High-resolution functional mapping of RAD51C by saturation genome editing.

Pathogenic variants in RAD51C confer an elevated risk of breast and ovarian cancer, while individuals homozygous for specific RAD51C alleles may develop Fanconi anemia. Using saturation genome editing (SGE), we functionally assess 9,188 unique variants, including >99.5% of all possible coding sequence single-nucleotide alterations. By computing changes in variant abundance and Gaussian mixture modeling (GMM), we functionally classify 3,094 variants to be disruptive and use clinical truth sets to reveal an accuracy/concordance of variant classification >99.9%. Cell fitness was the primary assay readout allowing us to observe a phenomenon where specific missense variants exhibit distinct depletion kinetics potentially suggesting that they represent hypomorphic alleles. We further explored our exhaustive functional map, revealing critical residues on the RAD51C structure and resolving variants found in cancer-segregating kindred. Furthermore, through interrogation of UK Biobank and a large multi-center ovarian cancer cohort, we find significant associations between SGE-depleted variants and cancer diagnoses.

Integrated analysis strategy of genome-wide functional gene mining reveals DKK2 gene underlying meat quality in Shaziling synthesized pigs.

BACKGROUND: Shaziling pig is a well-known indigenous breed in China who has superior meat quality traits. However, the genetic mechanism and genomic evidence underlying meat quality characteristics of Shaziling pigs are still unclear. To explore and investigate the germplasm characteristics of Shaziling pigs, we totally analyzed 67 individual's whole genome sequencing data for the first time (20 Shaziling pigs [S], 20 Dabasha pigs [DBS], 11 Yorkshire pigs [Y], 10 Berkshire pigs [BKX], 5 Basha pigs [BS] and 1 Warthog). RESULTS: A total of 2,538,577 SNPs with high quality were detected and 9 candidate genes which was specifically selected in S and shared in S to DBS were precisely mined and screened using an integrated analysis strategy of identity-by-descent (IBD) and selective sweep. Of them, dickkopf WNT signaling pathway inhibitor 2 (DKK2), the antagonist of Wnt signaling pathway, was the most promising candidate gene which was not only identified an association of palmitic acid and palmitoleic acid quantitative trait locus in PigQTLdb, but also specifically selected in S compared to other 48 Chinese local pigs of 12 populations and 39 foreign pigs of 4 populations. Subsequently, a mutation at 12,726-bp of DKK2 intron 1 (g.114874954 A > C) was identified associated with intramuscular fat content using method of PCR-RFLP in 21 different pig populations. We observed DKK2 specifically expressed in adipose tissues. Overexpression of DKK2 decreased the content of triglyceride, fatty acid synthase and expression of relevant genes of adipogenic and Wnt signaling pathway, while interference of DKK2 got contrary effect during adipogenesis differentiation of porcine preadipocytes and 3T3-L1 cells. CONCLUSIONS: Our findings provide an analysis strategy for mining functional genes of important economic traits and provide fundamental data and molecular evidence for improving pig meat quality traits and molecular breeding.

Radiation therapy with phenotypic medicine: towards N-of-1 personalization.

In current clinical practice, radiotherapy (RT) is prescribed as a pre-determined total dose divided over daily doses (fractions) given over several weeks. The treatment response is typically assessed months after the end of RT. However, the conventional one-dose-fits-all strategy may not achieve the desired outcome, owing to patient and tumor heterogeneity. Therefore, a treatment strategy that allows for RT dose personalization based on each individual response is preferred. Multiple strategies have been adopted to address this challenge. As an alternative to current known strategies, artificial intelligence (AI)-derived mechanism-independent small data phenotypic medicine (PM) platforms may be utilized for N-of-1 RT personalization. Unlike existing big data approaches, PM does not engage in model refining, training, and validation, and guides treatment by utilizing prospectively collected patient's own small datasets. With PM, clinicians may guide patients' RT dose recommendations using their responses in real-time and potentially avoid over-treatment in good responders and under-treatment in poor responders. In this paper, we discuss the potential of engaging PM to guide clinicians on upfront dose selections and ongoing adaptations during RT, as well as considerations and limitations for implementation. For practicing oncologists, clinical trialists, and researchers, PM can either be implemented as a standalone strategy or in complement with other existing RT personalizations. In addition, PM can either be used for monotherapeutic RT personalization, or in combination with other therapeutics (e.g. chemotherapy, targeted therapy). The potential of N-of-1 RT personalization with drugs will also be presented.

Genomic surveillance of omicron B.1.1.529 SARS-CoV-2 and its variants between December 2021 and March 2023 in Tamil Nadu, India-A state-wide prospective longitudinal study.

A state-wide prospective longitudinal investigation of the genomic surveillance of the omicron B.1.1.529 SARS-CoV-2 variant and its sublineages in Tamil Nadu, India, was conducted between December 2021 and March 2023. The study aimed to elucidate their mutational patterns and their genetic interrelationship in the Indian population. The study identified several unique mutations at different time-points, which likely could attribute to the changing disease characteristics, transmission, and pathogenicity attributes of omicron variants. The study found that the omicron variant is highly competent in its mutating potentials, and that it continues to evolve in the general population, likely escaping from natural as well as vaccine-induced immune responses. Our findings suggest that continuous surveillance of viral variants at the global scenario is warranted to undertake intervention measures against potentially precarious SARS-CoV-2 variants and their evolution.

Cost and outcomes of Hospital-based Usual cAre versus Tele-monitor self-directed Rehabilitation (HUATR) in patients with total knee arthroplasty: A randomized, controlled, non-inferiority trial.

OBJECTIVE: To evaluate the clinical efficacy and cost-effectiveness of telemonitored self-directed rehabilitation (TR) compared with hospital-based rehabilitation (HBR) for patients with total knee arthroplasty (TKA). DESIGN: In this randomized, non-inferiority clinical trial, 114 patients with primary TKA who were able to walk independently preoperatively were randomized to receive HBR (n = 58) or TR (n = 56). HBR comprised at least five physical therapy sessions over 10 weeks. TR comprised a therapist-led onboarding session, followed by a 10-week unsupervised home-based exercise program, with asynchronous monitoring of rehabilitation outcomes using a telemonitoring system. The primary outcome was fast-paced gait speed at 12 weeks, with a non-inferiority margin of 0.10 m/s. For economic analysis, quality-adjusted-life-years (QALY) was the primary economic outcome (non-inferiority margin, 0.027 points). RESULTS: In Bayesian analyses, TR had >95% posterior probability of being non-inferior to HBR in gait speed (week-12 adjusted TR-HBR difference, 0.02 m/s; 95%CrI, -0.05 to 0.10 m/s; week-24 difference, 0.01 m/s; 95%CrI, -0.07 to 0.10 m/s) and QALY (0.006 points; 95%CrI, -0.006 to 0.018 points). When evaluated from a societal perspective, TR was associated with lower mean intervention cost (adjusted TR-HBR difference, -S$227; 95%CrI, -112 to -330) after 24 weeks, with 82% probability of being cost-effective compared with HBR at a willingness to pay of S$0/unit of effect for the QALYs. CONCLUSIONS: In patients with uncomplicated TKAs and relatively good preoperative physical function, home-based, self-directed TR was non-inferior to and more cost-effective than HBR over a 24-week follow-up period. TR should be considered for this patient subgroup.

Adrenal Vein Sampling for Primary Aldosteronism: Recommendations From the Australian and New Zealand Working Group.

Adrenal vein sampling (AVS) is the current recommended procedure for identifying unilateral subtypes of primary aldosteronism (PA), which are amenable to surgery with the potential for cure. AVS is a technically challenging procedure usually undertaken by interventional radiologists at tertiary centres. However, there are numerous variations in AVS protocols relating to patient preparation, sampling techniques and interpretation which may impact the success of AVS and patient care. To reduce practice variations, improve the success rates of AVS and optimise patient outcomes, we established an Australian and New Zealand AVS Working Group and developed evidence-based expert consensus recommendations for the preparation, performance and interpretation of AVS. These recommendations can be used by all healthcare professionals in a multidisciplinary team who look after the diagnosis and management of PA.

Engineering strategies for enhanced 1', 4'-trans-ABA diol production by Botrytis cinerea.

BACKGROUND: Currently, industrial fermentation of Botrytis cinerea is a significant source of abscisic acid (ABA). The crucial role of ABA in plants and its wide range of applications in agricultural production have resulted in the constant discovery of new derivatives and analogues. While modifying the ABA synthesis pathway of existing strains to produce ABA derivatives is a viable option, it is hindered by the limited synthesis capacity of these strains, which hinders further development and application. RESULTS: In this study, we knocked out the bcaba4 gene of B. cinerea TB-31 to obtain the 1',4'-trans-ABA-diol producing strain ZX2. We then studied the fermentation broth of the batch-fed fermentation of the ZX2 strain using metabolomic analysis. The results showed significant accumulation of 3-hydroxy-3-methylglutaric acid, mevalonic acid, and mevalonolactone during the fermentation process, indicating potential rate-limiting steps in the 1',4'-trans-ABA-diol synthesis pathway. This may be hindering the flow of the synthetic pathway. Additionally, analysis of the transcript levels of terpene synthesis pathway genes in this strain revealed a correlation between the bchmgr, bcerg12, and bcaba1-3 genes and 1',4'-trans-ABA-diol synthesis. To further increase the yield of 1',4'-trans-ABA-diol, we constructed a pCBg418 plasmid suitable for the Agrobacterium tumefaciens-mediated transformation (ATMT) system and transformed it to obtain a single-gene overexpression strain. We found that overexpression of bchmgr, bcerg12, bcaba1, bcaba2, and bcaba3 genes increased the yield of 1',4'-trans-ABA-diol. The highest yielding ZX2 A3 strain was eventually screened, which produced a 1',4'-trans-ABA-diol concentration of 7.96 mg/g DCW (54.4 mg/L) in 144 h of shake flask fermentation. This represents a 2.1-fold increase compared to the ZX2 strain. CONCLUSIONS: We utilized metabolic engineering techniques to alter the ABA-synthesizing strain B. cinerea, resulting in the creation of the mutant strain ZX2, which has the ability to produce 1',4'-trans-ABA-diol. By overexpressing the crucial genes involved in the 1',4'-trans-ABA-diol synthesis pathway in ZX2, we observed a substantial increase in the production of 1',4'-trans-ABA-diol.

Multifaceted roles of mitochondria in asthma.

Mitochondria are essential organelles within cells, playing various roles in numerous cellular processes, including differentiation, growth, apoptosis, energy conversion, metabolism, and cellular immunity. The phenotypic variation of mitochondria is specific to different tissues and cell types, resulting in significant differences in their function, morphology, and molecular characteristics. Asthma is a chronic, complex, and heterogeneous airway disease influenced by external factors such as environmental pollutants and allergen exposure, as well as internal factors at the tissue, cellular, and genetic levels, including lung and airway structural cells, immune cells, granulocytes, and mast cells. Therefore, a comprehensive understanding of the specific responses of mitochondria to various external environmental stimuli and internal changes are crucial for elucidating the pathogenesis of asthma. Previous research on mitochondrial-targeted therapy for asthma has primarily focused on antioxidants. Consequently, it is necessary to summarize the multifaceted roles of mitochondria in the pathogenesis of asthma to discover additional strategies targeting mitochondria in this context. In this review, our goal is to describe the changes in mitochondrial function in response to various exposure factors across different cell types and other relevant factors in the context of asthma, utilizing a new mitochondrial terminology framework that encompasses cell-dependent mitochondrial characteristics, molecular features, mitochondrial activity, function, and behavior.

Unique association of anti-GABAA receptor encephalitis and myasthenia gravis in a patient with type A thymoma.

Association between anti-GABAAR encephalitis and myasthenia gravis is extremely rare with few reported cases. Herein, we report a case of a female patient diagnosed with anti-GABAAR encephalitis and thymoma at the first admission. She was administered glucocorticoids for long-term immunotherapy, and thymectomy with biopsy demonstrated a type A thymoma. After 4 months, the symptoms of encephalitis were relieved, but she then developed post-thymectomy myasthenia gravis with anti-AChR and anti-titin dual positivity. Antibodies to connective tissue (anti-ANA, anti-PCNA) and those characteristics of paraneoplastic syndrome (anti-Ma2/Ta) were also positive. She received oral glucocorticoids and tacrolimus as immunosuppressive therapy, and myasthenic symptoms were stable during a 2-year follow-up. Our case revealed that anti-GABAAR encephalitis and myasthenia gravis can appear in patient with type A thymoma at different periods, which alerts physicians to take long-term follow-up for anti-GABAAR encephalitis with thymoma, even after thymectomy. Concurrent positivity for more than one antibody after thymectomy is rarely observed, and their contribution to the clinical course and treatment decision remains to be further investigated.

Comparison of translation algorithms in determining maximum allowable CTV shifts for Real-Time Gated Proton Therapy (RGPT) robustness evaluation in prostate cancers.

INTRODUCTION: Real-Time Gated Proton Therapy (RGPT) is an active motion management technique that utilizes treatment gating and tumor tracking via fiducial markers. When performing RGPT treatment for prostate cancer, it is essential to account for the CTV displacement relative to the body in the clinical workflow. The workflow at the National Cancer Centre Singapore (NCCS) includes bone matching via CT-CBCT images, followed by fiducial matching via pulsed fluoroscopy (soft tissue matching), and finally, a robustness evaluation procedure to determine if the difference is within an allowable tolerance. In this study, we compare two CTV translation methods for robustness evaluation: (1) an in-house translation algorithm and (2) the RayStation "simulate organ motion" Deformable image registration (DIR) algorithm. METHODS: Nine RGPT prostate patient plans with CTV volumes ranging from 17.1 to 96.72 cm2 were included in this study. An in-house translation algorithm and "simulate organ motion" DIR RayStation algorithm were used to generate CTV shifts along R-L, I-S, and P-A axes between ± $ \pm $ 10 mm at 2 mm steps. At each step, dose metrics, which include CTV Dmax, CTV D95%, and CTV D98%, were extracted and used as comparative metrics for CTV target coverage and hot spot evaluation. RESULTS: Across all axes, there were no statistically significant differences between the two algorithms for all three dose metrics: CTV Dmax (P = 0.92, P = 0.91, and P = 0.47), CTV D95% (P = 0.97, P = 0.22, and P = 0.33), and CTV D98% (P = 0.85, P = 0.33, and P = 0.36). Further, the in-house translation algorithm evaluation time was less than 10 s, two orders of magnitude faster than the DIR algorithm. CONCLUSION: Our results demonstrate that the simpler in-house algorithm performs equivalently to the realistic DIR algorithm when simulating CTV motion in prostate cancers. Furthermore, the in-house algorithm completes the robustness evaluation two orders of magnitude faster than the DIR algorithm. This significant reduction in evaluation time is crucial especially when preparatory time efficiency is of paramount importance in a busy clinic.

Detecting outliers beyond tolerance limits derived from statistical process control in patient-specific quality assurance.

BACKGROUND: Tolerance limit is defined on pre-treatment patient specific quality assurance results to identify "out of the norm" dose discrepancy in plan. An out-of-tolerance plan during measurement can often cause treatment delays especially if replanning is required. In this study, we aim to develop an outlier detection model to identify out-of-tolerance plan early during treatment planning phase to mitigate the above-mentioned risks. METHODS: Patient-specific quality assurance results with portal dosimetry for stereotactic body radiotherapy measured between January 2020 and December 2021 were used in this study. Data were divided into thorax and pelvis sites and gamma passing rates were recorded using 2%/2 mm, 2%/1 mm, and 1%/1 mm gamma criteria. Statistical process control method was used to determine six different site and criterion-specific tolerance and action limits. Using only the inliers identified with our determined tolerance limits, we trained three different outlier detection models using the plan complexity metrics extracted from each treatment field-robust covariance, isolation forest, and one class support vector machine. The hyperparameters were optimized using the F1-score calculated from both the inliers and validation outliers' data. RESULTS: 308 pelvis and 200 thorax fields were used in this study. The tolerance (action) limits for 2%/2 mm, 2%/1 mm, and 1%/1 mm gamma criteria in the pelvis site are 99.1% (98.1%), 95.8% (91.1%), and 91.7% (86.1%), respectively. The tolerance (action) limits in the thorax site are 99.0% (98.7%), 97.0% (96.2%), and 91.5% (87.2%). One class support vector machine performs the best among all the algorithms. The best performing model in the thorax (pelvis) site achieves a precision of 0.56 (0.54), recall of 1.0 (1.0), and F1-score of 0.72 (0.70) when using the 2%/2 mm (2%/1 mm) criterion. CONCLUSION: The model will help the planner to identify an out-of-tolerance plan early so that they can refine the plan further during the planning stage without risking late discovery during measurement.

Repurposing DailyQA3 for an efficient and spot position sensitive daily quality assurance tool for proton therapy.

INTRODUCTION: Daily quality assurance is an integral part of a radiotherapy workflow to ensure the dose is delivered safely and accurately to the patient. It is performed before the first treatment of the day and needs to be time and cost efficient for a multiple gantries proton center. In this study, we introduced an efficient method to perform QA for output constancy, range verification, spot positioning accuracy and imaging and proton beam isocenter coincidence with DailyQA3. METHODS: A stepped acrylic block of specific dimensions is fabricated and placed on top of the DailyQA3 device. Treatment plans comprising of two different spread-out Bragg peaks and five individual spots of 1.0 MU each are designed to be delivered to the device. A mathematical framework to measure the 2D distance between the detectors and individual spot is introduced and play an important role in realizing the spot positioning and centering QA. Lastly, a 5 months trends of the QA for two gantries are presented. RESULTS: The outputs are monitored by two ion chambers in the DailyQA3 and a tolerance of ± 3 % $ \pm 3\% $ are used. The range of the SOBPs are monitored by the ratio of ion chamber signals and a tolerance of ± 1 mm $ \pm 1\ {\mathrm{mm}}$ is used. Four diodes at ± 10 cm $ \pm 10\ {\mathrm{cm}}$ from the central ion chambers are used for spot positioning QA, while the central ion chamber is used for imaging and proton beam isocenter coincidence QA. Using the framework, we determined the absolute signal threshold corresponding to the offset tolerance between the individual proton spot and the detector. A 1.5 mm $1.5\ {\mathrm{mm}}$ tolerances are used for both the positioning and centering QA. No violation of the tolerances is observed in the 5 months trends for both gantries. CONCLUSION: With the proposed approach, we can perform four QA items in the TG224 within 10 min.

Predictors of post stroke cognitive impairment: VITATOPS cognition substudy.

INTRODUCTION: Post stroke cognitive impairment (PSCI) is a common complication of ischemic stroke. PSCI can involve different depending on clinical and stroke related characteristics. The aim of this study is to determine the factors associated with impairments in specific cognitive domains. METHODS: The Vitamins to Prevent Stroke (VITATOPS) trial is a large, multinational randomised controlled trial. In this substudy, consecutive patients admitted for ischaemic stroke or transient ischaemic attack (TIA) at a tertiary hospital in Singapore were included. PSCI was defined as impairment of any of the six cognitive subgroups - visuoconstruction, attention, verbal memory, language, visual memory and visuomotor function - that were assessed annually for up to five years. Univariate and multivariate Cox proportional hazard models were used to determine factors associated with impairments in each of these cognitive domains. RESULTS: A total of 736 patients were included in this study, of which 173 (23.5 %) developed cognitive impairment. Out of the six cognitive domains, the greatest proportion of patients had an impairment in visuoconstruction (26.4 %) followed by attention (19.8 %), verbal memory (18.3 %), language (17.5 %), visual memory (17.3 %) and visuomotor function (14.8 %). Patients with posterior circulation cerebral infarction (POCI) as the index stroke subtype had higher rates of cognitive impairment. Further subgroup analyses show that Indian race and advanced age were predictive of language impairment, whilst fewer years of education and POCI were predictive of verbal memory impairment. POCI was predictive of visual memory impairment, and advanced age and POCI were predictive of visuomotor function impairment. CONCLUSION: We identified visuoconstruction and attention domains to be the most affected in our Asian cohort of PSCI. Advanced age, lower levels of education, posterior circulation strokes and concomitant comorbidities such as peripheral artery disease are independent predictors of PSCI.

Screening and stability verification of reference genes in Botrytis cinerea ZX2 fermentation.

Botrytis cinerea, an airborne plant pathogen, holds the potential to synthesize sesquiterpenes, which have been used for the industrial production of abscisic acid. Previously, through our genetic technology, we obtained strain ZX2, whose main product 1´,4´-trans-ABA-diol is physiologically active in plants. In this study, 50 L of fed fermentation was carried out with ZX2 strain to study the stability of expression of TUA, TUB, ATC, EF-1, GAPDH, UCE and GTP genes. Four kinds of software (GeNorm, NormFinder, BestKeeper and Delta Ct) were used to analyze the expression stability of candidate genes, and finally the best reference gene was screened by RefFinder. Based on the results, the ACT was the most stable gene. It was used to normalize the expression levels of two genes related to 1´,4´-trans-ABA-diol production (hmgr and bcaba3) when fed-batch fermentation. Guide the selection of appropriate internal reference genes during the fermentation process to accurately quantify the relative transcription levels of target genes in B.cinerea ZX2.

[Research Progress in Organocatalysts Used in the Synthesis of Medical Polyurethanes and Their Biotoxicity]. / åŒ»ç”¨èšæ°¨é ¯åˆæˆæ‰€ç”¨æœ‰æœºå‚¬åŒ–å‰‚åŠå ¶ç”Ÿç‰©æ¯’æ€§ç ”ç©¶è¿›å±•.

Medical polyurethanes have emerged as a leading choice for biomedical applications owing to their exceptional biocompatibility and good physical and mechanical properties. Catalysts play a crucial role as additives in the synthesis of medical polyurethanes, enhancing synthesis efficiency and material properties. However, the catalysts used may affect the biocompatibility of polyurethanes and pose potential harm to human health. This review encapsulates the latest findings regarding the catalysts employed in the synthesis of medical polyurethane materials and their biotoxicity. Initially, we reviewed the prevalent types of catalysts used in the synthesis of medical polyurethane materials and described their distinctive characteristics. Subsequently, our focus shifted to exploring the potential biotoxicity associated with these catalysts. Finally, we provided a forward-looking perspective and recommendations for the future trajectory of catalyst selection in the synthesis of medical polyurethane materials. By acquiring a more profound understanding of the properties and biotoxicity of catalysts used in the synthesis of medical polyurethane materials, and by uncovering existing issues and challenges, we can better guide the design of medical polyurethane materials. This, in turn, enables us to chart the course for future development and ultimately enhance the biocompatibility and safety profiles of medical polyurethane materials. Such advancements will promote the continued development and application of medical polyurethane materials in clinical settings.

[Functional characterization of ent-kaurane-type diterpenoid synthases from Stellera chamaejasme].

Sequential catalysis by ent-copalyl diphosphate(CPS) and ent-kaurene synthase(KS) is a critical step for plants to initiate the biosynthesis of gibberellin with geranylgeranyl pyrophosphate(GGPP) as the substrate. This study mined the transcriptome data of Stellera chamaejasme and cloned two key diterpene synthase genes, SchCPS and SchKS, involved in the gibberellin pathway. The two genes had the complete open reading frames of 2 595 bp and 1 701 bp, encoding two hydrophilic proteins composed of 864 and 566 amino acid residues and with the relative molecular mass of 97.9 kDa and 64.6 kDa and the theoretical isoelectric points of 5.61 and 6.12, respectively. Sequence comparison and phylogenetic tree showed that SchCPS contained LHS, PNV, and DxDD motifs conserved in the CPS family and was categorized in the TPS-c subfamily, while SchKS contained DDxxD, NSE/DTE and PIx motifs conserved in the KS family and was categorized in the TPS-e subfamily. Functional validation showed that SchCPS catalyzed the protonation and cyclization of GGPP to ent-CPP, while SchKS acted on ent-CPP dephosphorylation and re-cyclization to ent-kaurene. In this study, the full-length sequences of SchCPS and SchKS were cloned and functionally verified for the first time, which not only enriched the existing CPS and KS gene libraries but also laid a foundation for the cloning and biosynthesis pathway analysis of more genes involved in the synthesis of active components in S. chamaejasme.

Odor Enrichment Attenuates the Anesthesia/Surgery-induced Cognitive Impairment.

OBJECTIVE: To determine the association between olfactory function and cognition in patients and rodents. BACKGROUND: Perioperative neurocognitive disorders include delayed neurocognitive recovery (dNCR). The contribution of olfactory function to dNCR remains undetermined. It is unknown whether odor enrichment could mitigate dNCR. METHODS: We performed a prospective observational cohort study to determine potential association between olfactory impairment and dNCR in patients. We assessed the effects of anesthesia/surgery on olfactory and cognitive function in mice using the block test and Barnes maze. We measured interleukin-6 (IL-6), olfactory mature protein, growth-associated protein 43, mature and premature olfactory neurons, postsynaptic density 95, and synaptophysin in blood, nasal epithelium, and hippocampus of mice. Odor enrichment, IL-6 antibody, and knockout of IL-6 were used in the interaction experiments. RESULTS: Patients with dNCR had worse odor identification than the patients without dNCR [preoperative: 7 (1.25, 9) vs 10 (8, 11), median (interquartile range), P <0.001; postoperative: 8 (2.25, 10) vs 10 (8, 11), P <0.001]. Olfactory impairment associated with dNCR in patients before and after adjusting age, sex, education, preoperative mini-mental state examination score, and days of the neuropsychological tests. Anesthesia/surgery induced olfactory and cognitive impairment, increased levels of IL-6 in blood and nasal epithelium, decreased amounts of olfactory receptor neurons and their markers in the nasal epithelium, and reduced amounts of synapse markers in the hippocampus of mice. These changes were attenuated by odor enrichment and IL-6 antibody. CONCLUSION: The anesthesia/surgery-induced olfactory impairment may contribute to dNCR in patients and postoperative cognitive impairment in mice. Odor enrichment could be a potential intervention.

Variant Library Annotation Tool (VaLiAnT): an oligonucleotide library design and annotation tool for saturation genome editing and other deep mutational scanning experiments.

MOTIVATION: CRISPR/Cas9-based technology allows for the functional analysis of genetic variants at single nucleotide resolution whilst maintaining genomic context. This approach, known as saturation genome editing (SGE), a form of deep mutational scanning, systematically alters each position in a target region to explore its function. SGE experiments require the design and synthesis of oligonucleotide variant libraries which are introduced into the genome. This technology is applicable to diverse fields such as disease variant identification, drug development, structure-function studies, synthetic biology, evolutionary genetics and host-pathogen interactions. Here, we present the Variant Library Annotation Tool (VaLiAnT) which can be used to generate variant libraries from user-defined genomic coordinates and standard input files. The software can accommodate user-specified species, reference sequences and transcript annotations. RESULTS: Coordinates for a genomic range are provided by the user to retrieve a corresponding oligonucleotide reference sequence. A user-specified range within this sequence is then subject to systematic, nucleotide and/or amino acid saturating mutator functions. VaLiAnT provides a novel way to retrieve, mutate and annotate genomic sequences for oligonucleotide library generation. Specific features for SGE library generation can be employed. In addition, VaLiAnT is configurable, allowing for cDNA and prime editing saturation library generation, with other diverse applications possible. AVAILABILITY AND IMPLEMENTATION: VaLiAnT is a command line tool written in Python. Source code, testing data, example input and output files and executables are available (https://github.com/cancerit/VaLiAnT) in addition to a detailed user manual (https://github.com/cancerit/VaLiAnT/wiki). VaLiAnT is licensed under AGPLv3. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

One-Dimensional Selenidostannates Based on an Infrequent Tetrameric Cluster [Sn4Se12] Exhibiting Electro-Catalytic Properties.

The discovery of low-cost and efficient electro-catalytic materials for hydrogen evolution reaction (HER) is very desirable in hydrogen energy technology. Here, a new type of one-dimensional (1-D) organic hybrid selenidostannate [Ni(en)3]n[Sn2Se5]n (SnSe-1, en = ethylenediamine) with an in situ [Ni(en)3]2+ complex was achieved by the solvothermal reaction of Sn, Se, and NiCl2·6H2O in a mixed solvent of en and triethanolamine at 160 °C for 10 days. The crystal structure of SnSe-1 contains a unique 1-D [Sn2Se52-]n chain built up from the sharing-edge connection of a hitherto-unknown tetrameric [Sn4Se12] cluster, which is separated by discrete [Ni(en)3]2+ complexes. SnSe-1 is first combined with Ni nanoparticles supported on conductive porous Ni foam (NF) to constitute a Ni/SnSe-1/NF electrode as the HER electro-catalyst, displaying superior electro-catalytic activity in near-neutral conditions.

Conformation- and Coordination Mode-Dependent Stimuli-Responsive Salicylaldehyde Hydrazone Zn(II) Complexes.

Luminescent Zn(II) complexes that respond to external stimuli are of wide interest due to their potential applications. Schiff base with O,N,O-hydrazone shows excellent luminescence properties with multi-coordination sites for different coordination modes. In this work, three salicylaldehyde hydrazone Zn(II) complexes (1, 2a, 2b) were synthesized and their stimuli-responsive behaviors in different states were explored. Only complex 1 exhibits reversible and self-recoverable photochromic and photoluminescence properties in solution. This may be due to the configuration eversion and the excited-state intramolecular proton transfer (ESIPT) process. In the solid state, 2a has obvious mechanochromic luminescence property, which is caused by the destruction of intermolecular interactions and the transformation from crystalline state to amorphous state. 2a and 2b have delayed fluorescence properties due to effective halogen bond interactions in structures. 2a could undergo crystal-phase transformation into its polymorphous 2b by force/vapor stimulation. Interestingly, 2b shows photochromic property, which can be attributed to the electron transfer and generation of radicals induced by UV irradiation. Due to different conformations and coordination modes, the three Zn(II) complexes show different stimuli-responsive properties. This work presents the multi-stimuli-responsive behaviors of salicylaldehyde hydrazone Zn(II) complexes in different states and discusses the response mechanism in detail, which may provide new insights into the design of multi-stimuli-responsive materials.