Prefrontal cortical dopamine deficit may cause impaired glucose metabolism in schizophrenia.

The brain neurotramsmitter dopamine may play an important role in modulating systemic glucose homeostasis. In seven hundred and four drug- naïve patients with first-episode schizophrenia, we provide robust evidence of positive associations between negative symptoms of schizophrenia and high fasting blood glucose. We then show that glucose metabolism and negative symptoms are improved when intermittent theta burst stimulation (iTBS) on prefrontal cortex (PFC) is performed in patients with predominantly negative symptoms of schizophrenia. These findings led us to hypothesize that the prefrontal cortical dopamine deficit, which is known to be associated with negative symptoms, may be responsible for abnormal glucose metabolism in schizophrenia. To explore this, we optogenetically and chemogenetically inhibited the ventral tegmental area (VTA)-medial prefrontal cortex (mPFC) dopamine projection in mice and found both procedures caused glucose intolerance. Moreover, microinjection of dopamine two receptor (D2R) neuron antagonists into mPFC in mice significantly impaired glucose tolerance. Finally, a transgenic mouse model of psychosis named Disc1tr exhibited depressive-like symptoms, impaired glucose homeostasis, and compared to wild type littermates reduced D2R expression in prefrontal cortex.

Early non-response as a predictor of later non-response to antipsychotics in schizophrenia: a randomized trial.

BACKGROUND: It remains a challenge to predict the long-term response to antipsychotics in patients with schizophrenia who do not respond at an early stage. This study aimed to investigate the optimal predictive cut-off value for early non-response that would better predict later non-response to antipsychotics in patients with schizophrenia. METHODS: This multicenter, 8-week, open-label, randomized trial was conducted at 19 psychiatric centers throughout China. All enrolled participants were assigned to olanzapine, risperidone, amisulpride, or aripiprazole monotherapy for 8 weeks. The positive and negative syndrome scale (PANSS) was evaluated at baseline, week 2, week 4, and week 8. The main outcome was the prediction of nonresponse. Nonresponse is defined as a < 20% reduction in the total scores of PANSS from baseline to endpoint. Severity ratings of mild, moderate, and severe illness corresponded to baseline PANSS total scores of 58, 75, and 95, respectively. RESULTS: At week 2, a reduction of < 5% in the PANSS total score showed the highest total accuracy in the severe and mild schizophrenia patients (total accuracy, 75.0% and 80.8%, respectively), and patients who were treated with the risperidone and amisulpride groups (total accuracy, 82.4%, and 78.2%, respectively). A 10% decrease exhibited the best overall accuracy in the moderate schizophrenia patients (total accuracy, 84.0%), olanzapine (total accuracy, 79.2%), and aripiprazole group (total accuracy, 77.4%). At week 4, the best predictive cut-off value was < 20%, regardless of the antipsychotic or severity of illness (total accuracy ranging from 89.8 to 92.1%). CONCLUSIONS: Symptom reduction at week 2 has acceptable discrimination in predicting later non-response to antipsychotics in schizophrenia, and a more accurate predictive cut-off value should be determined according to the medication regimen and baseline illness severity. The response to treatment during the next 2 weeks after week 2 could be further assessed to determine whether there is a need to change antipsychotic medication during the first four weeks. TRIAL REGISTRATION: This study was registered on Clinicaltrials.gov (NCT03451734).

Diagnostic Stability in Psychiatric Patients From Hospital Admission to Discharge: A 10-Year Retrospective Study.

OBJECTIVE: This study aimed to evaluate the consistency or stability of mental disorders diagnosed in the psychiatry ward setting, investigate factors associated with consistency, and observe the disease distribution over the decade. METHODS: A total of 20,359 psychiatric inpatients were included in this retrospective study from June 2011 to December 2020. Diagnoses from the first admission to discharge were evaluated to determine the diagnostic consistency during hospitalization. Readmissions were selected as the subgroup, whose first and last discharge diagnoses were compared to analyze the relatively long-term diagnostic stability. Demographic and clinical characteristics were collected to identify predictors of diagnostic discrepancy. RESULTS: From 2011-2020, the hospitalization rate decreased from 42.7% to 20.7% for schizophrenia and grew from 13.3% to 23.8% for depression. Diagnoses were retained by 92.6% of patients at their first discharge diagnosis, ranging from 100% for disorders of psychological development to 16.3% for unspecified mental disorders. About 33.9% of diagnostic conversions were to bipolar disorder in patients having inconsistent diagnoses. However, among rehospitalizations, the diagnostic stability notably dropped to 71.3%. For rehospitalizations, mood disorders and schizophrenia spectrum disorders were relatively stable diagnoses categories, with 72.6% to 76.7% of patients receiving the same diagnosis, although results of specified diagnoses within these categories ranged from 5.9% to 91.0%. Except for mood disorders and schizophrenia spectrum disorders, the diagnoses of all other categories were below 70%. Long lengths of hospitalization and old age were associated with short-term diagnosis alterations. CONCLUSION: Longitudinal follow-up and integration of multiple aspects of information are essential for accurate diagnosis.

Relapse in patients with schizophrenia and amisulpride-induced hyperprolactinemia or olanzapine-induced metabolic disturbance after switching to other antipsychotics.

Hyperprolactinemia and metabolic disturbance are common side effects of antipsychotics that cause intolerance. Despite its potential influence on relapse, there are no established guidelines for antipsychotic switching. This naturalistic study explored the association between antipsychotic switching, baseline clinical status, metabolic changes, and relapse in patients with schizophrenia. In total, 177 patients with amisulpride-induced hyperprolactinemia and 274 with olanzapine-induced metabolic disturbance were enrolled. Relapse was determined by assessing changes in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to 6 months (increased over 20% or 10% reaching 70). Metabolic indices were measured at baseline and 3 months. Patients with baseline PANSS >60 were more likely to relapse. Further, patients switching to aripiprazole had a higher risk of relapse regardless of their original medication. Participants who originally used amisulpride had reduced prolactin levels following medication change, while switching to olanzapine caused increased weight and blood glucose levels. In patients originally using olanzapine, only switching to aripiprazole reduced insulin resistance. Adverse effects on weight and lipid metabolism were observed in patients who switched to risperidone, while amisulpride improved lipid profiles. Changing schizophrenia treatment requires careful consideration of multiple variables, particularly the choice of substituted drug and the patient's baseline symptoms.

Experimental demonstration of synchronous privacy enhanced chaotic temporal phase en/decryption for high speed secure optical communication.

Protecting confidential high speed optical signal transmission at the lowest physical layer is a critical challenge for modern fiber-optic communication systems. In this paper, we experimentally demonstrate a novel synchronous privacy enhanced chaotic temporal phase en/decryption scheme for high-speed physical layer secure optical communication. A remote chaos synchronization architecture relying on common source signal driving and private response hardware modules comprising of dispersive components and slave lasers is employed to generate synchronized private chaotic en/decryption signals, and simultaneously suppress residual driving-response correlation for enhancing the security. A proof-of-principle demonstration by secure transmission of a 28 Gb/s on-off-keying modulated confidential signal over 100 km single mode fiber link based on the private chaotic temporal phase en/decryption scheme is successfully achieved. The demonstrated hardware optical en/decryption approach may provide a promising way towards future ultra-high speed physical layer secure optical communication systems.

Photonic-layer secure 56 Gb/s PAM4 optical communication based on common noise driven synchronous private temporal phase en/decryption.

Achieving photonic layer security at the lowest network layer to supplement the upper layer digital cryptography in fiber-optic networks is a constant pursuit but a critical challenge. In this Letter, we propose and experimentally demonstrate a high-speed photonic-layer secure optical communication system based on a novel, to the best of our knowledge, common noise driven synchronous private temporal phase en/decryption scheme, which is capable of supporting high-order modulation formats and enhancing security. A record high bit rate of 56 Gb/s 4-level pulse amplitude modulation (PAM4) confidential signal is successfully encrypted and decrypted by remotely synchronized private noise-like en/decryption signals after secret transmission over 20 km of optical fiber with a bit-error-rate (BER) lower than the hard-decision forward error correction (HD-FEC) limit. The demonstrated scheme may provide a promising way for future ultrahigh-speed photonic-layer secure optical communication.

Developments in Biological Mechanisms and Treatments for Negative Symptoms and Cognitive Dysfunction of Schizophrenia.

The causal mechanisms and treatment for the negative symptoms and cognitive dysfunction in schizophrenia are the main issues attracting the attention of psychiatrists over the last decade. The first part of this review summarizes the pathogenesis of schizophrenia, especially the negative symptoms and cognitive dysfunction from the perspectives of genetics and epigenetics. The second part describes the novel medications and several advanced physical therapies (e.g., transcranial magnetic stimulation and transcranial direct current stimulation) for the negative symptoms and cognitive dysfunction that will optimize the therapeutic strategy for patients with schizophrenia in future.

Drugs Based on NMDAR Hypofunction Hypothesis in Schizophrenia.

Treatments for negative symptoms and cognitive dysfunction in schizophrenia remain issues that psychiatrists around the world are trying to solve. Their mechanisms may be associated with N-methyl-D-aspartate receptors (NMDARs). The NMDAR hypofunction hypothesis for schizophrenia was brought to the fore mainly based on the clinical effects of NMDAR antagonists and anti-NMDAR encephalitis pathology. Drugs targeted at augmenting NMDAR function in the brain seem to be promising in improving negative symptoms and cognitive dysfunction in patients with schizophrenia. In this review, we list NMDAR-targeted drugs and report on related clinical studies. We then summarize their effects on negative symptoms and cognitive dysfunction and analyze the unsatisfactory outcomes of these clinical studies according to the improved glutamate hypothesis that has been revealed in animal models. We aimed to provide perspectives for scientists who sought therapeutic strategies for negative symptoms and cognitive dysfunction in schizophrenia based on the NMDAR hypofunction hypothesis.

A novel construct of anhedonia revealed in a Chinese sample via the Revised Physical and Social Anhedonia Scales.

BACKGROUND: Anhedonia is a core clinical symptom of mental disorders. The Revised Physical Anhedonia Scale (RPAS) and the Revised Social Anhedonia Scale (RSAS) have been applied in clinical and non-clinical samples since 1980s. However, the construct of a unified RPAS&RSAS for comprehensive measurement of anhedonia has never been explored. Therefore, the purpose of our study was to examine the factor structure of the unified RPAS&RSAS among undergraduates and clinical patients. METHODS: A total of 3435 undergraduates from two universities and 294 clinical patients with mental disorders had completed the Chinese version of the RPAS and the RSAS. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were each conducted to reveal the constructs of the RPAS and the RSAS. CFA was used to evaluate first- and second-order models for the unified RPAS&RSAS in undergraduates and clinical patients. The internal consistency and test-retest reliability of the RPAS and the RSAS were also evaluated. RESULTS: EFA and CFA indicated 2-factor structures for RPAS and RSAS, with the factors being defined as anticipatory anhedonia and consummatory anhedonia. The second-order model of the unified RPAS&RSAS in the undergraduates and clinical patients both had satisfactory fit index values (Undergraduate sample: CFI = 0.901, TLI = 0.899, RMSEA = 0.055, SRMR = 0.086; Clinical sample: CFI = 0.922, TLI = 0.911, RMSEA = 0.052, SRMR = 0.078). The psychometric robustness of the RPAS&RSAS were confirmed by high internal consistency and test-retest reliability values. CONCLUSIONS: The unified RPAS&RSAS with a second-order structure was confirmed in both undergraduates and clinical samples in Chinese. The construct of anhedonia was refreshed as covering physical and social domains, and each of them includes both anticipatory and consummatory components.

Deregulation of Circular RNAs in Cancer From the Perspectives of Aberrant Biogenesis, Transport and Removal.

CircRNAs (circular RNAs) are a class of RNAs generated from circularization with multiple novel functions. Recent studies have revealed the aberrant expression and aberrant functions of circRNAs in various tumors; thus, circRNAs have been recognized as promising cancer biomarkers. However, the underlying mechanisms behind their aberrant expression and functions remain unclear. In this review, we discuss at length the cancer-specific deregulation of circRNAs and the potential underlying aberrant events in circRNA biogenesis, localization and removal in cancer cells.

Partial DNA-guided Cas9 enables genome editing with reduced off-target activity.

CRISPR-Cas9 is a versatile RNA-guided genome editing tool. Here we demonstrate that partial replacement of RNA nucleotides with DNA nucleotides in CRISPR RNA (crRNA) enables efficient gene editing in human cells. This strategy of partial DNA replacement retains on-target activity when used with both crRNA and sgRNA, as well as with multiple guide sequences. Partial DNA replacement also works for crRNA of Cpf1, another CRISPR system. We find that partial DNA replacement in the guide sequence significantly reduces off-target genome editing through focused analysis of off-target cleavage, measurement of mismatch tolerance and genome-wide profiling of off-target sites. Using the structure of the Cas9-sgRNA complex as a guide, the majority of the 3' end of crRNA can be replaced with DNA nucleotide, and the 5 - and 3'-DNA-replaced crRNA enables efficient genome editing. Cas9 guided by a DNA-RNA chimera may provide a generalized strategy to reduce both the cost and the off-target genome editing in human cells.

Universal Multifunctional Nanoplatform Based on Target-Induced in Situ Promoting Au Seeds Growth to Quench Fluorescence of Upconversion Nanoparticles.

Construction of a new multifunctional chemo/biosensing platform for small biomolecules and tumor markers is of great importance in analytical chemistry. Herein, a novel universal multifunctional nanoplatform for biomolecules and enzyme activity detection was proposed based on fluorescence resonance energy transfer (FRET) between upconversion nanoparticles (UCNPs) and target-inducing enlarged gold nanoparticles (AuNPs). The reductive molecule such as H2O2 can act as the reductant to reduce HAuCl4, which will make the Au seeds grow. The enlarged AuNPs can effectively quench the fluorescence of UCNPs owing to the good spectral overlap between the absorption band of the AuNPs and the emission band of the UCNPs. Utilizing the FRET between the UCNPs and enlarged AuNPs, good linear relationship between the fluorescence of UCNPs and the concentration of H2O2 can be found. Based on this strategy, H2O2 related molecules such as l-lactate, glucose, and uric acid can also be quantified. On the basis of UCNPs and PVP/HAuCl4, a general strategy for other reductants such as ascorbic acid (AA), dopamine (DA), or enzyme activity can be established. Therefore, the universal multifunctional nanoplatform based on UCNPs and the target-inducing in situ enlarged Au NPs will show its potential as a simple method for the detection of some life related reductive molecules, enzyme substrates, as well as enzyme activity.

Structure-guided chemical modification of guide RNA enables potent non-viral in vivo genome editing.

Efficient genome editing with Cas9-sgRNA in vivo has required the use of viral delivery systems, which have limitations for clinical applications. Translational efforts to develop other RNA therapeutics have shown that judicious chemical modification of RNAs can improve therapeutic efficacy by reducing susceptibility to nuclease degradation. Guided by the structure of the Cas9-sgRNA complex, we identify regions of sgRNA that can be modified while maintaining or enhancing genome-editing activity, and we develop an optimal set of chemical modifications for in vivo applications. Using lipid nanoparticle formulations of these enhanced sgRNAs (e-sgRNA) and mRNA encoding Cas9, we show that a single intravenous injection into mice induces >80% editing of Pcsk9 in the liver. Serum Pcsk9 is reduced to undetectable levels, and cholesterol levels are significantly lowered about 35% to 40% in animals. This strategy may enable non-viral, Cas9-based genome editing in the liver in clinical settings.

CRISPR/Cas9-mediated genome editing induces exon skipping by alternative splicing or exon deletion.

CRISPR is widely used to disrupt gene function by inducing small insertions and deletions. Here, we show that some single-guide RNAs (sgRNAs) can induce exon skipping or large genomic deletions that delete exons. For example, CRISPR-mediated editing of ß-catenin exon 3, which encodes an autoinhibitory domain, induces partial skipping of the in-frame exon and nuclear accumulation of ß-catenin. A single sgRNA can induce small insertions or deletions that partially alter splicing or unexpected larger deletions that remove exons. Exon skipping adds to the unexpected outcomes that must be accounted for, and perhaps taken advantage of, in CRISPR experiments.

Upconversion ratiometric fluorescence and colorimetric dual-readout assay for uric acid.

A new upconversion colorimetric and ratiometric fluorescence detection method for uric acid (UA) has been designed. Yb(3+), Er(3+) and Tm(3+) co-doped NaYF4 nanoparticles (UCNPs) was synthesized. The co-doped NaYF4 nanoparticles, emit upconversion fluorescence with four typical emission peaks centered at 490nm, 557nm, 670nm and 705nm under the 980nm near-infrared (NIR) irradiation. The ZnFe2O4 magnetic nanoparticles (MNPs) possessing excellent peroxidase-like activity was prepared and used to catalyze oxidation the coupling of N-ethyl-N-(3-sulfopropyl)-3-methylaniline sodium salt (TOPS) and 4-amino-antipyrine (4-AAP) in the presence of H2O2 to form purple products (compound 1) which has a characteristic absorption peak located at 550nm. The upconversion fluorescence at 557nm was quenched by the compound 1 while the upconversion emission at 705nm was essentially unchanged, the fluorescence ratio ((I557/I705)0/(I557/I705)) is positively proportional to UA concentration in existence of uricase. More importantly, colorimetric signal can be easily observed and applied to directly distinguish the concentration of UA by the naked eye. Under the optimized conditions, the linear range of colorimetric and ratiometric fluorescence sensing towards UA was 0.01-1mM, the detection limits were as low as 5.79µM and 2.86µM (S/N=3), respectively. The proposed method has been successfully applied to the analysis of UA in human serum. These results indicate that the colorimetric and ratiometric fluorescence dual-readout assay method has great potential for applications in physiological and pathological diagnosis.

Therapeutic genome editing by combined viral and non-viral delivery of CRISPR system components in vivo.

The combination of Cas9, guide RNA and repair template DNA can induce precise gene editing and the correction of genetic diseases in adult mammals. However, clinical implementation of this technology requires safe and effective delivery of all of these components into the nuclei of the target tissue. Here, we combine lipid nanoparticle-mediated delivery of Cas9 mRNA with adeno-associated viruses encoding a sgRNA and a repair template to induce repair of a disease gene in adult animals. We applied our delivery strategy to a mouse model of human hereditary tyrosinemia and show that the treatment generated fumarylacetoacetate hydrolase (Fah)-positive hepatocytes by correcting the causative Fah-splicing mutation. Treatment rescued disease symptoms such as weight loss and liver damage. The efficiency of correction was >6% of hepatocytes after a single application, suggesting potential utility of Cas9-based therapeutic genome editing for a range of diseases.

Enzymatic-induced upconversion photoinduced electron transfer for sensing tyrosine in human serum.

This paper reports a novel nanosensor for tyrosine based on photoinduced electron-transfer (PET) between NaYF4:Yb, Tm upconversion nanoparticles (UCNPs) and melanin-like polymers. Melanin-like films were obtained from catalytic oxidation of tyrosine by tyrosinase, and deposited on the surface of UCNPs, and then quenched the fluorescence of UCNPs. Under the optimized conditions, the fluorescence quenching of UCNPs showed a good linear response to tyrosine concentration in the range of 0.8-100 µΜ with a detection limit of 1.1 µΜ. Meanwhile, it showed good sensitivity, stability and has been successfully applied to the detection of tyrosine in human serum.

Upconversion nanosensor for sensitive fluorescence detection of Sudan I-IV based on inner filter effect.

Sudan dyes are banned as food additives due to the carcinogenicity of their metabolites in the human body. Therefore, it is of great significance for sensitive detection of Sudan dyes. This paper reports a novel nanosensor for Sudan dyes detection based on fluorescence (FL) quenching of hexadecyl trimethyl ammonium bromide (CTAB) stabilized upconversion nanoparticles (UCNPs) through the inner filter effect (IFE). In the presence of Sudan I-IV, the fluorescence emission of UCNPs was effectively quenched due to the absorption bands of Sudan I-IV largely covered the emission bands of UCNPs. Under the optimized conditions, the FL was quenched with Sudan concentration over the range of 0.05-40, 0.01-20, 0.01-40 and 0.05-40 µg/mL for Sudan I-IV, respectively. The corresponding limit of detection is 15.1, 2.83, 3.52 and 16.7 ng/mL (at 3σ/slope) respectively. Meanwhile, the nanosensor shows good selectivity, sensitivity and can be successfully applied to detection of Sudan in chili powder samples.

An upconversion fluorescence resonance energy transfer nanosensor for one step detection of melamine in raw milk.

Here we report a nanosensor based on fluorescence resonance energy transfer (FRET) between upconversion nanoparticles (UCNPs) and gold nanoparticles (AuNPs) for melamine detection. The positively charged UCNPs as donor and the negatively charged AuNPs as acceptor bound together through electrostatic interaction, which caused the fluorescence quenching of UCNPs. Upon addition of melamine, AuNPs were released from the surface of UCNPs and aggregation due to the N-Au interaction between melamine and AuNPs, which results in the fluorescence of UCNPs gradually recovered. Under the optimal conditions including media pH (7.0), the concentration of AuNPs (1.23nM) and incubation time (12min), the fluorescence enhanced efficiency shows a linear response to the melamine concentration ranging from 32.0 to 500nM with a detection limit of 18.0nM. Compared with other fluorescence methods, the fluorimetric nanosensor shows high sensitivity of 0.968, ease of operation and can be used for the determination of melamine in raw milk samples.

Insights into pyrroindomycin biosynthesis reveal a uniform paradigm for tetramate/tetronate formation.

The natural products pyrroindomycins (PYRs), active against various drug-resistant pathogens, possess a characteristic, cyclohexene ring spiro-linked tetramate moiety. In this study, investigation into PYR biosynthesis revealed two new proteins, both of which, phylogenetically distinct from but functionally substitutable to each other in vivo, individually catalyze a Dieckmann cyclization in vitro for converting an N-acetoacetyl-l-alanyl thioester into a tetramate. Their counterparts are commonly present in the biosynthetic pathways of spiro and polyether tetronates, supporting a uniform paradigm for tetronate/tetramate formation, which features an enzymatic way to generate the C-X (X = O or N) bond first and the C-C bond next in building of the 5-membered heterocycle.