehension of the microscopic mechanisms underlying anion recognition in the realm of supramolecular chemistry.

Two new isoquinolines from Corydalis saxicola.

Two new isoquinolines (1 and 3), along with 4 known isoquinolines were obtained from the ethanol extract of Corydalis saxicola Bunting. Their structures were elucidated based on detailed spectroscopic data (NMR, HR-ESIMS) and comparison with literature data. The absolute configurations of the new compounds were assigned by comparing computed electronic circular dichroism (ECD). The anti-inflammatory effects of the isolates were assessed by inhibiting NO production in LPS-induced RAW264.7 macrophage cells, and the results showed that compounds 1-6 exhibited anti-inflammatory activities, with IC50 values ranged from 44.24 ± 1.16 to 69.00 ± 5.41 µM.

A New Cell Signal Regulation Theory: Blocking the Signal from being Reactivated Before a New Activation.

Currently, the concept of cell signal regulation has two basic steps: activation and deactivation. There are many activators of the signals in vivo (e.g., hormones, growth factors, signal cross-talk, etc.). According to the two step theory, cell signals are expected to keep activating, deactivating, activating, deactivating,……However, cell signals in vivo are usually quiescent for the most of the time. This indicates that, there is a mechanism that blocks the signal from being reactivated for a certain period of time after an activation is terminated. Here, we propose that cell's signal regulation consists of three basic steps: activation, deactivation, and blocking the signal from being reactivated for a certain period of time until cells are ready for a new activation. We explain the third step of regulation using GH/STAT5 and insulin/AKT signal pathways as examples, and discuss why the third step in regulation is important for cell homeostasis and the development of diseases.

Mitochondrial-Targeted and Near-Infrared Fluorescence Probe for Bioimaging and Evaluating Monoamine Oxidase A Activity in Hepatic Fibrosis.

Monoamine oxidase A (MAO-A) is a promising diagnostic marker for cancer, depression, Parkinson's disease, and liver disease. The fluorescence detection of MAO-A in living animals is of extreme importance for the early diagnosis of related diseases. However, the development of specific and mitochondrial-targeted and near-infrared (NIR) fluorescence MAO-A probes is still inadequate. Here, we designed and synthesized four NIR fluorescence probes containing a dihydroxanthene (DH) skeleton to detect MAO-A in complex biological systems. The specificity of our representative probe DHMP2 displays a 31-fold fluorescence turn-on in vitro, and it can effectively accumulate in the mitochondria and specifically detect the endogenous MAO-A concentrations in PC-3 and SH-SY5Y cell lines. Furthermore, the probe DHMP2 can be used to visualize the endogenous MAO-A activity in zebrafish and tumor-bearing mice. More importantly, it is the first time that the MAO-A activity of hepatic fibrosis tissues is detected through the probe DHMP2. The present study shows that the synthesized DHMP2 might serve as a potential tool for monitoring MAO-A activity in vivo and diagnosing related diseases.

HBV infection and extra-hepatic cancers in adolescents and 20s: A retrospective study in China.

BACKGROUND: The mean age at cancer diagnosis is younger in hepatitis B virus (HBV) infected than non-infected patients. It remains unknown whether this association reflects an increase in the incidence rates of extra-hepatic cancers in adolescents and younger. METHODS: We examined 10 common extra-hepatic cancers (lung, breast, gastric, prostate, esophageal, rectal, cervical, nasopharyngeal, lymphatic, and urinary bladder) among patients diagnosed at three Chinese hospitals during 2007-2016. We compared the percentage distribution (frequencies at each age point are shown as a percentage of the total frequency) of HBsAg+ with HBsAg- patients, and calculated the standardized incidence ratio for each age group. RESULTS: A total of 60,323 patients were identified. The mean age at cancer diagnosis was 1.5-5.5 years younger in hepatitis B surface antigen (HBsAg) positive patients compared to HBsAg- patients (p ≤ 0.001). Lymphoma patients had the highest prevalence rate of HBV infection (20.7%). Among the pooled HBsAg+ cancer patients, 14.8% (1138/7666) were aged ≤39 years; by contrast, 9.7% (5122/52657) of HBsAg- cancer patients were in the same age range, giving an odds ratio of 1.6 [95%CI1.509-1.733)]. The observations were similar when each cancer was considered individually. The odds ratio was greater in pooled male patients aged ≤39 years [1.9(95%CI1.705-2.085)] compared with females [1.6(95%CI1.382-1.83)]. The ratio of the observed to the expected number of HBsAg+ patients aged 15-19, 20-24, and 25-29 years were 3.3, 4.8 and 2.0, respectively, higher than 1.2-1.7 observed for older age-groups. CONCLUSION: HBV infection is a risk factor for diverse extra-hepatic cancers in adolescents and 20s.

A self-administered method of acute pressure block of sciatic nerves for short-term relief of dental pain: a randomized study.

OBJECTIVES: While stimulation of the peripheral nerves increases the pain threshold, chronic pressure stimulation of the sciatic nerve is associated with sciatica. We recently found that acute pressure block of the sciatic nerve inhibits pain. Therefore, we propose that, the pain pathology-causing pressure is chronic, not acute. Here, we report a novel self-administered method: acute pressure block of the sciatic nerves is applied by the patients themselves for short-term relief of pain from dental diseases. DESIGN: This was a randomized, single-blind study. SETTING: Hospital patients. PATIENTS: Patients aged 16-60 years with acute pulpitis, acute apical periodontitis, or pericoronitis of the third molar of the mandible experiencing pain ≥3 on the 11-point numerical pain rating scale. INTERVENTIONS: Three-minute pressure to sciatic nerves was applied by using the hands (hand pressure method) or by having the patients squat to force the thigh and shin as tightly as possible on the sandwiched sciatic nerve bundles (self-administered method). OUTCOMES: The primary efficacy variable was the mean difference in pain scores from the baseline. RESULTS: One hundred seventy-two dental patients were randomized. The self-administered method produced significant relief from pain associated with dental diseases (P ≤ 0.001). The analgesic effect of the self-administered method was similar to that of the hand pressure method. CONCLUSIONS: The self-administered method is easy to learn and can be applied at any time for pain relief. We believe that patients will benefit from this method.

A comparison between acute pressure block of the sciatic nerve and acupressure: methodology, analgesia, and mechanism involved.

Acupressure is an alternative medicine methodology that originated in ancient China. Treatment effects are achieved by stimulating acupuncture points using acute pressure. Acute pressure block of the sciatic nerve is a newly reported analgesic method based on a current neuroscience concept: stimulation of the peripheral nerves increases the pain threshold. Both methods use pressure as an intervention method. Herein, we compare the methodology and mechanism of these two methods, which exhibit several similarities and differences. Acupressure entails variation in the duration of manipulation, and the analgesic effect achieved can be short-or long-term. The acute effect attained with acupressure presents a scope that is very different from that of the chronic effect attained after long-term treatment. This acute effect appears to have some similarities to that achieved with acute pressure block of the sciatic nerve, both in methodology and mechanism. More evidence is needed to determine whether there is a relationship between the two methods.

The role of PTEN in chronic growth hormone-induced hepatic insulin resistance.

Chronic growth hormone (GH) therapy has been shown to cause insulin resistance, but the mechanism remains unknown. PTEN, a tumor suppressor gene, is a major negative regulator of insulin signaling. In this study, we explored the effect of chronic GH on insulin signaling in the context of PTEN function. Balb/c healthy mice were given recombinant human or bovine GH intraperitoneally for 3 weeks. We found that phosphorylation of Akt was significantly decreased in chronic GH group and the expression of PTEN was significantly increased. We further examined this effect in the streptozotocin-induced Type I diabetic mouse model, in which endogenous insulin secretion was disrupted. Insulin/PI3K/Akt signaling was impaired. However, different from the observation in healthy mice, the expression of PTEN did not increase. Similarly, PTEN expression did not significantly increase in chronic GH-treated mice with hypoinsulinemia induced by prolonged fasting. We conducted in-vitro experiments in HepG2 cells to validate our in-vivo findings. Long-term exposure to GH caused similar resistance of insulin/PI3K/Akt signaling in HepG2 cells; and over-expression of PTEN enhanced the impairment of insulin signaling. On the other hand, disabling the PTEN gene by transfecting the mutant PTEN construct C124S or siPTEN, disrupted the chronic GH induced insulin resistance. Our data demonstrate that PTEN plays an important role in chronic-GH-induced insulin resistance. These findings may have implication in other pathological insulin resistance.

Acute pressure on the sciatic nerve results in rapid inhibition of the wide dynamic range neuronal response.

BACKGROUND: Acute pressure on the sciatic nerve has recently been reported to provide rapid short-term relief of pain in patients with various pathologies. Wide dynamic range (WDR) neurons transmit nociceptive information from the dorsal horn to higher brain centers. In the present study, we examined the effect of a 2-min application of sciatic nerve pressure on WDR neuronal activity in anesthetized male Sprague-Dawley rats. RESULTS: Experiments were carried out on 41 male Sprague-Dawley albino rats weighing 160-280 grams. Dorsal horn WDR neurons were identified on the basis of characteristic responses to mechanical stimuli applied to the cutaneous receptive field. Acute pressure was applied for 2 min to the sciatic nerve using a small vascular clip. The responses of WDR neurons to three mechanical stimuli applied to the cutaneous receptive field were recorded before, and 2, 5 and 20 min after cessation of the 2-min pressure application on the sciatic nerve. Two-min pressure applied to the sciatic nerve caused rapid attenuation of the WDR response to pinching, pressure and brushing stimuli applied to the cutaneous receptive field. Maximal attenuation of the WDR response to pinching and pressure was noted 5 min after release of the 2-min pressure on the sciatic nerve. The mean firing rate decreased from 31.7±1.7 Hz to 13±1.4 Hz upon pinching (p < 0.001), from 31.2±2.3 Hz to 10.9±1.4 Hz (p < 0.001) when pressure was applied, and from 18.9±1.2 Hz to 7.6±1.1 Hz (p < 0.001) upon brushing. Thereafter, the mean firing rates gradually recovered. CONCLUSIONS: Our results indicate that acute pressure applied to the sciatic nerve exerts a rapid inhibitory effect on the WDR response to both noxious and innocuous stimuli. Our results may partially explain the rapid analgesic effect of acute sciatic nerve pressure noted in clinical studies, and also suggest a new model for the study of pain.

A novel mutation in STK11 gene is associated with Peutz-Jeghers syndrome in Chinese patients.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is caused by mutations in the tumor suppressor gene, STK11, and is characterized by gastrointestinal hamartomas, melanin spots on the lips, and an increased risk of developing cancer. METHODS: Blood samples were collected from two unrelated Chinese PJS families totaling 20 individuals (9 male and 11 females), including 6 PJS patients. The entire coding region of the STK11 gene was amplified by polymerase chain reaction and analyzed by direct sequencing. RESULTS: A novel mutation, c.904C > T, in exon 7 was identified in both families. A C > T substitution changed codon 302 from CAG (glutamine) to TAG (stop), truncating the STK11 protein, thus leading to the partial loss of the kinase domain and complete loss of the α-helix C-terminus. Furthermore, one PJS patient from each family was diagnosed with a visceral cancer, a colon cancer and a liver cancer respectively. CONCLUSION: We predict that this novel mutation, p.Q302X, is most likely responsible for development of the PJS phenotype and may even contribute to malignancy.