Fullerene and fullerene whisker are not carcinogenic to the lungs and pleura in rat long-term study after 2-week intra-tracheal intrapulmonary administration.

Fullerene whiskers (FLW)s are thin rod-like structures composed of C60 and C70 fullerene (FL). The shape of FLWs suggests potential toxic effects including carcinogenicity to the lung and pleura, similar to effects elicited by asbestos and multi-walled carbon nanotubes (MWCNT)s. However, no long-term carcinogenic studies of FL or FLW have been conducted. In the present study we investigated the pulmonary and pleural carcinogenicity of FL and FLW. Twelve-week-old male F344 rats were administered 0.25 or 0.5 mg FL, FLW, MWCNT-7, and MWCNT-N by intra-tracheal intra-pulmonary spraying (TIPS). Acute lung lesions and carcinogenicity were analyzed at 1 and 104 weeks after 8 doses/15 days TIPS administration. At week 1, FLW, MWCNT-7, and MWCNT-N significantly increased alveolar macrophage infiltration. Expression of Ccl2 and Ccl3, reactive oxygen species production, and cell proliferation were significantly increased by administration of MWCNT-7 and MWCNT-N but not FL or FLW. At week 104, the incidence of bronchiolo-alveolar adenoma plus adenocarcinoma was significantly increased in the MWCNT-7 and MWCNT-N groups, and the incidence of mesothelioma was significantly increased in the MWCNT-7 group. No significant induction of pulmonary or pleural tumorigenesis was observed in the FL or FLW groups. The number of 8-OHdG-positive cells in the alveolar epithelium was significantly increased in the MWCNT-7 and MWCNT-N groups but not in the FL or FLW groups. FL and FLW did not exert pulmonary or pleural carcinogenicity in our study. In addition, oxidative DNA damage was implicated in MWCNT-induced lung carcinogenesis, suggesting that it may be a useful initial marker of carcinogenicity.

Complete genome sequence of Luteolibacter sp. strain Populi, a member of phylum Verrucomicrobiota isolated from the Populus trichocarpa rhizosphere.

Luteolibacter sp. strain Populi is a bacterium from the phylum Verrucomicrobiota, isolated from the rhizosphere of a black cottonwood tree, Populus trichocarpa, from the Cascade mountains in Washington. Its 6.6-Mb chromosome was completely sequenced using Oxford Nanopore long-read sequencing and is predicted to encode 5,301 proteins and 60 RNAs.

Adjunctive Intranasal Esketamine for Comorbid Treatment-Resistant Depression with Suicidal Ideation in Patients Receiving Palliative Care at a Comprehensive Cancer Center: A Case Series.

Background: The psychiatric needs of those with cancer and other advanced illnesses are becoming increasingly recognized. Ketamine is emerging as a promising treatment option for depressive disorders in psychiatric and palliative care. In the palliative care setting, its study has been hindered by lack of consistent administration routes and dosing. Intranasal (IN) esketamine (Spravato®) has recently received U.S. Food and Drug Administration (FDA) approval as an adjunctive agent for treatment-resistant depression (TRD) and major depressive disorder (MDD) with suicidal ideation (SI). Objective: We sought to offer IN esketamine to patients suffering from TRD and SI at a comprehensive cancer center. Methods: We designed and implemented a protocol to administer IN esketamine and describe three cases in which it was provided to patients with TRD and SI at a palliative care clinic in the United States. Results: Following treatment, all three patients had substantial reduction in depression severity and no further suicidalideation. These improvements were maintained for up to a year. No serious adverse events occurred. Conclusions: These cases illustrate the potential utility of IN esketamine in the palliative care setting.

Evolution and engineering of pathways for aromatic O-demethylation in Pseudomonas putida KT2440.

Biological conversion of lignin from biomass offers a promising strategy for sustainable production of fuels and chemicals. However, aromatic compounds derived from lignin commonly contain methoxy groups, and O-demethylation of these substrates is often a rate-limiting reaction that influences catabolic efficiency. Several enzyme families catalyze aromatic O-demethylation, but they are rarely compared in vivo to determine an optimal biocatalytic strategy. Here, two pathways for aromatic O-demethylation were compared in Pseudomonas putida KT2440. The native Rieske non-heme iron monooxygenase (VanAB) and, separately, a heterologous tetrahydrofolate-dependent demethylase (LigM) were constitutively expressed in P. putida, and the strains were optimized via adaptive laboratory evolution (ALE) with vanillate as a model substrate. All evolved strains displayed improved growth phenotypes, with the evolved strains harboring the native VanAB pathway exhibiting growth rates ∼1.8x faster than those harboring the heterologous LigM pathway. Enzyme kinetics and transcriptomics studies investigated the contribution of selected mutations toward enhanced utilization of vanillate. The VanAB-overexpressing strains contained the most impactful mutations, including those in VanB, the reductase for vanillate O-demethylase, PP_3494, a global regulator of vanillate catabolism, and fghA, involved in formaldehyde detoxification. These three mutations were combined into a single strain, which exhibited approximately 5x faster vanillate consumption than the wild-type strain in the first 8 h of cultivation. Overall, this study illuminates the details of vanillate catabolism in the context of two distinct enzymatic mechanisms, yielding a platform strain for efficient O-demethylation of lignin-related aromatic compounds to value-added products.

Diagnosis and treatment of hypogonadism in men seeking to preserve fertility - what are the options?

Male hypogonadism is a clinical syndrome that results in low testosterone levels and frequently leads to infertility. The syndrome occurs due to disruption at one or more levels of the hypothalamic-pituitary-gonadal axis. Testosterone replacement therapy (TRT) is the most common treatment utilised for male hypogonadism. However, long-acting forms of TRT leads to infertility and so is inappropriate for patients wishing to conceive. For patients who wish to remain fertile, nasal TRT, clomiphene citrate, exogenous gonadotropins, gonadotropin releasing hormone and aromatase inhibitors have been used as alternative treatment options with different degrees of success. A review of the literature was performed to identify the safety and efficacy of alternative treatment options. Gonadotropin releasing hormone can successfully induce spermatogenesis but is impractical to administer. Likewise, aromatase inhibitors have limited use due to inducing osteopenia. Nasal TRT may be a good treatment option for these patients, but its efficacy has so far only been demonstrated in small sample sizes. However, clomiphene citrate and exogenous gonadotropins are safe, offer good symptom control and can successfully induce fertility in hypogonadism patients.

Radial forearm free flap reconstruction in a 3-month-old patient with undifferentiated pharyngeal sarcoma.

There is minimal information regarding free tissue transfers in very young infants, especially those less than a year old. It is often thought that that age remains a limit to free tissue transfers, with younger patients having smaller vessels, making the operation technically challenging. In this case report, we discuss the youngest and smallest recorded case of a free flap reconstruction. A 3-month-old patient with a malignant parapharyngeal undifferentiated round cell sarcoma underwent a resection and reconstruction with a radial forearm free flap (RFFF). The defect was 35 by 20 by 15 mm, and required a pharyngeal "patch," as opposed to a "tube," reconstruction. The defect was templated, and the RFFF then raised in a standard subfascial fashion, and inset with resorbable sutures. The patient was observed in the ICU postoperatively. The patient was subsequently diagnosed with Stage IV primary undifferentiated sarcoma with regional metastasis and received adjuvant chemotherapy. Fifteen-month follow up revealed no signs of recurrence, full oral intake, a well-reconstructed pharynx on nasoendoscopic examination, and minimal donor site morbidity. This report illustrates several unique adaptations of free flap transfer in infants and adds to the emerging body of evidence that age is not a contraindication for head and neck reconstruction.

Smad4 restricts injury-provoked biliary proliferation and carcinogenesis.

Cholangiocarcinoma (CCA) is a deadly and heterogeneous type of cancer characterized by a spectrum of epidemiologic associations as well as genetic and epigenetic alterations. We seek to understand how these features inter-relate in the earliest phase of cancer development and through the course of disease progression. For this, we studied murine models of liver injury integrating the most commonly occurring gene mutations of CCA - including Kras, Tp53, Arid1a and Smad4 - as well as murine hepatobiliary cancer models and derived primary cell lines based on these mutations. Among commonly mutated genes in CCA, we found that Smad4 functions uniquely to restrict reactive cholangiocyte expansion to liver injury through restraint of the proliferative response. Inactivation of Smad4 accelerates carcinogenesis, provoking pre-neoplastic biliary lesions and CCA development in an injury setting. Expression analyses of Smad4-perturbed reactive cholangiocytes and CCA lines demonstrated shared enriched pathways, including cell-cycle regulation, MYC signaling and oxidative phosphorylation, suggesting that Smad4 may act via these mechanisms to regulate cholangiocyte proliferation and progression to CCA. Overall, we showed that TGFß/SMAD4 signaling serves as a critical barrier restraining cholangiocyte expansion and malignant transformation in states of biliary injury.

Impact of primary care triage using the Head and Neck Cancer Risk Calculator version 2 on tertiary head and neck services in the post-coronavirus disease 2019 period.

OBJECTIVE: This study investigates the impact of primary care utilisation of a symptom-based head and neck cancer risk calculator (Head and Neck Cancer Risk Calculator version 2) in the post-coronavirus disease 2019 period on the number of primary care referrals and cancer diagnoses. METHODS: The number of referrals from April 2019 to August 2019 and from April 2020 to July 2020 (pre-calculator) was compared with the number from the period January 2021 to August 2022 (post-calculator) using the chi-square test. The patients' characteristics, referral urgency, triage outcome, Head and Neck Cancer Risk Calculator version 2 score and cancer diagnosis were recorded. RESULTS: In total, 1110 referrals from the pre-calculator period were compared with 1559 from the post-calculator period. Patient characteristics were comparable for both cohorts. More patients were referred on the cancer pathway in the post-calculator cohort (pre-calculator patients 51.1 per cent vs post-calculator 64.0 per cent). The cancer diagnosis rate increased from 2.7 per cent in the pre-calculator cohort to 3.3 per cent in the post-calculator cohort. A lower rate of cancer diagnosis in the non-cancer pathway occurred in the cohort managed using the Head and Neck Cancer Risk Calculator version 2 (10 per cent vs 23 per cent, p = 0.10). CONCLUSION: Head and Neck Cancer Risk Calculator version 2 demonstrated high sensitivity in cancer diagnosis. Further studies are required to improve the predictive strength of the calculator.

From compost to culver: genome sequence and annotation of a cluster CQ1 Gordonia phage.

Phage Culver, with a siphovirus morphology, was isolated using Gordonia terrae CAG3. Culver is assigned to phage cluster CQ1 based on gene content similarity to actinobacteriophages. Notably, Culver is predicted to encode eight tRNAs, lysin A by two adjacent genes, and, unlike other CQ1 phages, two putative integrase genes.

Swan-Neck Correction by FDS Tenodesis and Dynamic Lateral Band Volar Relocation in the Setting of Cerebral Palsy.

While there are many proposed surgical treatment options for the correction of swan-neck deformities, none are perfect. We describe a partial flexor digitorum superficialis tenodesis that combines both a static volar plate with a dynamic oblique retinacular ligament vector reconstruction. This is performed through a single, short mid-lateral incision and requires no tendon grafts. The protected early active exercises are encouraged postoperatively, and our long-term results have been promising. The technique was designed for children with cerebral palsy, but the indications have since expanded. Level of Evidence: Level V (Therapeutic).

Quantum biological insights into CRISPR-Cas9 sgRNA efficiency from explainable-AI driven feature engineering.

CRISPR-Cas9 tools have transformed genetic manipulation capabilities in the laboratory. Empirical rules-of-thumb have been developed for only a narrow range of model organisms, and mechanistic underpinnings for sgRNA efficiency remain poorly understood. This work establishes a novel feature set and new public resource, produced with quantum chemical tensors, for interpreting and predicting sgRNA efficiency. Feature engineering for sgRNA efficiency is performed using an explainable-artificial intelligence model: iterative Random Forest (iRF). By encoding quantitative attributes of position-specific sequences for Escherichia coli sgRNAs, we identify important traits for sgRNA design in bacterial species. Additionally, we show that expanding positional encoding to quantum descriptors of base-pair, dimer, trimer, and tetramer sequences captures intricate interactions in local and neighboring nucleotides of the target DNA. These features highlight variation in CRISPR-Cas9 sgRNA dynamics between E. coli and H. sapiens genomes. These novel encodings of sgRNAs enhance our understanding of the elaborate quantum biological processes involved in CRISPR-Cas9 machinery.

Characterisation and comparative genomics of three new Varanus-associated Borrelia spp. from Indonesia and Australia.

BACKGROUND: Borrelia are important disease-causing tick- and louse-borne spirochaetes than can infect a wide variety of vertebrates, including humans and reptiles. Reptile-associated (REP) Borrelia, once considered a peculiarity, are now recognised as a distinct and important evolutionary lineage, and are increasingly being discovered worldwide in association with novel hosts. Numerous novel Borrelia spp. associated with monitor lizards (Varanus spp.) have been recently identified throughout the Indo-Pacific region; however, there is a lack of genomic data on these Borrelia. METHODS: We used metagenomic techniques to sequence almost complete genomes of novel Borrelia spp. from Varanus varius and Varanus giganteus from Australia, and used long- and short-read technologies to sequence the complete genomes of two strains of a novel Borrelia sp. previously isolated from ticks infesting Varanus salvator from Indonesia. We investigated intra- and interspecies genomic diversity, including plasmid diversity and relatedness, among Varanus-associated Borrelia and other available REP Borrelia and, based on 712 whole genome orthologues, produced the most complete phylogenetic analysis, to the best of our knowledge, of REP Borrelia to date. RESULTS: The genomic architecture of Varanus-associated Borrelia spp. is similar to that of Borrelia spp. that cause relapsing fever (RF), and includes a highly conserved megaplasmid and numerous smaller linear and circular plasmids that lack structural consistency between species. Analysis of PF32 and PF57/62 plasmid partitioning genes indicated that REP Borrelia plasmids fall into at least six distinct plasmid families, some of which are related to previously defined Borrelia plasmid families, whereas the others appear to be unique. REP Borrelia contain immunogenic variable major proteins that are homologous to those found in Borrelia spp. that cause RF, although they are limited in copy number and variability and have low sequence identities to RF variable major proteins. Phylogenetic analyses based on single marker genes and 712 single copy orthologs also definitively demonstrated the monophyly of REP Borrelia as a unique lineage. CONCLUSIONS: In this work we present four new genomes from three novel Borrelia, and thus double the number of REP Borrelia genomes publicly available. The genomic characterisation of these Borrelia clearly demonstrates their distinctiveness as species, and we propose the names Borrelia salvatorii, 'Candidatus Borrelia undatumii', and 'Candidatus Borrelia rubricentralis' for them.

Dissociation and integration of outcome and state uncertainty signals in cognitive control.

Signals related to uncertainty are frequently observed in regions of the cognitive control network, including anterior cingulate/medial prefrontal cortex (ACC/mPFC), dorsolateral prefrontal cortex (dlPFC), and anterior insular cortex. Uncertainty generally refers to conditions in which decision variables may assume multiple possible values and can arise at multiple points in the perception-action cycle, including sensory input, inferred states of the environment, and the consequences of actions. These sources of uncertainty are frequently correlated: noisy input can lead to unreliable estimates of the state of the environment, with consequential influences on action selection. Given this correlation amongst various sources of uncertainty, dissociating the neural structures underlying their estimation presents an ongoing issue: a region associated with uncertainty related to outcomes may estimate outcome uncertainty itself, or it may reflect a cascade effect of state uncertainty on outcome estimates. In this study, we derive signals of state and outcome uncertainty from mathematical models of risk and observe regions in the cognitive control network whose activity is best explained by signals related to state uncertainty (anterior insula), outcome uncertainty (dlPFC), as well as regions that appear to integrate the two (ACC/mPFC).

Complete Genome Sequence of Desulfomicrobium sp. Strain ZS1 from Zodletone Spring in Oklahoma, USA.

Desulfomicrobium sp. strain ZS1 is an obligate anaerobic, sulfate-reducing member of the Desulfobacterota from Zodletone Spring, an anoxic sulfide-rich spring in southwestern Oklahoma. Its complete genome was sequenced using a combination of Illumina and Oxford Nanopore platforms and encodes 3,364 proteins and 81 RNAs on a single chromosome.

Codon modification of Tuba1a alters mRNA levels and causes a severe neurodevelopmental phenotype in mice.

The tubulinopathies are an umbrella of rare diseases that result from mutations in tubulin genes and are frequently characterised by severe brain malformations. The characteristics of a given disease reflect the expression pattern of the transcript, the function of a given tubulin gene, and the role microtubules play in a particular cell type. Mouse models have proved to be valuable tools that have provided insight into the molecular and cellular mechanisms that underlie the disease state. In this manuscript we compare two Tuba1a mouse models, both of which express wild-type TUBA1A protein but employ different codon usage. We show that modification of the Tuba1a mRNA sequence results in homozygous lethality and a severe neurodevelopmental phenotype. This is associated with a decrease in the number of post-mitotic neurons, PAX6 positive progenitors, and an increase in the number of apoptotic cells. We attribute this to a decrease in the stability of the modified Tuba1a transcript, and the absence of compensation by the other neurogenic tubulins. Our findings highlight the importance of maintaining the wild-type coding sequence when engineering mouse lines and the impact of synonymous genetic variation.

Polycentric agglomeration and haze pollution: evidence from China.

Polycentric agglomeration has gradually become a salient feature of rapid growth in urbanization in China. Using province-level balanced panel data over the period 2000-18, we examine the impact of polycentric agglomeration on haze pollution and its mechanism of action. The results show that the impact of polycentric agglomeration on haze pollution exhibits a significant inverted U-shaped feature. Nevertheless, except for a few provinces where polycentric agglomeration exceeds the turning point, the degree of polycentric concentration in most provinces lies to the left of the turning point. Further, a mediating effect model illustrates that industrial structure rationalization and technological progress are effective paths through which polycentric agglomeration affects haze pollution. Finally, we demonstrate that the effect of polycentric agglomeration on haze pollution is influenced by transportation and communication infrastructure; improved transportation and communication infrastructure contributes to the haze control effect of polycentric agglomeration.

Multisensory integration in humans with spinal cord injury.

Although multisensory integration (MSI) has been extensively studied, the underlying mechanisms remain a topic of ongoing debate. Here we investigate these mechanisms by comparing MSI in healthy controls to a clinical population with spinal cord injury (SCI). Deafferentation following SCI induces sensorimotor impairment, which may alter the ability to synthesize cross-modal information. We applied mathematical and computational modeling to reaction time data recorded in response to temporally congruent cross-modal stimuli. We found that MSI in both SCI and healthy controls is best explained by cross-modal perceptual competition, highlighting a common competition mechanism. Relative to controls, MSI impairments in SCI participants were better explained by reduced stimulus salience leading to increased cross-modal competition. By combining traditional analyses with model-based approaches, we examine how MSI is realized during normal function, and how it is compromised in a clinical population. Our findings support future investigations identifying and rehabilitating MSI deficits in clinical disorders.

Clinical effectiveness of tenotomy versus tenodesis for long head of biceps pathology: a systematic review and meta-analysis.

OBJECTIVES: The comparative clinical effectiveness of common surgical techniques to address long head of biceps (LHB) pathology is unclear. We synthesised the evidence to compare the clinical effectiveness of tenotomy versus tenodesis. DESIGN: A systematic review and meta-analysis using the Grading of Recommendations Assessment, Development and Evaluation approach. DATA SOURCES: EMBASE, Medline, PsycINFO and the Cochrane Library of randomised controlled trials were searched through 31 October 2021. ELIGIBILITY CRITERIA: We included randomised controlled trials, reporting patient reported outcome measures, comparing LHB tenotomy with tenodesis for LHB pathology, with or without concomitant rotator cuff pathology. Studies including patients treated for superior labral anterior-posterior tears were excluded. No language limits were employed. All publications from database inception to 31 October 2021 were included. DATA EXTRACTION AND SYNTHESIS: Screening was performed by two authors independently. A third author reviewed the article, where consensus for inclusion was required. Data were extracted by two authors. Data were synthesised using RevMan. Inverse variance statistics and a random effects model were used. RESULTS: 860 patients from 11 RCTs (426 tenotomy vs 434 tenodesis) were included. Pooled analysis of patient-reported functional outcome measures data demonstrated comparable outcomes (n=10 studies; 403 tenotomy vs 416 tenodesis; standardised mean difference (SMD): 0.14, 95% CI -0.04 to 0.32, p=0.13). There was no significant difference for pain (Visual Analogue Scale) (n=8 studies; 345 tenotomy vs 350 tenodesis; MD: -0.11, 95% CI -0.28 to 0.06, p=0.21). Tenodesis resulted in a lower rate of Popeye deformity (n=10 studies; 401 tenotomy vs 410 tenodesis; OR: 0.29, 95% CI 0.19 to 0.45, p<0.00001). Tenotomy demonstrated shorter operative time (n=4 studies; 204 tenotomy vs 201 tenodesis; MD 15.2, 95% CI 1.06 to 29.36, p<0.00001). CONCLUSIONS: Aside from a lower rate of cosmetic deformity, tenodesis yielded no significant clinical benefit to tenotomy for addressing LHB pathology. PROSPERO REGISTRATION NUMBER: CRD42020198658.

Arid1a mutation suppresses TGF-ß signaling and induces cholangiocarcinoma.

Activating KRAS mutations and functional loss of members of the SWI/SNF complex, including ARID1A, are found together in the primary liver tumor cholangiocarcinoma (CC). How these mutations cooperate to promote CC has not been established. Using murine models of hepatocyte and biliary-specific lineage tracing, we show that Kras and Arid1a mutations drive the formation of CC and tumor precursors from the biliary compartment, which are accelerated by liver inflammation. Using cultured cells, we find that Arid1a loss causes cellular proliferation, escape from cell-cycle control, senescence, and widespread changes in chromatin structure. Notably, we show that the biliary proliferative response elicited by Kras/Arid1a cooperation and tissue injury in CC is caused by failed engagement of the TGF-ß-Smad4 tumor suppressor pathway. We thus identify an ARID1A-TGF-ß-Smad4 axis as essential in limiting the biliary epithelial response to oncogenic insults, while its loss leads to biliary pre-neoplasia and CC.