Sirtuin 6 maintains epithelial STAT6 activity to support intestinal tuft cell development and type 2 immunity.

Dynamic regulation of intestinal epithelial cell (IEC) differentiation is crucial for both homeostasis and the response to helminth infection. SIRT6 belongs to the NAD+-dependent deacetylases and has established diverse roles in aging, metabolism and disease. Here, we report that IEC Sirt6 deletion leads to impaired tuft cell development and type 2 immunity in response to helminth infection, thereby resulting in compromised worm expulsion. Conversely, after helminth infection, IEC SIRT6 transgenic mice exhibit enhanced epithelial remodeling process and more efficient worm clearance. Mechanistically, Sirt6 ablation causes elevated Socs3 expression, and subsequently attenuated tyrosine 641 phosphorylation of STAT6 in IECs. Notably, intestinal epithelial overexpression of constitutively activated STAT6 (STAT6vt) in mice is sufficient to induce the expansion of tuft and goblet cell linage. Furthermore, epithelial STAT6vt overexpression remarkedly reverses the defects in intestinal epithelial remodeling caused by Sirt6 ablation. Our results reveal a novel function of SIRT6 in regulating intestinal epithelial remodeling and mucosal type 2 immunity in response to helminth infection.

Effect of early integrated robot-assisted gait training on motor and balance in patients with acute ischemic stroke: a single-blinded randomized controlled trial.

Background: Gait disruption is a common poststroke problem. Robot-assisted gait training (RAGT) might improve motor function, balance, and activities of daily living. Objective: We compared the clinical effectiveness of early integrated RAGT using the Walkbot robotic gym with an intensity-matched enhanced lower limb therapy (ELLT) program and with conventional rehabilitation therapy (CRT) in patients with acute ischemic stroke. Methods: A total of 192 patients with acute ischemic stroke were randomly assigned (1:1:1) to receive RAGT, ELLT, or CRT. All three groups received 45 min of training daily, 3 days a week, for 4 weeks consecutively. Before and after the 4-week treatment, the patients were assessed based on a 6-minute walking test (6MWT), functional ambulation classification (FAC), timed up and go (TUG) test, dual-task walking (DTW) test, Tinetti's test, Barthel's index (BI), stroke-specific quality of life (SS-QOL) scale, and gait analysis parameters. Results: After the 4-week intervention, the results of the 6MWT, FAC, TUG, DTW, Tinetti's test, BI, SS-QOL, and gait in the three groups significantly improved. Compared with ELLT and CRT groups, participants in the RAGT group had a better performance in 6MWT (199.11 ± 60.72 versus 182.47 ± 59.72 versus 173.69 ± 40.58, p = 0.035), FAC (4.10 ± 0.91 versus 3.69 ± 0.88 versus 3.58 ± 0.81, p = 0.044), DTW (10.29 ± 2.38 versus 12.92 ± 2.64 versus 13.89 ± 2.62, p = 0.031), SS-QOL (184.46 ± 20.53 versus 165.39 ± 20.49 versus 150.72 ± 20.59, p = 0.012), velocity (0.66 ± 0.22 versus 0.55 ± 0.23 versus 0.51 ± 0.20, p = 0.008), cycle duration (1.38 ± 0.40 versus 1.50 ± 0.38 versus 1.61 ± 0.30, p = 0.040), and swing phase symmetry ratio (SPSR, 1.10 ± 0.33 versus 1.21 ± 0.22 versus 1.48 ± 0.25, p = 0.021). The TUG, Tinetti's test, BI, and RMT results were similar, however. Conclusion: In the acute stroke phase, early integrated RAGT showed greater performance in gait rehabilitation than CRT and ELLT. Registration: ChiCTR1900026225.

Multidimensional intervention in individuals with mild cognitive impairment: a pilot nonrandomized study.

BACKGROUND: There is an increasing need for non-pharmacological treatments that can enhance the cognitive function of individuals with mild cognitive impairment. We firstly performed multidimensional intervention based on the concept of the International Classification of Functioning, Disability and Health, and aimed to explore its short-term effect on the improvement of cognitive function in individuals with mild cognitive impairment. METHODS: Twenty-four individuals with mild cognitive impairment in this pilot study were recruited from the memory clinic and neurology ward in Shanghai Tenth People's Hospital from August 2018 to August 2019. According to participants' personal wishes, 13 and 11 participants were enrolled into an intervention group and a control group, respectively. Based on the International Classification of Functioning, Disability and Health, we performed baseline assessments to all participants. According to the assessment results and the wishes and hobbies of the patients, then doctors, therapists, nurses, patients and their families together chose the appropriate multidimensional interventions to the intervention group in seven 1-hour sessions and health education to the both groups. After one week, all participants underwent reevaluation of cognitive function. RESULTS: There were significant differences between the two groups on the improvement of cognitive function. The intervention group (mean ± SD, 3.460±1.613) scored higher than the control group (1.360±0.924) on the change score of the total score in the Montreal Cognitive Assessment (t =3.808, P<0.001, 95% CI: 0.955-3.240), though not on the change score of any cognitive domain score. Regression results showed that the change score of the total score was negatively correlated with the baseline score of Abstraction score (aR2 =0.583, ß =-0.506, P=0.031) and the modified Barthel index score (ß =-0.464, P=0.045) in the intervention group. CONCLUSIONS: The pilot study demonstrated that the short-term multidimensional intervention may produce cognitive benefits in individuals with mild cognitive impairment.

Association between Dix-Hallpike test parameters and successful repositioning maneuver in posterior semicircular canal benign paroxysmal positional vertigo: a case-control study.

BACKGROUND: Nystagmus (i.e., involuntary eye movement) provoked by the Dix-Hallpike test (DHT) is considered the gold standard for diagnosing posterior semicircular canal benign paroxysmal positional vertigo (psc-BPPV). However, robust evidence regarding this diagnostic maneuver's treatment efficacy is still lacking. This study aimed to investigate the parameters of positional nystagmus in the DHT as prognostic factors for unilateral psc-BPPV. METHODS: We reviewed 357 patients with unilateral psc-BPPV who underwent the computer-controlled canalith repositioning procedure (CCRP), which mimics the Epley maneuver. Additionally, positional nystagmus in the DHT was observed through a video-oculography. Patients were retrospectively divided into two groups according to resistance to the CCRP. Univariable and multivariable analyses were performed on age, gender, blood pressure, and nystagmus parameters of the affected side in the DHT in order to reveal associated factors causing resistance to the CCRP. RESULTS: With univariate and multivariate analysis, we observed a decrease in vertical time course during slow phase nystagmus on the affected side (odds ratio, OR 0.77, P=0.011 vs. OR 0.80, P=0.027). Moreover, an increased vertical velocity amplitude in the DHT during slow phase nystagmus (OR 3.16, P=0.029 vs. OR 2.96, P=0.035) remained an associated factor of maneuver resistance. CONCLUSIONS: Decreased canalith weight on the affected side was associated with resistance to the CCRP. This association corresponded to the observation that psc-BPPV patients with a decreased time course and increased velocity in the slow phase of recording nystagmus have a worse prognosis of their BPPV persisting after a single CCRP.

Quantification of Proliferative and Dead Cells in Enteroids.

The intestinal epithelium acts as a barrier that prevents luminal contents, such as pathogenic microbiota and toxins, from entering the rest of the body. Epithelial barrier function requires the integrity of intestinal epithelial cells. While epithelial cell proliferation maintains a continuous layer of cells that forms a barrier, epithelial damage leads to barrier dysfunction. As a result, luminal contents can across the intestinal barrier via an unrestricted pathway. Dysfunction of intestinal barrier has been associated with many intestinal diseases, such as inflammatory bowel disease. Isolated mouse intestinal crypts can be cultured and maintained as crypt-villus-like structures, which are termed intestinal organoids or "enteroids". Enteroids are ideal to study the proliferation and cell death of intestinal epithelial cells in vitro. In this protocol, we describe a simple method to quantify the number of proliferative and dead cells in cultured enteroids. 5-ethynyl-2'-deoxyuridine (EdU) and propidium iodide are used to label proliferating and dead cells in enteroids, and the proportion of proliferating and dead cells are then analyzed by flow cytometry. This is a useful tool to test the effects of drug treatment on intestinal epithelial cell proliferation and cell survival.

Interleukin 22 Expands Transit-Amplifying Cells While Depleting Lgr5+ Stem Cells via Inhibition of Wnt and Notch Signaling.

BACKGROUND & AIMS: Epithelial regeneration is essential for homeostasis and repair of the mucosal barrier. In the context of infectious and immune-mediated intestinal disease, interleukin (IL) 22 is thought to augment these processes. We sought to define the mechanisms by which IL22 promotes mucosal healing. METHODS: Intestinal stem cell cultures and mice were treated with recombinant IL22. Cell proliferation, death, and differentiation were assessed in vitro and in vivo by morphometric analysis, quantitative reverse transcriptase polymerase chain reaction, and immunohistochemistry. RESULTS: IL22 increased the size and number of proliferating cells within enteroids but decreased the total number of enteroids. Enteroid size increases required IL22-dependent up-regulation of the tight junction cation and water channel claudin-2, indicating that enteroid enlargement reflected paracellular flux-induced swelling. However, claudin-2 did not contribute to IL22-dependent enteroid loss, depletion of Lgr5+ stem cells, or increased epithelial proliferation. IL22 induced stem cell apoptosis but, conversely, enhanced proliferation within and expanded numbers of transit-amplifying cells. These changes were associated with reduced wnt and notch signaling, both in vitro and in vivo, as well as skewing of epithelial differentiation, with increases in Paneth cells and reduced numbers of enteroendocrine cells. CONCLUSIONS: IL22 promotes transit-amplifying cell proliferation but reduces Lgr5+ stem cell survival by inhibiting notch and wnt signaling. IL22 can therefore promote or inhibit mucosal repair, depending on whether effects on transit-amplifying or stem cells predominate. These data may explain why mucosal healing is difficult to achieve in some inflammatory bowel disease patients despite markedly elevated IL22 production.

Proposed Hydrogen-Bonding Index of Donor or Acceptor Reflecting Its Intrinsic Contribution to Hydrogen-Bonding Strength.

In this work, we tentatively propose that the hydrogen-bonding strength EHB (referring to the minimal hydrogen-bonding energy) and its corresponding hydrogen-bond (HB) distance (referring to the optimal HB distance dHB) for simple mono-HB systems have an exponential relationship on the basis of MP2 and DFT computational results. We take a step further and propose that the hydrogen-bonding indices of the donor (Idonor) and acceptor (Iacceptor), reflecting their intrinsic contributions to hydrogen-bonding strength, also have an exponential relation with the hypothetical effective hydrogen-bond radii of the donor (rdonor) and acceptor (racceptor), respectively. On the basis of extensive quantum-mechanical calculations, relevant assumptions about the hydrogen-bonding index are rationalized. Moreover, the hydrogen-bonding index is also suggested as an additional prefiltering criterion for virtual screening besides the widely accepted Lipinski's rule of five. Finally, a "Hydrogen-Bond Index Estimator (HBIE)" module has been implemented in our Visual Force Field Derivation Toolkit (VFFDT) program to approximately and rapidly estimate the hydrogen-bonding indices of any small molecules in batch and screen possible stronger donors or acceptors from the small-molecule database. To the best of our knowledge, the concept of the hydrogen-bonding index and its potential application are proposed here for the first time.

VFFDT: A New Software for Preparing AMBER Force Field Parameters for Metal-Containing Molecular Systems.

Force fields are fundamental to molecular dynamics simulations. However, the incompleteness of force field parameters has been a long-standing problem, especially for metal-related systems. In our previous work, we adopted the Seminario method based on the Hessian matrix to systematically derive the zinc-related force field parameters for AMBER. In this work, in order to further simplify the whole protocol, we have implemented a user-friendly Visual Force Field Derivation Toolkit (VFFDT) to derive the force field parameters via simply clicking on the bond or angle in the 3D viewer, and we have further extended our previous program to support the Hessian matrix output from a variety of quantum mechanics (QM) packages, including Gaussian 03/09, ORCA 3.0, QChem, GAMESS-US, and MOPAC 2009/2012. In this toolkit, a universal VFFDT XYZ file format containing the raw Hessian matrix is available for all of the QM packages, and an instant force field parametrization protocol based on a semiempirical quantum mechanics (SQM) method is introduced. The new function that can automatically obtain the relevant parameters for zinc, copper, iron, etc., which can be exported in AMBER Frcmod format, has been added. Furthermore, our VFFDT program can read and write files in AMBER Prepc, AMBER Frcmod, and AMBER Mol2 format and can also be used to customize, view, copy, and paste the force field parameters in the context of the 3D viewer, which provides utilities complementary to ANTECHAMBER, MCPB, and MCPB.py in the AmberTools.

Stressful Parental-Bonding Exaggerates the Functional and Emotional Disturbances of Primary Dysmenorrhea.

BACKGROUND: Some evidence suggests that women with primary dysmenorrhea (or painful period) often have traumatic experience with parental attachments, but the exact relationship is still unclear. PURPOSE: This study aims to investigate associations between styles of the parental bonding and the detailed aspects of the disorder in Chinese university-student women. METHODS: From university-student women, we have invited 50 primary dysmenorrhea patients and 111 healthy volunteers, to undergo tests of the Functional and Emotional Measure of Dysmenorrhea (FEMD), the Family Relationship Questionnaire (FRQ), and the visual analogue scale for the pain intensity experienced. RESULTS: Besides the high scores of the FEMD Functional and Emotional scales, the dysmenorrhea patients also scored significantly higher than the healthy controls on the FRQ scales of Paternal Dominance and Maternal Abuse. In patients, the FEMD Emotional scale was negatively predicted by the Paternal Freedom Release scale, and the FEMD Functional scale was positively predicted by the Maternal Dominance scale. CONCLUSIONS: Inappropriate parental bonding or chronic traumatic attachment styles have respective relationships with the functional and emotional disturbances experienced by the primary dysmenorrhea patients.

Development of a structure-validated Family Relationship Questionnaire (FRQ) with Chinese university students.

Consistent results have shown a relationship between the psychological world of children and their perceived parental bonding or family attachment style, but to date there is no single measure covering both styles. The authors designed a statement matrix with 116 items for this purpose and compared it with the Parental Bonding Instrument (PBI) in a study with 718 university students. After exploratory and confirmatory factor analyses, five factors (scales)--namely, Paternal/Maternal Encouragement (5 items each), Paternal/Maternal Abuse (5 items each), Paternal/Maternal Freedom Release (5 items each), General Attachment (5 items), and Paternal/Maternal Dominance (4 items each)--were defined to form a Family Relationship Questionnaire (FRQ). The internal alphas of the factors ranged from .64 to .83, and their congruency coefficients were .93 to .98 in samples regarding father and mother. Women scored significantly higher on FRQ General Attachment and Maternal Encouragement and lower on Paternal Abuse than men did; only children scored significantly higher on Paternal and Maternal Encouragements than children with siblings did. Women also scored significantly higher on PBI Paternal Autonomy Denial; only children scored significantly higher on Paternal and Maternal Cares and Maternal Autonomy Denial. All intercorrelations between FRQ scales were low to medium, and some correlations between FRQ and PBI scales were medium to high. This study demonstrates that the FRQ has a structure of five factors with satisfactory discriminant and convergent validities, which might help to characterize family relationships in healthy and clinical populations.

The Zuckerman-Kuhlman personality questionnaire in bipolar I and II disorders: a preliminary report.

Patients with bipolar disorder have tendencies of higher impulsivity and sensation seeking, they might contribute differently to the emotional states of bipolar I (BD I) and II (BD II). We administered the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ), the Plutchik-van Praag Depression Inventory (PVP), the Mood Disorder Questionnaire (MDQ), and the Hypomania Checklist (HCL-32) in 23 patients with BD I, 22 BD II, and 64 healthy volunteers. Both BD I and II scored higher on ZKPQ Impulsive sensation seeking (and its Impulsivity facet), Neuroticism-anxiety and Aggression-hostility, and on PVP and HCL-32 scales than controls did; BD I scored higher on MDQ and General sensation seeking facet than controls did. Compared to BD II, BD I scored higher on Impulsive sensation seeking (and General sensation seeking) and on MDQ. Moreover, General sensation seeking predicted MDQ, and Activity predicted HCL-32 in BD I. Aggression-hostility predicted HCL-32 in BD II. General sensation seeking predicted MDQ and HCL-32, and together with Neuroticism-anxiety, predicted PVP in controls. Our study suggests that Impulsive sensation seeking, and its General sensation seeking facet might help to delineate the two types of bipolar disorder.

Personality trait correlates of color preference in schizophrenia.

BACKGROUND: The goal of the present study was to evaluate the color preferences of patients with schizophrenia and their correlations with personality traits. METHODOLOGY: Sixty-three patients with schizophrenia and 59 healthy volunteers were asked to undertake the color preference and the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ) tests. RESULTS: The healthy volunteers showed a greater preference for green but a lesser one for brown compared to the patients with schizophrenia. Patients scored higher than the healthy volunteers on the ZKPQ Neuroticism-Anxiety and Activity scales. Moreover, in patients, black preference ranking was associated with the Neuroticism-Anxiety, whereas pink and orange preferences were negatively associated with Activity; white preference correlated negatively with Sociability. CONCLUSIONS: Patients with schizophrenia preferred green less but brown more, and displayed their personality correlates of these color preferences. These findings are suggesting that patients with schizophrenia should be encouraged to be more exposed to bright colors such as green and white, and less to dark colors such as black, during therapy and rehabilitation sessions.

Passive event-related potentials to a single tone in treatment-resistant depression, generalized anxiety disorder, and borderline personality disorder patients.

PURPOSE: Treatment-resistant depression is comorbid with personality or anxiety disorder; how passive attention functions in these disorders remains unknown. A single tone-elicited event-related potential P3 component (passive P3) might help to characterize the passive attention in these disorders. METHODS: The passive P3 test was applied to 32 patients with treatment-resistant depression, 35 with generalized anxiety disorder, and 21 with borderline personality disorder, as well as to 31 healthy volunteers. The Zung Self-rating Depression and Anxiety Scales were used to measure the respective depression and anxiety levels in these participants. RESULTS: All patients scored significantly higher on depression and anxiety than the healthy participants did. P3 amplitude was significantly reduced in groups with treatment-resistant depression and generalized anxiety disorder but not in the group with borderline personality disorder or healthy controls. Anxiety level was negatively correlated with P3 amplitude in healthy controls rather than in other groups. CONCLUSIONS: This study did not discriminate treatment-resistant depression and generalized anxiety disorder regarding the passive P3 but suggested that there was a generalized impairment of passive attention in these disorders.

Speeding up the self-assembly of a DNA nanodevice using a variety of polar solvents.

The specific recognition and programmable assembly properties make DNA a potential material for nanodevices. However, the more intelligent the nanodevice is, the more complicated the structure of the nanodevice is, which limits the speed of DNA assembly. Herein, to address this problem, we investigate the performance of DNA Strand Displacement Reaction (DSDR) in a mixture of polar organic solvents and aqueous buffer and demonstrate that the organic polar solvent can speed up DNA self-assembly efficiently. Taking DSDR in 20% ethanol as an example, first we have demonstrated that the DSDR is highly accelerated in the beginning of the reaction and it can complete 60% of replacement reactions (160% enhancement compared with aqueous buffer) in the first 300 seconds. Secondly, we calculated that the ΔΔG of the DSDR in 20% ethanol (-18.2 kcal mol(-1)) is lower than that in pure aqueous buffer (-32.6 kcal mol(-1)), while the activation energy is lowered by introducing ethanol. Finally, we proved that the DSDR on the electrode surface can also be accelerated using this simple strategy. More importantly, to test the efficacy of this approach in nanodevices with a complicated and slow DNA self-assembly process, we apply this strategy in the hybridization chain reaction (HCR) and prove the acceleration is fairly obvious in 20% ethanol, which demonstrates the feasibility of the proposed strategy in DNA nanotechnology and DNA-based biosensors.

Sensitive and bidirectional detection of urine telomerase based on the four detection-color states of difunctional gold nanoparticle probe.

Telomerase, a valuable biomarker, is highly correlated with the development of most of human cancers. Here, we develop a bidirectional strategy for telomerase activity detection and bladder cancer diagnosis based on four detection-color states of difunctional gold nanoparticle (GNP) probes such as blue, purple, red, and precipitate. Specifically, we define the red GNP probe as origin, which represents urine extracts with inactive telomerase and implies normal individuals. The forward direction is corresponding to the detection of a relatively high concentration of active telomerase, in which system GNP probes assemble obviously and precipitate, predicting bladder cancer samples. The negative direction is corresponding to extracts with a relatively low concentration (purple) and without any telomerase (blue), which can be differentiated by naked eyes or UV-vis spectrum, indicating bladder cancer and normal individuals, respectively. More importantly, this noninvasive strategy shows great sensitivity and selectivity when tested by 18 urine specimens from bladder cancer patients, inflammation, and normal individuals.

Imparting biomolecules to a metal-organic framework material by controlled DNA tetrahedron encapsulation.

Recently, the incorporation of biomolecules in Metal-organic frameworks (MOFs) attracts many attentions because of controlling the functions, properties and stability of trapped molecules. Although there are few reports on protein/MOFs composites and their applications, none of DNA/MOFs composite is reported, as far as we know. Here, we report a new composite material which is self-assembled from 3D DNA (guest) and pre-synthesized MOFs (host) by electrostatic interactions and hydrophilic interactions in a well-dispersed fashion. Its biophysical characterization is well analyzed by fluorescence spectroscopy, quartz crystal microbalance (QCM) and transmission electron microscopy (TEM). This new composite material keeps 3D DNA nanostructure more stable than only 3D DNA nanostructure in DI water at room temperature, and stores amounts of genetic information. It will make DNA as a guest for MOFs and MOFs become a new platform for the development of DNA nanotechnology.

Personality disorder functioning styles are associated with the effects of the cognitive-behavioral therapy for panic disorder: a preliminary study.

BACKGROUND: The effect of the cognitive behavioral therapy (CBT) for panic disorder varies, but how personality disorder functioning style influences it remains unclear. SUBJECTS AND METHODS: In 30 healthy volunteers and 44 patients with panic disorder (22 treated and 22 waiting list), we administered the Parker Personality Measure (PERM) and the Plutchik-van Praag Depression Inventory (PVP). Before and during the CBT or waiting period, patients were asked to record their panic attacks using the Panic Attack Record (PAR). RESULTS: Patients scored significantly higher on PERM Antisocial, Borderline, Histrionic, Avoident, Dependent, and Passive-aggressive styles and on depression. After CBT, all PAR parameters were significantly reduced in the treated group. The Obsessive-compulsive style was positively correlated with the panic attack duration and the total-thought before CBT or waiting period in all patients. In treated patients, the decreased panic attack duration was positively correlated with Histrionic, Obsessive-compulsive and Passive-aggressive; the decreased total symptom number was positively correlated with Antisocial and Histrionic; the decreased total-sensation was positively correlated with antisocial; and the total-thought was positively correlated with Narcissistic style. CONCLUSIONS: The length and duration of CBT was short and mainly with behavioral strategies, how personality influenced the related cognition per se remains unknown here. However, our preliminary results indicate that personality disorder functioning styles related to the externalized behaviors and the Obsessive-compulsive style have positive effects on CBT for panic disorder, implying that CBT practitioners should note their personality styles when treating these patients.

Further evidence for the fifth higher trait of personality pathology: a correlation study using normal and disordered personality measures.

Studies between disordered personality and the Big-Five or the Alternative Five-Factor model of normal personality have consistently shown four higher traits. The fifth higher trait, relating to Openness to Experience or Impulsive Sensation Seeking was less supported. The culture-free Nonverbal Personality Questionnaire (NPQ) might help us to characterise the fifth higher trait. We therefore tried the Dimensional Assessment of Personality Pathology (DAPP), the NEO-Personality Inventory-Revised (NEO-PI-R), the Zuckerman-Kuhlman Personality Questionnaire (ZKPQ) and the NPQ in 253 healthy participants. Our results yielded five factors, four of which resembled the previous ones. The fifth one, namely Peculiarity Seeking, was defined by NPQ and NEO-PI-R Openness to Experience, ZKPQ Impulsive Sensation Seeking and DAPP Stimulus Seeking. Whether the fifth factor is linked to the schizotypal personality disorder as proposed remains unanswered.