Exploring the origin of a unique mutant allele in twin-tail goldfish using CRISPR/Cas9 mutants.

Artificial selection has been widely applied to genetically fix rare phenotypic features in ornamental domesticated animals. For many of these animals, the mutated loci and alleles underlying rare phenotypes are known. However, few studies have explored whether these rare genetic mutations might have been fixed due to competition among related mutated alleles or if the fixation occurred due to contingent stochastic events. Here, we performed genetic crossing with twin-tail ornamental goldfish and CRISPR/Cas9-mutated goldfish to investigate why only a single mutated allele-chdS with a E127X stop codon (also called chdAE127X)-gives rise to the twin-tail phenotype in the modern domesticated goldfish population. Two closely related chdS mutants were generated with CRISPR/Cas9 and compared with the E127X allele in F2 and F3 generations. Both of the CRISPR/Cas9-generated alleles were equivalent to the E127X allele in terms of penetrance/expressivity of the twin-tail phenotype and viability of carriers. These findings indicate that multiple truncating mutations could have produced viable twin-tail goldfish. Therefore, the absence of polymorphic alleles for the twin-tail phenotype in modern goldfish likely stems from stochastic elimination or a lack of competing alleles in the common ancestor. Our study is the first experimental comparison of a singular domestication-derived allele with CRISPR/Cas9-generated alleles to understand how genetic fixation of a unique genotype and phenotype may have occurred. Thus, our work may provide a conceptual framework for future investigations of rare evolutionary events in domesticated animals.

Integrated assessment of potentially toxic elements in soil of the Kangdian metallogenic province: A two-point machine learning approach.

The accumulation of potentially toxic elements in soil poses significant risks to ecosystems and human well-being due to their inherent toxicity, widespread presence, and persistence. The Kangdian metallogenic province, famous for its iron-copper deposits, faces soil pollution challenges due to various potentially toxic elements. This study explored a comprehensive approach that combinescombines the spatial prediction by the two-point machine learning method and ecological-health risk assessment to quantitatively assess the comprehensive potential ecological risk index (PERI), the total hazard index (THI) and the total carcinogenic risk (TCR). The proportions of copper (Cu), cadmium (Cd), manganese (Mn), lead (Pb), zinc (Zn), and arsenic (As) concentrations exceeding the risk screening values (RSVs) were 15.03%, 5.1%, 3.72%, 1.24%, 1.1%, and 0.13%, respectively, across the 725 collected samples. Spatial prediction revealed elevated levels of As, Cd, Cu, Pb, Zn, mercury (Hg), and Mn near the mining sites. Potentially toxic elements exert a slight impact on soil, some regions exhibit moderate to significant ecological risk, particularly in the southwest. Children face higher non-carcinogenic and carcinogenic health risks compared to adults. Mercury poses the highest ecological risk, while chromium (Cr) poses the greatest health hazard for all populations. Oral ingestion represents the highest non-oncogenic and oncogenic risks in all age groups. Adults faced acceptable non-carcinogenic risks. Children in the southwest region confront higher health risks, both non-carcinogenic and carcinogenic, from mining activities. Urgent measures are vital to mitigate Hg and Cr contamination while promoting handwashing practices is essential to minimize health risks.

Rack1-mediated ferroptosis affects hindgut development in rats with anorectal malformations: Spatial transcriptome insights.

Anorectal malformation (ARM), a common congenital anomaly of the digestive tract, is a result of insufficient elongation of the urorectal septum. The cytoplasmic protein Receptor of Activated C-Kinase 1 (Rack1) is involved in embryonic neural development; however, its role in embryonic digestive tract development and ARM formation is unexplored. Our study explored the hindgut development and cell death mechanisms in ARM-affected rats using spatial transcriptome analysis. We induced ARM in rats by administering ethylenethiourea via gavage on gestational day (GD) 10. On GDs 14-16, embryos from both normal and ARM groups underwent spatial transcriptome sequencing, which identified key genes and signalling pathways. Rack1 exhibited significant interactions among differentially expressed genes on GDs 15 and 16. Reduced Rack1 expression in the ARM-affected hindgut, verified by Rack1 silencing in intestinal epithelial cells, led to increased P38 phosphorylation and activation of the MAPK signalling pathway. The suppression of this pathway downregulated Nqo1 and Gpx4 expression, resulting in elevated intracellular levels of ferrous ions, reactive oxygen species (ROS) and lipid peroxides. Downregulation of Gpx4 expression in the ARM hindgut, coupled with Rack1 co-localisation and consistent mitochondrial morphology, indicated ferroptosis. In summary, Rack1, acting as a hub gene, modulates ferrous ions, lipid peroxides, and ROS via the P38-MAPK/Nqo1/Gpx4 axis. This modulation induces ferroptosis in intestinal epithelial cells, potentially influencing hindgut development during ARM onset.

Transient Receptor Potential Ankyrin 1-dependent Activation of Extracellular Signal-regulated Kinase 2 in the Cerebral Cortices Contributes to Cortical Spreading Depolarization.

Extracellular signal-regulated kinase (ERK) are serine/threonine-selective proteins and ERK1/2 can be phosphorylated in peripheral and central brain regions after cortical spreading depolarization (CSD) and calcitonin gene-related peptide; However, it remains unclear about whether and how ERK activity modulates CSD that correlates to migraine aura. Here, we determined the role of ERK in regulating CSD and explored the underlying mechanism involving transient receptor potential ankyrin 1 (TRPA1), a stress-sensing cation channel. CSD was recorded using intrinsic optical imaging in mouse brain slices, and electrophysiology in rats. Phosphorylated ERK (pERK1/2) and interleukin-1ß (IL-1ß) protein levels were detected using Western blot or enzyme-linked immunosorbent assay, respectively. IL-1ß mRNA level was detected using qPCR. The results showed that an ERK inhibitor, SCH77298, markedly prolonged CSD latency and reduced propagation rate in mouse brain slices. Corresponding to this, CSD induction increased levels of cytosolic pERK1/2 in ipsilateral cerebral cortices of rats, the elevation of which correlated to the level of IL-1ß mRNA. Mechanistic analysis showed that pre-treatment of an anti-TRPA1 antibody reduced the cytosolic pERK2 level but not pERK1 following CSD in cerebral cortices of rats and this level of pERK2 correlated with that of cerebral cortical IL-1ß protein. Furthermore, an ERK activator, AES16-2M, but not its scrambled control, reversed the prolonged CSD latency by a TRPA1 inhibitor, HC-030031, in mouse brain slices. These data revealed a crucial role of ERK activity in regulating CSD, and elevation of pERK and IL-1ß production induced by CSD is predominantly TRPA1 channel-dependent, thereby contributing to migraine pathogenesis.

Epidemiology of spinal cord injury and spinal cord injury-induced urinary tract stones in Taiwan: A 2005-2015 population-based cohort study.

CONTEXT: Patients with spinal cord injury (SCI) can develop urinary tract stones (UTSs) up to years after the injury, which is especially common in the first few months. However, relevant epidemiological studies and up-to-date epidemiological data for SCI in Taiwan are lacking. PURPOSE: To estimate SCI and SCI-induced UTS incidence and trauma severity, neurological deficits, and injury site in patients with SCI-induced UTSs in Taiwan. DESIGN: Retrospective cohort study.Patient sample: Taiwan National Health Insurance Research Database (NHIRD) data and death data from the Department of Health and Welfare Data Science Center (HWDC) collected over 2005-2015 from 13,977 patients with SCI aged >18 years. OUTCOME MEASURES: Cumulative incidence (CI), incidence density (ID), relative ratios (RRs), odds ratios (ORs), and hazard ratios (HRs) were measured. METHODS: By using Cox regression, we assessed UTS risk in patients with SCI. RESULTS: Although standardized SCI incidence demonstrated a decreasing trend annually, the average annual incidence remained at 60.4 per million. Most (65.7%) of the included patients were men. SCI incidence was 1.98 times higher in men than in women. The most common injury site was the cervical spine (63.8%); the incidence at this site was 2.83 times higher in men than in women. Most (76.1%) of the patients had traumatic SCI (TSCI), and the standardized incidence of TSCI and non-TSCI was 45.9 and 14.4 per million, respectively. 46.1% of the patients had severe SCI (RISS ≥ 16). Over the 11-year follow-up period, UTSs occurred in 10.4% of the patients, with a standardized incidence of 2.39 per 100 person-years, and UTS risk was 1.56 times higher in men than in women. Age of 45-65 years, SCIs at multiple sites, and neurological deficits (e.g. paraplegia) were noted to be UTS risk factors. Finally, UTS onset mainly occurred in the first year after SCI. CONCLUSION: The risk of UTS among patients with SCI is influenced by age, sex, injury site, and paraplegia but not by paralysis resulting from other neurological deficits. Even though SCI incidence is declining annually, severe SCI remains a significant issue. Therefore, continuing to reduce SCI incidence and strengthening urinary tract management in patients with SCI are essential for reducing UTS occurrence and their impact on health.

Habitual salt preference worsens blood pressure in hospitalized hypertensive patients with omicron infection under epidemic-related stress.

BACKGROUND: We investigated the synergistic effect of stress and habitual salt preference (SP) on blood pressure (BP) in the hospitalized Omicron-infected patients. METHODS: From 15,185 hospitalized Omicron-infected patients who reported having high BP or hypertension, we recruited 662 patients. All patients completed an electronic questionnaire on diet and stress, and were required to complete morning BP monitoring at least three times. RESULTS: The hypertensive group (n = 309) had higher habitual SP (P = 0.015) and COVID-19 related stress (P < 0.001), and had longer hospital stays (7.4 ± 1.5 days vs. 7.2 ± 0.5 days, P = 0.019) compared with controls (n = 353). After adjusting for a wide range of covariates including Omicron epidemic-related stress, habitual SP was found to increase both systolic (4.9 [95% confidence interval (CI), 2.3-7.4] mmHg, P < 0.001) and diastolic (2.1 [95%CI, 0.6-3.6] mmHg, P = 0.006) BP in hypertensive patients, and increase diastolic BP (2.0 [95%CI, 0.2-3.7] mmHg, P = 0.026) in the control group. 31 (8.8%) patients without a history of hypertension were discovered to have elevated BP during hospitalization, and stress was shown to be different in those patients (P < 0.001). In contrast, habitual SP was more common in hypertensive patients with uncontrolled BP, compared with patients with controlled BP (P = 0.002). CONCLUSIONS: Habitual SP and psychosocial stress were associated with higher BP in Omicron-infected patients both with and without hypertension. Nonpharmaceutical intervention including dietary guidance and psychiatric therapy are crucial for BP control during the long COVID-19 period.

Tandem Photon Avalanches for Various Nanoscale Emitters with Optical Nonlinearity up to 41st-Order through Interfacial Energy Transfer.

Photon avalanche has received continuous attention owing to its superior nonlinear dynamics and promising advanced applications. However, its impact is limited due to the intrinsic energy levels as well as the harsh requirements for the composites and sizes of doped materials. Here, with a universal mechanism named tandem photon avalanche (TPA), giant optical nonlinear response up to 41st-order in erbium ions, one of the most important lanthanide emitters, has been achieved on the nanoscale through interfacial energy transfer process. After capturing energy directly from the avalanched energy state 3 H4 of Tm3+ (800-nm emission), erbium ions also exhibit bright green and red PA emissions with intensities comparable to that of Tm3+ at a low excitation threshold (7.1 kWcm-2 ). Using the same strategy, effective PA looping cycles are successfully activated in Ce3+ and Ho3+ . Additionally, Yb3+ -mediated networks are constructed to further propagate PA effects to lowly-doped Tm3+ , enabling 475-nm PA emission. The newly proposed TPA strategy provides a facile route for generating photon avalanche not only from erbium ions but also from various emitters in multilayered core-shell nanoparticles.

Corrigendum: PPy@Fe3O4 nanoparticles inhibit the proliferation and metastasis of CRC via suppressing the NF-κB signaling pathway and promoting ferroptosis.

[This corrects the article DOI: 10.3389/fbioe.2022.1001994.].

Chaos Raman distributed optical fiber sensing.

The physics principle of pulse flight positioning is the main theoretical bottleneck that restricts the spatial resolution of the existing Raman distributed optical fiber sensing scheme. Owing to the pulse width of tens of nanoseconds, the spatial resolution of the existing Raman distributed optical fiber sensing scheme with kilometer-level sensing distance is limited to the meter level, which seriously restricts the development of the optical time-domain reflection system. In this paper, a chaos laser is proposed in the context of the physical principle of the Raman scattering effect, and a novel theory of chaos Raman distributed optical fiber sensing scheme is presented. The scheme reveals the characteristics of chaos Raman scattering light excited by a chaotic signal on the sensing fiber. Further, the chaos time-domain compression demodulation mechanism between the temperature variation information and chaos correlation peak is demonstrated. Then, the position of the temperature variation signal is precisely located using the delay time of the chaos correlation peak combined with the chaos pulse flight time. Based on this novel optical sensing mechanism, an experiment with 10 cm spatial resolution and 1.4 km sensing distance was conducted, and the spatial resolution was found to be independent of the sensing distance. Within the limit of the existing spatial resolution theory, the spatial resolution of the proposed scheme is 50 times higher than that of the traditional scheme. The scheme also provides a new research direction for optical chaos and optical fiber sensing.

Urolithin A alleviates neuropathic pain and activates mitophagy.

Neuropathic pain (NP) occurs frequently in the general population and has a negative impact on the quality of life. There is no effective therapy available yet owing to the complex pathophysiology of NP. In our previous study, we found that urolithin A (UA), a naturally occurring microflora-derived metabolite, could relieve NP in mice by inhibiting the activation of microglia and release of inflammation factors. Here in this study, we sought to investigate whether mitophagy would be activated when UA alleviated NP in mice. We showed that the autophagy flow was blocked in the spinal dorsal horn of the chronic constriction injury (CCI) mice when the most obvious pain behavior occurs. Intraperitoneal injection of UA markedly activated the mitophagy mediated by PTEN-induced kinase 1/Parkin, promoted mitobiogenesis in both neurons and microglia, and alleviated NP in the CCI mice. In summary, our data suggest that UA alleviates NP in mice and meanwhile induces mitophagy activation, which highlights a therapeutic potential of UA in the treatment of NP.

A novel inflammation-related prognostic model for predicting the overall survival of primary central nervous system lymphoma: A real-world data analysis.

Background: Primary central nervous system lymphoma (PCNSL) is a type of extranodal non-Hodgkin lymphoma. Although there are widely used prognostic scores, their accuracy and practicality are insufficient. Thus, a novel prognostic prediction model was developed for risk stratification of PCNSL patients in our research. Methods: We retrospectively collected 122 patients with PCNSL from two medical centers in China from January 2010 to June 2022. Among them, 72 patients were used as the development cohort to construct a new model, and 50 patients were used for the validation. Then, by using univariate and multivariate Cox regression analsis and Lasso analysis, the Xijing model was developed and composed of four variables, including lesion number, ß2-microglobulin (ß2-MG), systemic inflammation response index (SIRI) and Karnofsky performance status (KPS). Finally, we evaluated the Xijing model through internal and external validation. Results: Compared with the original prognostic scores, the Xijing model has an overall improvement in predicting the prognosis of PCNSL according to the time-dependent area under the curve (AUC), Harrell's concordance index (C-index), decision curve analysis (DCA), integrated discrimination improvement (IDI) and continuous net reclassification index (NRI). For overall survival (OS) and progression-free survival (PFS), the Xijing model can divide PCNSL patients into three groups, and shows more accurate stratification ability. In addition, the Xijing model can still stratify and predict prognosis similarly better in the elderly with PCNSL and subgroups received high-dose methotrexate (HD-MTX) or Bruton's tyrosine kinase inhibitors (BTKi). Finally, external validation confirmed the above results. Conclusions: Integrating four prognostic factors, including imaging findings, tumor burden, systemic inflammation response index, and comprehensive physical condition, we provided a novel prognostic model for PCNSL based on real-world data and evaluated its predictive capacity.

An On-Chip Bandpass Filter Using Complementary Slit-Ring-Resonator-Loaded Spoof Surface Plasmon Polaritons with a Flexible Notch-Band.

In this paper, an on-chip bandpass filter with enhanced notch-band is proposed based on the artificial spoof surface plasmon polariton (SSPP) structure around 60 GHz. The shapes of the tabs are modified to incorporate complementary slit-ring resonators (CSRRs) between tabs. The passband is produced by the first higher mode of the SSPP structure. By adding CSRRs, two notch frequencies have been produced in the passband. The advantage of the proposed structure is that these two transmission zeros are almost independent of each other and they do not have much impact on the frequency of the passband. Based on the measured results, the proposed filter has an insertion loss of 2.6 dB with the bandwidth of 14.3 GHz. The return loss is better than 12 dB. The notch-band has a bandwidth of 3.3 GHz with a suppression level over 20 dB. The proposed filter can be applied in the shared millimeter waveband of 5G communication systems.

Corrigendum: Yu et al. PPy@Fe3O4 nanoparticles inhibit the proliferation and metastasis of CRC via suppressing the NF-κB signaling pathway and promoting ferroptosis.

[This corrects the article DOI: 10.3389/fbioe.2022.1001994.].

Pleiotropic functions of chordin gene causing drastic morphological changes in ornamental goldfish.

Breeders and fanciers have established many peculiar morphological phenotypes in ornamental goldfish. Among them, the twin-tail and dorsal-finless phenotypes have particularly intrigued early and recent researchers, as equivalent morphologies are extremely rare in nature. These two mutated phenotypes appeared almost simultaneously within a short time frame and were fixed in several strains. However, little is known about how these two different mutations could have co-occurred during such a short time period. Here, we demonstrate that the chordin gene, a key factor in dorsal-ventral patterning, is responsible not only for the twin-tail phenotype but also for the dorsal-finless phenotype. Our F2 backcrossing and functional analyses revealed that the penetrance/expressivity of the dorsal-finless phenotype can be suppressed by the wild-type allele of chdS. Based on these findings, we propose that chdSwt may have masked the expression of the dorsal-finless phenotype, acting as a capacitor buffering gene to allow accumulation of genetic mutations. Once this gene lost its original function in the twin-tail goldfish lineages, the dorsal-finless phenotype could be highly expressed. Thus, this study experimentally demonstrates that the rapid genetic fixation of morphological mutations during a short domestication time period may be related to the robustness of embryonic developmental mechanisms.

The Acceptability of Remotely Delivered Cognitive Adaptation Training.

Cognitive Adaptation Training (CAT) is a psychosocial treatment using environmental supports such as signs, checklists, technology, and the organization of belongings to bypass cognitive and motivational impairments for those with serious behavioral health problems. We conducted a survey of 204 members of managed Medicaid in Texas to examine the acceptability of, opinions about and preferences for CAT delivered in-person (CAT) or remotely (R-CAT) where supplies would be mailed and visits would occur via videoconferencing. The telephone survey presented descriptions of CAT and R-CAT in counterbalanced order eliciting general opinions about the treatments, such as (1) whether they would accept the treatments if they were offered the day of the survey at no cost, (2) which treatment was preferred, and (3) the extent to which they agreed or disagreed with a number of statements about components of the treatments. Results indicated that both R-CAT and CAT were acceptable to respondents with overall acceptance rates significantly higher for R-CAT 87% than for CAT (78%). With respect to preferences, 27% and 28% of respondents preferred CAT and R-CAT, respectively, and 41% of respondents preferred both equally. Black respondents more often preferred in-person CAT to other alternatives. Respondents agreed that they needed help, that they were comfortable with technology, and that they believed the programs would help them. The vast majority of qualitative comments about the treatments were positive. Results suggest that it will be important to assess the efficacy and effectiveness of CAT delivered remotely in randomized trials.

PPy@Fe3O4 nanoparticles inhibit the proliferation and metastasis of CRC via suppressing the NF-κB signaling pathway and promoting ferroptosis.

Colorectal cancer (CRC) is one of the most common cancers of the digestive tract, and patients with advanced-stage cancer have poor survival despite the use of multidrug conventional chemotherapy regimens. Intra-tumor heterogeneity of cancerous cells is the main obstacle in the way to effective cancer treatments. Therefore, we are looking for novel approaches to eliminate just cancer cells including nanoparticles (NPs). PPy@Fe3O4 NPs were successfully synthesized through a portable method. The characterization of transmission electron microscopy (TEM), Fourier-Transformed infrared spectrometer, and X-ray powder diffraction have further proved successful preparation of PPy@Fe3O4 NPs. NIR irradiation was used to test the photothermal properties of NPs and an infrared camera was used to record their temperature. The direct effects of PPy@Fe3O4 NPs on colorectal cancer cell DLD1 were assessed using CCK8, plate clone, transwell, flow cytometry, and western blotting in CRC cell. The effect of PPy@Fe3O4 NPs on neoplasm growth in nude mice was evaluated in vivo. This study demonstrated that PPy@ Fe3O4 NPs significantly inhibit the growth, migration, and invasion and promote ferroptosis to the untreated controls in colorectal cancer cells. Mechanical exploration revealed that PPy@Fe3O4 NPs inhibit the multiplication, migration, and invasion of CRC cells in vitro by modulating the NF-κB signaling pathway. Importantly, Ferroptosis inhibitors Fer-1 can reverse the changes in metastasis-associated proteins caused by NPs treatment. Collectively, our observations revealed that PPy@Fe3O4 NPs were blockers of tumor progression and metastasis in CRC. This study brought new insights into bioactive NPs, with application potential in curing CRC or other human disorders.

Analysis of Differential Diagnosis of Benign and Malignant Partially Cystic Thyroid Nodules Based on Ultrasound Characterization With a TIRADS Grade-4a or Higher Nodules.

Partially cystic thyroid nodules (PCTNs) are a kind of thyroid nodule with both solid and cystic components, and are usually misdiagnosed as benign nodules. The objective of this study was to determine the ultrasound (US) characterizations with a TIRADS Grade-4a or higher partially cystic thyroid nodules (PCTNs) which are associated with being malignant or benign. In this study, 133 PCTNs with a TIRADS Grade-4a or higher were enrolled; 83 were malignant and 50 were benign. TI-RADS classification can detect malignant PCTNs, and its sensitivity, specificity, positive predictive value, negative predictive value, and accuracy are 39.8%, 96.0%, 94.3%, 49.0%, and 60.9%, respectively. Univariate analyses revealed that nodule shape, margin, and structure were related to PCTNs' being benign and malignant, among which nodules taller-than-wide, with an irregular shape, non-smooth margin, eccentric sharp angle, or edge sharp angle were significantly associated with malignancy while ovoid to round nodules, smooth margins, multiple separation, and eccentric obtuse angle structures were significantly associated with a benign nature. For the solid part of PCTNs, its free margin, echo, and calcification are related to benign and malignant PCTNs. Among them, the free margin of the solid part is non-smooth, hypoechoic, and microcalcification, which are related to malignant PCTNs, while the free margin of the solid part is smooth, isoechoic, macrocalcification, non-calcification and are related to benign PCTNs. Calcification of solid part and free margin are important factors for predicting malignant PCTNs. In addition, nodules' composition, blood flow signal, and other factors had nothing to do with PCTNs' being benign or malignant. In the multivariate Logistic regression analysis, solid part calcification (OR: 17.28; 95%CI: 5.14~58.08) and free margin (OR: 3.18; 95%CI: 1.01~10.00) were revealed to be the strongest independent predictors for malignancy (P<0.05). Our study indicated that understanding the ultrasound characteristics of malignant PCTNs, to avoid misdiagnosed PCTNs patients, is important to make a precise diagnosis and prognosis of PCTNs.

Toll like receptor 4 gene Asp299Gly polymorphism increases the risk of diabetic microvascular complications: a meta analysis.

OBJECTIVE: The relationship between Toll like receptor 4(TLR4) gene Asp299Gly polymorphism and diabetic microvascular complications (DMI) is unclear. Therefore, the aim of this meta analysis was to explore the relationship between TLR4 Asp299Gly polymorphism and DMI. METHODS: System search PubMed, Web of science, Springer, Cochrane library, ELSEVIER, Wanfang database, VIP, CNKI, a case-control study of the correlation between TLR4 gene Asp299Gly polymorphism and DMI published before June 2020 was collected. RESULTS: We included 6 articles, a total of 11 studies involving patients with type 2 diabetes mellitus (T2DM) complicated by microvascular complications 1834 cases, without corresponding microvascular complications 4069 cases. TLR4 gene Asp299Gly polymorphism increased the risk of microvascular complications in T2DM (dominant model OR = 1.52, 95% CI 1.10-2.09, p = 0.01; allelic model OR = 1.42, 95% CI 1.02-1.96, p = 0.04). Subgroup analysis by race and different type of microvascular complications, we found that TLR4 gene Asp299Gly polymorphism was associated with increased risk of microvascular complications in the Caucasian population (dominant model OR = 1.69, 95% CI 1.22-2.35, P = 0.002; allelic model OR = 1.56, 95% CI 1.10-2.21, P = 0.01) and increased the risk of retinopathy in patients with T2DM(dominant model OR = 1.81, 95% CI 1.04-3.14, P = 0.03; allelic model OR = 1.77, 95% CI 1.05-2.98, P = 0.03). CONCLUSION: TLR4 gene Asp299Gly polymorphism was associated with increased risk of microvascular complications in patients with T2DM, especially diabetic retinopathy (DR).

Probiotic in the prevention of ventilator-associated pneumonia in critically ill patients: evidence from meta-analysis and trial sequential analysis of randomized clinical trials.

BACKGROUND: Probiotic might have a role in the prevention of ventilator-associated pneumonia (VAP) among mechanically ventilated patients, but the efficacy and safety remained inconsistent. The aim of this systematic review and meta-analysis was to evaluate the efficacy and safety of probiotic (prebiotic, synbiotic) versus placebo in preventing VAP in critically ill patients undergoing mechanical ventilation. METHODS: PubMed, Embase and the Cochrane library databases were searched to 10 October 2021 without language restriction for randomized or semi-randomized controlled trials evaluating probiotic (prebiotic, synbiotic) vs. placebo in prevention of VAP in critically ill mechanically ventilated patients. The pooled relative risk (RR) along with 95% confidence intervals (CI) were combined using a random-effects model. Furthermore, the trial sequential analysis (TSA) and subgroup analyses were performed. Statistical significance was regarded as P < 0.05. RESULTS: Twenty-three trials involving 5543 patients were eligible for this meta-analysis. The combined RR of decreasing the risk of VAP by probiotic was 0.67 (0.56, 0.81) for all eligible studies, 0.69 (n = 5136; 95% CI = 0.57 to 0.84; P < 0.01) for adults studies and 0.55 (n = 407; 95%CI = 0.31 to 0.99; P = 0.046) for neonates/children studies. Additionally, the above-mentioned positive finding in 20 adults studies was verified by the results of TSA, subgroup analyses and cumulative meta-analysis. Ample evidences demonstrated a 31% decrease in RR of incidence of VAP was noted when prophylactic probiotic therapy was administrated among adult patients. Finally, there were no effects on the ICU/hospital/28-/90-day mortality, bacteremia, CRBSI, diarrhea, ICU-acquired infections, infectious complications, pneumonia, UTI and wound infection between two groups (P > 0.05 for all). CONCLUSIONS: Based on the results of our study, the current evidences suggested that prophylactic administration of probiotic might be utilized as a preventive method for VAP in neonates/children and adults patients who required mechanical ventilation. However, further large, high-quality RCTs are warranted to assess the efficacy and safety of probiotic treatment in critically ill patients, especially for the neonates/children studies and the long-term consequences of this therapy.

Far-Red Light Triggered Production of Bispecific T Cell Engagers (BiTEs) from Engineered Cells for Antitumor Application.

Bispecific T-cell engagers (BiTEs), which have shown potent antitumor activity in humans, are emerging as one of the most promising immunotherapeutic strategies for cancer treatment in recent years. However, the clinical application of BiTEs nowadays has been hampered by their short half-life in the circulatory system due to their low molecular weight and rapid renal clearance. Inevitable continuous infusion of BiTEs has become a routine operation in order to achieve effective treatment, although it is costly, inconvenient, time-consuming, and even painful for patients in some cases. To develop an on-demand, tunable, and reversible approach to overcome these limitations, we assembled a transcription-control device into mammalian cells based on a bacterial far-red light (FRL) responsive signaling pathway to drive the expression of a BiTE against Glypican 3 (GPC3), which is a highly tumor-specific antigen expressed in most hepatocellular carcinomas (HCC). As demonstrated in in vitro experiments, we proved that the FRL sensitive device spatiotemporally responded to the control of FRL illumination and produced a therapeutic level of BiTEs that recruited and activated human T cells to eliminate GPC3 positive tumor cells. By functionally harnessing the power of optogenetics to remotely regulate the production of BiTEs from bioengineered cells and demonstrating its effectiveness in treating tumor cells, this study provides a novel approach to achieve an in vivo supply of BiTEs, which could be potentially applied to other formats of bispecific antibodies and facilitate their clinical applications.