Self-Supported WO3@RuO2 Nanowires for Electrocatalytic Acidic Water Oxidation.

Developing catalysts with high catalytic activity and stability in acidic media is crucial for advancing hydrogen production in proton exchange membrane water electrolyzers (PEMWEs). To this end, a self-supported WO3@RuO2 nanowire structure was grown in situ on a titanium mesh using hydrothermal and ion-exchange methods. Despite a Ru loading of only 0.098 wt %, it achieves an overpotential of 246 mV for the oxygen evolution reaction (OER) at a current density of 10 mA·cm-2 in acidic 0.5 M H2SO4 while maintaining excellent stability over 50 h, much better than that of the commercial RuO2. After the establishment of the WO3@RuO2 heterostructure, a reduced overpotential of the rate-determining step from M-O* to M-OOH* is confirmed by the DFT calculation. Meanwhile, its enhanced OER kinetics are also greatly improved by this self-supported system in the absence of the organic binder, leading to a reduced interface resistance between active sites and electrolytes. This work presents a promising approach to minimize the use of noble metals for large-scale PEMWE applications.

A study on the treatment of brain tumors with BNCT using several moderators with different thicknesses.

Boron neutron capture therapy (BNCT) is an effective binary radiation therapy that depends on nuclear capture reactions. In recent years, BNCT can be performed without a reactor owing to the development of accelerator-based neutron sources. A new BNCT irradiation facility is proposed, which is based on a 15 mA 2.5 MeV proton accelerator with a 100 µm thickness natural lithium target as a neutron converter. A great quantity of studies has shown that neutron beams with different spectra have unique therapeutic effects on tumors. An appropriate neutron beam for BNCT is obtained by Beam Shaping Assembly (BSA) and the moderator plays a main role in determining the BSA outlet beam spectrum. To figure out the dose distribution in phantom with various kinds of neutron spectrum modes during BNCT, a series of cases are calculated by MCNPX code. The results give a database for treatment of brain tumors with BNCT by using different moderators.

On the genetic basis of tail-loss evolution in humans and apes.

The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the 'anthropomorphous apes'1-3, with a proposed role in contributing to human bipedalism4-6. Yet, the genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Here we present evidence that an individual insertion of an Alu element in the genome of the hominoid ancestor may have contributed to tail-loss evolution. We demonstrate that this Alu element-inserted into an intron of the TBXT gene7-9-pairs with a neighbouring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated multiple mouse models that express both full-length and exon-skipped isoforms of Tbxt, mimicking the expression pattern of its hominoid orthologue TBXT. Mice expressing both Tbxt isoforms exhibit a complete absence of the tail or a shortened tail depending on the relative abundance of Tbxt isoforms expressed at the embryonic tail bud. These results support the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype. Moreover, mice expressing the exon-skipped Tbxt isoform develop neural tube defects, a condition that affects approximately 1 in 1,000 neonates in humans10. Thus, tail-loss evolution may have been associated with an adaptive cost of the potential for neural tube defects, which continue to affect human health today.

Mouse genome rewriting and tailoring of three important disease loci.

Genetically engineered mouse models (GEMMs) help us to understand human pathologies and develop new therapies, yet faithfully recapitulating human diseases in mice is challenging. Advances in genomics have highlighted the importance of non-coding regulatory genome sequences, which control spatiotemporal gene expression patterns and splicing in many human diseases1,2. Including regulatory extensive genomic regions, which requires large-scale genome engineering, should enhance the quality of disease modelling. Existing methods set limits on the size and efficiency of DNA delivery, hampering the routine creation of highly informative models that we call genomically rewritten and tailored GEMMs (GREAT-GEMMs). Here we describe 'mammalian switching antibiotic resistance markers progressively for integration' (mSwAP-In), a method for efficient genome rewriting in mouse embryonic stem cells. We demonstrate the use of mSwAP-In for iterative genome rewriting of up to 115 kb of a tailored Trp53 locus, as well as for humanization of mice using 116 kb and 180 kb human ACE2 loci. The ACE2 model recapitulated human ACE2 expression patterns and splicing, and notably, presented milder symptoms when challenged with SARS-CoV-2 compared with the existing K18-hACE2 model, thus representing a more human-like model of infection. Finally, we demonstrated serial genome writing by humanizing mouse Tmprss2 biallelically in the ACE2 GREAT-GEMM, highlighting the versatility of mSwAP-In in genome writing.

Manipulating the 3D organization of the largest synthetic yeast chromosome.

Whether synthetic genomes can power life has attracted broad interest in the synthetic biology field. Here, we report de novo synthesis of the largest eukaryotic chromosome thus far, synIV, a 1,454,621-bp yeast chromosome resulting from extensive genome streamlining and modification. We developed megachunk assembly combined with a hierarchical integration strategy, which significantly increased the accuracy and flexibility of synthetic chromosome construction. Besides the drastic sequence changes, we further manipulated the 3D structure of synIV to explore spatial gene regulation. Surprisingly, we found few gene expression changes, suggesting that positioning inside the yeast nucleoplasm plays a minor role in gene regulation. Lastly, we tethered synIV to the inner nuclear membrane via its hundreds of loxPsym sites and observed transcriptional repression of the entire chromosome, demonstrating chromosome-wide transcription manipulation without changing the DNA sequences. Our manipulation of the spatial structure of synIV sheds light on higher-order architectural design of the synthetic genomes.

Genomic context sensitizes regulatory elements to genetic disruption.

Enhancer function is frequently investigated piecemeal using truncated reporter assays or single deletion analysis. Thus it remains unclear to what extent enhancer function at native loci relies on surrounding genomic context. Using the Big-IN technology for targeted integration of large DNAs, we analyzed the regulatory architecture of the murine Igf2/H19 locus, a paradigmatic model of enhancer selectivity. We assembled payloads containing a 157-kb functional Igf2/H19 locus and engineered mutations to genetically direct CTCF occupancy at the imprinting control region (ICR) that switches the target gene of the H19 enhancer cluster. Contrasting the activity of payloads delivered to the endogenous locus or to a safe harbor locus (Hprt) revealed that the Igf2/H19 locus includes additional, previously unknown long-range regulatory elements. Exchanging components of the Igf2/H19 locus with the well-studied Sox2 locus showed that the H19 enhancer cluster functioned poorly out of context, and required its native surroundings to activate Sox2 expression. Conversely, the Sox2 locus control region (LCR) could activate both Igf2 and H19 outside its native context, but its activity was only partially modulated by CTCF occupancy at the ICR. Analysis of regulatory DNA actuation across different cell types revealed that, while the H19 enhancers are tightly coordinated within their native locus, the Sox2 LCR acts more independently. We show that these enhancer clusters typify broader classes of loci genome-wide. Our results show that unexpected dependencies may influence even the most studied functional elements, and our synthetic regulatory genomics approach permits large-scale manipulation of complete loci to investigate the relationship between locus architecture and function.

Interactions between MFAP5 + fibroblasts and tumor-infiltrating myeloid cells shape the malignant microenvironment of colorectal cancer.

BACKGROUND: The therapeutic targeting of the tumor microenvironment (TME) in colorectal cancer (CRC) has not yet been fully developed and utilized because of the complexity of the cell-cell interactions within the TME. The further exploration of these interactions among tumor-specific clusters would provide more detailed information about these communication networks with potential curative value. METHODS: Single-cell RNA sequencing, spatial transcriptomics, and bulk RNA sequencing datasets were integrated in this study to explore the biological properties of MFAP5 + fibroblasts and their interactions with tumor-infiltrating myeloid cells in colorectal cancer. Immunohistochemistry and multiplex immunohistochemistry were performed to confirm the results of these analyses. RESULTS: We profiled heterogeneous single-cell landscapes across 27,414 cells obtained from tumors and adjacent tissues. We mainly focused on the pro-tumorigenic functions of the identified MFAP5 + fibroblasts. We demonstrated that tumor-resident MFAP5 + fibroblasts and myeloid cells (particularly C1QC + macrophages) were positively correlated in both spatial transcriptomics and bulk RNA-seq public cohorts. These cells and their interactions might shape the malignant behavior of CRC. Intercellular interaction analysis suggested that MFAP5 + fibroblasts could reciprocally communicate with C1QC + macrophages and other myeloid cells to remodel unfavorable conditions via MIF/CD74, IL34/CSF1R, and other tumor-promoting signaling pathways. CONCLUSION: Our study has elucidated the underlying pro-tumor mechanisms of tumor-resident MFAP5 + fibroblasts and provided valuable targets for the disruption of their properties.

In-situ constructing self-supported NiO/RuO2 heterostructure for reinforced alkaline hydrogen evolution reaction.

Rationally designing a strongly coupled heterostructure with rich functional sites and high catalytic stability is essential for efficient energy conversion. This work synthesizes a self-supported NiO/RuO2 heterostructure for hydrogen production via facile dealloying following an in-situ electrochemical oxidation method. It only requires 88 ± 1 mV to drive a current density of -100 mA/cm2 in the alkaline electrolyte during hydrogen evolution reaction (HER), outperforming NiO, RuO2, and Pt foil. The higher anodic potential applied to the dealloyed ribbons results in lower overpotentials and faster reaction kinetics. Meanwhile, the catalytic activity and stability of the individual NiO can be significantly improved once coupled with a small amount of heterogeneous RuO2. The strong synergistic effect between NiO and RuO2 contributes to exposing abundant active sites, optimizing electronic structure, facilitating charge transfer at the interface, and most importantly, maintaining structural stability. These advantages make the self-supported NiO/RuO2 heterostructure a promising candidate for replacing the Pt-based catalysts.

Tumour Seeding Following Core Biopsy of a Mucoepidermoid Carcinoma of the Parotid: Radiological Evidence and a Surgical Approach to En-Bloc Dissection of the Mass and Tract.

Tumour seeding along the needle tract following core needle biopsy of the parotid is a recognised complication. We present a unique case of mucoepidermoid carcinoma of the parotid in an 18-year-old patient with associated tumour seeding within the core needle biopsy tract. Tumour seeding was confirmed both histologically and radiologically on magnetic resonance imaging as early as 35 days post-biopsy. The patient was treated successfully with a combination of surgery and adjuvant proton beam therapy. This case also visually demonstrates a surgical approach to en-block excision of the mass and tract.

A conditional counterselectable Piga knockout in mouse embryonic stem cells for advanced genome writing applications.

Overwriting counterselectable markers is an efficient strategy for removing wild-type DNA or replacing it with payload DNA of interest. Currently, one bottleneck of efficient genome engineering in mammals is the shortage of counterselectable (negative selection) markers that work robustly without affecting organismal developmental potential. Here, we report a conditional Piga knockout strategy that enables efficient proaerolysin-based counterselection in mouse embryonic stem cells. The conditional Piga knockout cells show similar proaerolysin resistance as full (non-conditional) Piga deletion cells, which enables the use of a PIGA transgene as a counterselectable marker for genome engineering purposes. Native Piga function is readily restored in conditional Piga knockout cells to facilitate subsequent mouse development. We also demonstrate the generality of our strategy by engineering a conditional knockout of endogenous Hprt. Taken together, our work provides a new tool for advanced mouse genome writing and mouse model establishment.

Element immiscibility assisted Ru@Ni3B as an efficient electrocatalyst toward alkaline and acidic hydrogen evolution reaction.

Based on the element immiscibility of Ni-Ru, xRu@Ni3B (x = 0, 0.2, 0.5, 1.0) were facilely synthesized through a one-step dealloying method. Of them, 1.0Ru@Ni3B requires overpotentials of 40 ± 0.2 and 72 ± 0.3 mV to reach a current density of -20 mA cm-2 for acidic and alkaline hydrogen evolution reaction, respectively, which are close to or even better than those of metallic Pt foil. In addition, it could maintain superior catalytic and chemical stability after 24 hours of testing. This work provides a promising strategy for improving the atomic utilization efficiency of highly active noble metals toward the hydrogen evolution reaction (HER).

Electrochemical incorporation of heteroatom into surface reconstruction induced Ni vacancy of NixO nanosheet for enhanced water oxidation.

Surface reconstruction of non-oxide oxygen evolution reaction (OER) electrocatalysts has been intensively studied to improve their catalytic performances. However, further modification of the reconstructed active surfaces for better catalytic performances has not been reported. In this work, NiSe nanorods are prepared on nickel foam (NiSe@NF) as the pre-catalyst for electrochemical OER. It is revealed that non-stoichiometric NiO nanosheets with abundant Ni vacancies (NixO) are formed on the surfaces of NiSe nanorods (NixO/NiSe@NF) via in-situ electrochemical oxidation. Furthermore, the OER performances are obviously improved after heteroatom Fe is incorporated electrochemically into NixO nanosheets ((FeNi)O/NiSe@NF). For OER to have a current density of 20 mA cm-2 in 1 M KOH solution, the as-prepared (FeNi)O/NiSe@NF electrode only needs an overpotential of 268 mV. Density functional theory (DFT) calculations reveal that the formation of Ni vacancy can increase the free energy of *OH. More importantly, the incorporation of heteroatom Fe into Ni vacancy can significantly decrease the free energy of *O, which enables Fe-NiO to have the lowest theoretical overpotential for OER in this work. The present work provides a facile and universal strategy to modify the reconstructed active oxides' surfaces for higher electrocatalytic performances.

A Nomogram Model for Predicting the Response to Transcatheter Arterial Embolization in Patients With Symptomatic Hepatic Hemangioma.

Background: Transcatheter arterial embolization (TAE) is regarded as an effective treatment for patients with symptomatic hepatic hemangioma. However, few studies have evaluated the efficacy of TAE alone for treating hepatic hemangioma. The aim of this study was to identify the factors that influence the response to TAE and formulate a quantitative nomogram to optimize the individualized management of hepatic hemangioma. Methods: We retrospectively studied 276 patients treated with TAE for hepatic hemangioma at our center from January 2011 to December 2019. The full cohort was randomly divided into training and validation cohorts. After assessing the potential predictive factors for the efficacy of TAE in the training cohort, a nomogram model was established and evaluated by discrimination and calibration. Results: During follow-up, the symptom relief rate was 100%. The tumor blood supply (p < 0.001), tumor number (p = 0.004), and tumor size (p = 0.006) were identified as significant predictors of the failure of tumor shrinkage in response to TAE. The nomogram model showed favorable discrimination and calibration, with a C-index of 0.775 (95% CI, 0.705-0.845) in the training cohort, which was further confirmed in the validation cohort (C-index 0.768; 95% CI, 0.680-0.856). The side effects of TAE were relatively minor and included mainly abdominal pain, nausea, vomiting, fever, and the presence of elevated hepatic transaminases. Conclusion: TAE is a safe and effective treatment for symptomatic hepatic hemangioma. The established nomogram performed well for the estimation of the effect of TAE in patients with hepatic hemangioma and can facilitate the selection of patients who would benefit most from the treatment.

An Unusual Case of Ludwig's Angina Following Mandibular Fracture.

The mandible is the most commonly fractured bone in the maxillofacial region following trauma. Severe infections are rare, and so we highlight an unusual presentation of Ludwig's angina following a late presentation of a mandibular fracture in a 68-year-old gentleman with significant medical co-morbidities. The recovery process was prolonged and involved multi-disciplinary input. This case makes a recommendation for early recognition of mandibular fractures, antibiotic therapy where appropriate, and hypervigilance when caring for patients with systemic illnesses.

Patient Satisfaction With the Head and Neck Cancer Telephone Triage Service During the COVID-19 Pandemic.

Background A telephone triage consultation, as part of the two-week wait head and neck cancer referral pathway, was implemented nationally in March 2020. This was in response to the COVID-19 pandemic to stream cancer referrals to minimize unnecessary interactions and appointments with health services. The aim of this study is to assess patient satisfaction with this novel telephone triage system in the setting of a district general hospital. Methods A custom designed patient satisfaction questionnaire covering different facets of the patient experience was used. These questions were adapted from several internally validated questionnaires. A retrospective telephone survey was conducted by interviewers for all continuous new head and neck cancer referrals over two 4-week periods in 2020. Questionnaire responses to the initial modality of consult (either telephone triage or face to face) were collected, and data were analysed both qualitatively and quantitatively. Results Seventy-five responses were received, with 51 patients providing feedback on an initial telephone triage consultation. Patients rated the telephone triage consultation to be between satisfied and very satisfied across most domains, with an overall score of 4.29 out of 5. Accessibility and efficiency of the telephone triage were the domains with the least satisfaction. Fifty-five percent of patients would be happy to receive a similar telephone triage consultation beyond the pandemic. Qualitative analysis showed praise for the safety and convenience of the telephone triage consultation during the pandemic but highlighted a general preference for a face-to-face consultation and dissatisfaction regarding a lack of physical examination. Conclusions Overall, patients are satisfied with the telephone triage consultation employed in the pandemic, with high satisfaction rates for multiple aspects of care. However, there were concerns regarding the accessibility and inefficiency associated with a lack of/delayed physical examination and inability to adequately address the fear and anxiety associated with the referral. A mixed response is obtained on whether the telephone triage system should stay for the long run.

Camrelizumab Plus Sorafenib Versus Sorafenib Monotherapy for Advanced Hepatocellular Carcinoma: A Retrospective Analysis.

BACKGROUND: Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis. Immunotherapy has gained great interest for various solid tumors due to its promising clinical efficacy. Targeted therapy also plays a crucial role in anticancer treatment. However, studies on the combination of immunotherapy and targeted therapy for advanced HCC are limited. Thus, the objective of this study was to investigate the efficacy and safety of camrelizumab combined with sorafenib in the treatment of advanced HCC. METHODS: From January 2019 to January 2021, 100 consecutive patients with advanced HCC in our hospital were enrolled for this study. Patients were assigned into two groups: a combined-therapy group (camrelizumab + sorafenib) and a sorafenib-only group. Progression-free survival (PFS), overall survival (OS), treatment response, and relevant adverse effects (AEs) were evaluated and recorded. RESULTS: Of a total of 100 patients, 35 received a combination of camrelizumab and sorafenib, and 65 were treated with sorafenib alone. After 1:1 propensity score matching (PSM), each group had 34 patients. The overall response rate (ORR) of the combined-therapy group was statistically significantly higher than that of the sorafenib-only group (before PSM, p = 0.037; after PSM, p = 0.010). However, there was no significant difference in disease control rate (DCR) between the two groups (before PSM, p = 0.695; after PSM, p = 1.000). Patients who received the combination therapy had significantly longer PFS than those who received the sorafenib monotherapy (before PSM, p = 0.041; after PSM, p = 0.043). However, the two groups exhibited comparable median OS (before PSM, p = 0.135; after PSM, p = 0.105). Although the combined-therapy group showed a higher incidence of AEs such as thrombocytopenia than the sorafenib-only group after PSM, most of these AEs were easily controlled after treatment. CONCLUSION: Camrelizumab plus sorafenib showed favorable efficacy and manageable toxicity for patients with advanced HCC. However, more prospective randomized trials are necessary to further verify the potential clinical benefits of this combination therapy.

Comparison of Intramedullary Nail and Volar Locking Plate for Distal Radius Fractures: A Systematic Review and Meta-Analysis of Randomised Controlled Trials.

Operative intervention with a volar locking plate (VLP) is currently the gold standard for the fixation of distal radius fractures. Intramedullary nailing (IMN) of the distal radius is a novel technique that aims to reduce soft tissue complications due to a smaller surgical incision while maintaining the benefits of a rigid fracture fixation. The aim of this systematic review and meta-analysis was to investigate the functional, clinical, and radiological outcomes of all published randomised controlled trials (RCTs) comparing patient outcomes of VLP and IMN in distal radius fracture fixation. Three databases (Ovid MEDLINE, EMBASE, and Cochrane Library) were searched in July 2021. The inclusion criteria were RCTs comparing fixation of extra-articular or simple intra-articular distal radius with VLP or IMN and availability of full text in English. Children under the age of 18 were excluded. Seven trials with a total of 398 patients were included in this meta-analysis. The meta-analysis showed that there were improved short-term clinical outcomes favouring IMN, although there were no significant differences in terms of functional, radiological, and long-term clinical outcomes. Analysis showed that outcomes of IMN are comparable with VLP for fixation of extra-articular and simple intra-articular distal radius fractures. However, these results should be interpreted with caution due to the small sample size. We recommend that further high-quality trials are required to establish the role of IMN in distal radius fixation.

Patient perspectives on surveillance after head and neck cancer treatment: A systematic review.

OBJECTIVES: Current guidelines advise post-treatment surveillance of head and neck cancer (HNC) patients should involve scheduled appointments with a variety of practitioners. Increasing numbers of HNC survivors raise the burden to provide efficient and effective care. With resource limitation, there is growing importance to identify how surveillance can be justified and optimised for survivors. This systematic review presents current evidence on patient perspectives of post-treatment HNC surveillance, aiming to inform future work putting patient priorities at the forefront of surveillance planning. DESIGN: MEDLINE, Embase, the Cochrane Library, NIHR Dissemination Centre, The Kings Fund Library, Clinical Evidence, NHS Evidence and NICE Clinical Evidence were searched to identify publications regarding patient perspectives of HNC post-treatment surveillance. Studies not reporting on both surveillance and patient perspectives were excluded. RESULTS: Three thousand five hundred fifty-eight citations were screened and 49 full-text articles reviewed. Sixteen studies were included in the final review. Three authors reviewed all articles prior to final analysis to ensure all met inclusion criteria. Most evidence was low quality. Study models returned included cross-sectional surveys, structured interviews and one systematic review. Overall, positive perceptions of HNC surveillance were mostly related to increased reassurance. Negative perceptions predominantly focused on anxiety and fear of recurrence, but a lack of psychological support and inadequate access to certain aspects of care were also reported. CONCLUSIONS: This systematic review demonstrates that patients' perceptions of surveillance after HNC are mostly positive, feeling it provides reassurance. However, several studies report unmet needs, particularly regarding managing anxiety.

Antimetastatic Effects of Ganoderma lucidum Polysaccharide Peptide on B16-F10-luc-G5 Melanoma Mice With Sleep Fragmentation.

Ganoderma lucidum (Lingzhi) polysaccharide peptide (GL-pp) is a component of the globally acknowledged traditional Chinese medicine Ganoderma lucidum; Ganoderma lucidum is known for its sedative, hypnotic, immune regulatory, antitumor, and other pharmacological effects. In recent years, sleep disorders have been linked to many diseases and human body disorders, including cancer. Some experimental studies in mice found that sleep fragmentation could promote tumor development and progression. However, effects on GL-pp on tumor metastasis under circumstances of sleep disorders have rarely been studied. Thus, in this study, we used mice with sleep fragmentation (SF) bearing B16-F10-luc-G5 melanoma tumors to investigate the effect of SF on melanoma metastasis. Furthermore, we investigated the antitumor and antimetastatic effects of GL-pp (80 mg/kg) in mice suffering from SF and bearing B16-F10-luc-G5. Then, whole proteomics was used to analyze the differences in protein expression in the lung tissue between SF mice bearing B16-F10-luc-G5 with and without GL-pp administration. High-throughput pyrosequencing of 16S rRNA was also used to analyze the impact of GL-pp on the gut microbiota composition in SF mice bearing B16-F10-luc-G5. Last, the effects of GL-pp on macrophage polarization and TNF-α serum levels were detected. Collectively, we found that SF significantly facilitated the B16-F10-luc-G5 melanoma tumor metastasis in mice, while GL-pp significantly reduced B16-F10-luc-G5 melanoma tumor metastasis under the condition of SF, in which proteomics and gut microbiota had been changed greatly.