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Abstract Background The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n = 302), we now functionally assess the mechanistic role of a novel driver, PARP4. Methods In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4’s interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations. Results PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4’s tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss. Conclusions PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex—unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis.

Summary: Background: Tyrosine kinase inhibitors (TKIs) are currently the standard therapy for patients with non-small cell lung cancer (NSCLC) bearing mutations in epidermal growth factor receptor (EGFR). Unfortunately, drug-acquired resistance is inevitable due to the emergence of new mutations in EGFR. Moreover, the TKI treatment is associated with severe toxicities due to the unspecific inhibition of wild-type (WT) EGFR. Thus, treatment that is customised to an individual's genetic alterations in EGFR may offer greater therapeutic benefits for patients with NSCLC. Methods: In this study, we demonstrate a new therapeutic strategy utilising customised antisense oligonucleotides (ASOs) to selectively target activating mutations in the EGFR gene in an individualised manner that can overcome drug-resistant mutations. We use extracellular vesicles (EVs) as a vehicle to deliver ASOs to NSCLC cells. Findings: Specifically guided by the mutational profile identified in NSCLC patients, we have successfully developed ASOs that selectively inhibit point mutations in the EGFR gene, including L858R and T790M, while sparing the WT EGFR. Delivery of the EGFR-targeting ASOs by EVs significantly reduced tumour growth in xenograft models of EGFR-L858R/T790M-driven NSCLC. Importantly, we have also shown that EGFR-targeting ASOs exhibit more potent anti-cancer effect than TKIs in NSCLC with EGFR mutations, effectively suppressing a patient-derived TKI-resistant NSCLC tumour. Interpretation: Overall, by harnessing the specificity and efficacy of ASOs, we present an effective and adaptable therapeutic platform for NSCLC treatment. Funding: This study was funded by Singapore’s Ministry of Health (NMRC/OFIRG/MOH-000643-00, OFIRG21nov-0068, NMRC/OFLCG/002-2018, OFYIRG22jul-0034), National Research Foundation (NRF-NRFI08-2022, NRF-CRP22-2019-0003, NRF-CRP23-2019-0004), A∗STAR, and Ministry of Education.

Irritant contact dermatitis (ICD) is one of the most common occupational skin diseases, which is hard to differentiate from allergic contact dermatitis (ACD) clinically. Failure to identify the different forms of contact dermatitis can lead to suboptimal management of the patient, with long-term impacts on occupation and quality of life. We describe a case of ICD in a military healthcare personnel during the COVID-19 pandemic. He was exposed to butyl gloves from his protective equipment as well as frequent hand-washing during the COVID-19 period. The diagnostic approach to contact dermatitis as well as holistic management plan is further discussed in this case study.

The integration of Wireless Sensor Network (WSN) technology with the Internet of Things (IoT) in agriculture plays a pivotal role in addressing a range of challenges and constraints faced by the sector, encompassing issues such as labour shortages, suboptimal farm management practises, and unpredictable weather conditions. In response to these pressing concerns, this study focuses on the development of WSN with IoT for agriculture, employing a spread spectrum modulation technique named the Long Range (LoRa) module. By leveraging LoRa devices and wireless radio frequencies, this technology serves as a versatile platform for delivering wireless, long-range, and energy-efficient communication to support small and medium-sized agricultural operations. These operations often lack adequate technological assistance due to factors such as limited expertise and the high costs associated with cutting-edge agricultural technology. The research undertakes a comprehensive exploration, involving LoRa parameter testing, Line-of-Sight evaluations, Non-Line-Of-Sight (NLOS) simulations, and sensor calibration, to assess the efficacy of LoRa-based IoT-enabled sensor networks within plantation environments. The overarching objective of this research endeavour is to provide valuable insights that contribute to the optimisation of agricultural practises through streamlined IoT solutions. By implementing practical and cost-effective strategies, the local agricultural sector stands poised to achieve seamless strides in both sustainable and efficient food production.

Abstract Mass spectrometry-coupled cellular thermal shift assay (MS-CETSA), a biophysical principle-based technique that measures the thermal stability of proteins at the proteome level inside the cell, has contributed significantly to the understanding of drug mechanisms of action and the dissection of protein interaction dynamics in different cellular states. One of the barriers to the wide applications of MS-CETSA is that MS-CETSA experiments must be performed on the specific cell lines of interest, which is typically time-consuming and costly in terms of labeling reagents and mass spectrometry time. In this study, we aim to predict CETSA features in various cell lines by introducing a computational framework called CycleDNN based on deep neural network technology. For a given set of n cell lines, CycleDNN comprises n auto-encoders. Each auto-encoder includes an encoder to convert CETSA features from one cell line into latent features in a latent space $$\mathbb {Z}$$ Z . It also features a decoder that transforms the latent features back into CETSA features for another cell line. In such a way, the proposed CycleDNN creates a cyclic prediction of CETSA features across different cell lines. The prediction loss, cycle-consistency loss, and latent space regularization loss are used to guide the model training. Experimental results on a public CETSA dataset demonstrate the effectiveness of our proposed approach. Furthermore, we confirm the validity of the predicted MS-CETSA data from our proposed CycleDNN through validation in protein–protein interaction prediction.

Abstract The liver has a remarkable regenerative capacity. Nevertheless, under chronic liver-damaging conditions, this capacity becomes exhausted, allowing the accumulation of fibrotic tissue and leading to end-stage liver disease. Enhancing the endogenous regenerative capacity by targeting regeneration breaks is an innovative therapeutic approach. We set up an in vivo functional genetic screen to identify such regeneration breaks. As the top hit, we identified Microfibril associated protein 4 (Mfap4). Knockdown of Mfap4 in hepatocytes enhances cell proliferation, accelerates liver regeneration, and attenuates chronic liver disease by reducing liver fibrosis. Targeting Mfap4 modulates several liver regeneration-related pathways including mTOR. Our research opens the way to siRNA-based therapeutics to enhance hepatocyte-based liver regeneration.

Optical microscopy is widely regarded to be an indispensable tool in healthcare and manufacturing quality control processes, although its inability to resolve structures separated by a lateral distance under ~200 nm has culminated in the emergence of a new field named fluorescence nanoscopy, while this too is prone to several caveats (namely phototoxicity, interference caused by exogenous probes and cost). In this regard, we present a triplet string of concatenated O-Net (‘bead’) architectures (termed ‘Θ-Net’ in the present study) as a cost-efficient and non-invasive approach to enhancing the resolution of non-fluorescent phase-modulated optical microscopical images in silico. The quality of the afore-mentioned enhanced resolution (ER) images was compared with that obtained via other popular frameworks (such as ANNA-PALM, BSRGAN and 3D RCAN), with the Θ-Net-generated ER images depicting an increased level of detail (unlike previous DNNs). In addition, the use of cross-domain (transfer) learning to enhance the capabilities of models trained on differential interference contrast (DIC) datasets [where phasic variations are not as prominently manifested as amplitude/intensity differences in the individual pixels unlike phase-contrast microscopy (PCM)] has resulted in the Θ-Net-generated images closely approximating that of the expected (ground truth) images for both the DIC and PCM datasets. This thus demonstrates the viability of our current Θ-Net architecture in attaining highly resolved images under poor signal-to-noise ratios while eliminating the need for a priori PSF and OTF information, thereby potentially impacting several engineering fronts (particularly biomedical imaging and sensing, precision engineering and optical metrology).

Since 2017, up to 41% of Malaysia's land has been cultivated for durian, making it the most widely planted crop. The rapid increase in demand urges the authorities to search for a more systematic way to control durian cultivation and manage the productivity and quality of the fruit. This research paper proposes a deep-learning approach for detecting and sizing durian fruit in any given image. The aim is to develop zero-shot learning models that can accurately identify and measure the size of durian fruits in images, regardless of the image’s background. The proposed methodology leverages two cutting-edge models: Grounding DINO and Segment Anything (SAM), which are trained using a limited number of samples to learn the essential features of the fruit. The dataset used for training and testing the model includes various images of durian fruits captured from different sources. The effectiveness of the proposed model is evaluated by comparing it with the Segmentation Generative Pre-trained Transformers (SegGPT) model. The results show that the Grounding DINO model, which has a 92.5% detection accuracy, outperforms the SegGPT in terms of accuracy and efficiency. This research has significant implications for computer vision and agriculture, as it can facilitate automated detection and sizing of durian fruits, leading to improved yield estimation, quality control, and overall productivity.

Abstract AXL is a receptor tyrosine kinase that is often overexpressed in cancers. It contributes to pathophysiology in cancer progression and therapeutic resistance, making it an emerging therapeutic target. The first-in-class AXL inhibitor bemcentinib (R428/BGB324) has been granted fast track designation by the U.S. Food and Drug Administration (FDA) in STK11-mutated advanced metastatic non-small cell lung cancer and was also reported to show selective sensitivity towards ovarian cancers (OC) with a Mesenchymal molecular subtype. In this study, we further explored AXL’s role in mediating DNA damage responses by using OC as a disease model. AXL inhibition using R428 resulted in the increase of DNA damage with the concurrent upregulation of DNA damage response signalling molecules. Furthermore, AXL inhibition rendered cells more sensitive to the inhibition of ATR, a crucial mediator for replication stress. Combinatory use of AXL and ATR inhibitors showed additive effects in OC. Through SILAC co-immunoprecipitation mass spectrometry, we identified a novel binding partner of AXL, SAM68, whose loss in OC cells harboured phenotypes in DNA damage responses similar to AXL inhibition. In addition, AXL- and SAM68-deficiency or R428 treatment induced elevated levels of cholesterol and upregulated genes in the cholesterol biosynthesis pathway. There might be a protective role of cholesterol in shielding cancer cells against DNA damage induced by AXL inhibition or SMA68 deficiency.

The kinase inhibitor Ponatinib inhibits an ABL1-JUN signalling axis and alters telomere homeostasis, reduces telomere synthesis, and provokes telomere dysfunction in cancer cells which employ the alternative lengthening of telomeres mechanisms.

Abstract Cancer cells undergo transcriptional reprogramming to drive tumor progression and metastasis. Using cancer cell lines and patient-derived tumor organoids, we demonstrate that loss of the negative elongation factor (NELF) complex inhibits breast cancer development through downregulating epithelial-mesenchymal transition (EMT) and stemness-associated genes. Quantitative multiplexed Rapid Immunoprecipitation Mass spectrometry of Endogenous proteins (qPLEX-RIME) further reveals a significant rewiring of NELF-E-associated chromatin partners as a function of EMT and a co-option of NELF-E with the key EMT transcription factor SLUG. Accordingly, loss of NELF-E leads to impaired SLUG binding on chromatin. Through integrative transcriptomic and genomic analyses, we identify the histone acetyltransferase, KAT2B, as a key functional target of NELF-E-SLUG. Genetic and pharmacological inactivation of KAT2B ameliorate the expression of EMT markers, phenocopying NELF ablation. Elevated expression of NELF-E and KAT2B is associated with poorer prognosis in breast cancer patients, highlighting the clinical relevance of our findings. Taken together, we uncover a crucial role of the NELF-E-SLUG-KAT2B epigenetic axis in breast cancer carcinogenesis.

Here the authors identify distinct mechanisms by which domain-specific p53 mutations activate cancer cell growth via the epidermal growth factor receptor (EGFR). These mechanisms affect sensitivity to EGFR inhibitors, opening avenues for targeted therapy.

Background Combination therapy with radioembolization (yttrium-90)-resin microspheres) followed by nivolumab has shown a promising response rate of 30.6% in a Phase II trial (CA209-678) for advanced hepatocellular carcinoma (HCC); however, the response mechanisms and relevant biomarkers remain unknown.Methods By collecting both pretreatment and on-treatment samples, we performed multimodal profiling of tissue and blood samples and investigated molecular changes associated with favorable responses in 33 patients from the trial.Results We found that higher tumor mutation burden, NCOR1 mutations and higher expression of interferon gamma pathways occurred more frequently in responders. Meanwhile, non-responders tended to be enriched for a novel Asian-specific transcriptomic subtype (Kaya_P2) with a high frequency of chromosome 16 deletions and upregulated cell cycle pathways. Strikingly, unlike other cancer types, we did not observe any association between T-cell populations and treatment response, but tumors from responders had a higher proportion of CXCL9+/CXCR3+ macrophages. Moreover, biomarkers discovered in previous immunotherapy trials were not predictive in the current cohort, suggesting a distinctive molecular landscape associated with differential responses to the combination therapy.Conclusions This study unraveled extensive molecular changes underlying distinctive responses to the novel treatment and pinpointed new directions for harnessing combination therapy in patients with advanced HCC.

In order to design cancer immune therapies, it is important to understand how tumours evade the immune response that is mounted against them. Authors here analyse the distribution and properties of immune cells in hepatocellular carcinoma and describe a progressive tumour-immune co-evolution programme from early to late stage cancer.

The need for cloud servers for training deep neural network (DNN) models is increasing as more complex architecture designs of DNN models are developed. Nevertheless, cloud servers are considered semi-honest. With great attention to the privacy issues of medical diagnoses using a DNN, previous studies have proposed the idea of learnable image encryption. Though some methods have been presented to partially attack previous encryption schemes, there is still some space for improvement. We proposed a learnable image encryption scheme that is an enhanced version of previous methods and can be used to train a great DNN model and simultaneously keep the privacy of training images. We conducted an experiment on medical datasets from open sources and the result demonstrates the effectiveness of our proposed method in performance and privacy-preserving.

Introduction: Although immune checkpoint inhibitors (ICIs) have dramatically improved outcomes for nononcogene-addicted NSCLC, monotherapy with programmed cell death protein-1 (PD1) inhibition has been associated with low efficacy in the EGFR-mutant setting. Given the potential for synergism with combination checkpoint blockade, we designed a trial to test the activity of combination nivolumab (N)-ipilimumab (NI) in EGFR-mutant NSCLC. Methods: This is a randomized phase 2 study (NCT03091491) of N versus NI combination in EGFR tyrosine kinase inhibitor (TKI)–resistant NSCLC, with crossover permitted on disease progression. The primary end point was the objective response rate, and the secondary end points included progression-free survival, overall survival, and safety of ICI after EGFR TKI. Results: Recruitment ceased owing to futility after 31 of 184 planned patients were treated. A total of 15 patients received N and 16 received NI combination. There were 16 patients (51.6%) who had programmed death-ligand (PDL1) 1 greater than or equal to 1%, and 15 (45.2%) harbored EGFR T790M. Five patients derived clinical benefits from ICI with one objective response (objective response rate 3.2%), and median progression-free survival was 1.22 months (95% confidence interval: 1.15–1.35) for the overall cohort. None of the four patients who crossed over achieved salvage response by NI. PDL1 and tumor mutational burden (TMB) were not able to predict ICI response. Rates of all grade immune-related adverse events were similar (80% versus 75%), with only two grade 3 events. Conclusions: Immune checkpoint inhibition is ineffective in EGFR TKI–resistant NSCLC. Whereas a small subgroup of EGFR-mutant NSCLC may be immunogenic and responsive to ICI, better biomarkers are needed to select appropriate patients.

In this work, user pairing and power allocation are proposed as a hybrid scheme to maximise throughput and achieve system fairness in the non-orthogonal multiple access (NOMA) system in 5G networks. The proposed approach is designed to improve the throughput and fairness performance of the downlink NOMA system in 5G networks. User pairing and power allocation schemes are separated to reduce resource allocation complexity. Integer linear programming is applied to perform user pairing, and particle swarm optimisation is used for power allocation. Moreover, the optimisation problem is formulated by converting multi-objective functions into a single function using the scalarisation of multi-objective optimisation problems, and the penalty function is used to prevent optimisation from violating the power, fairness, and data rate constraints. Simulation results show that the proposed model outperforms the conventional numerical approach by at least 9% of throughput maximisation and achieves an acceptable fairness rate.

Molecularly targeted cancer therapy has improved outcomes for patients with cancer with targetable oncoproteins, such as mutant EGFR in lung cancer. Yet, the long-term survival of these patients remains limited, because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations of EGFR often harbor additional co-occurring genetic alterations. This hypothesis remains untested for most genetic alterations that co-occur with mutant EGFR. Here, we report the functional impact of inactivating genetic alterations of the mRNA splicing factor RNA-binding motif 10 (RBM10) that co-occur with mutant EGFR. RBM10 deficiency decreased EGFR inhibitor efficacy in patient-derived EGFR-mutant tumor models. RBM10 modulated mRNA alternative splicing of the mitochondrial apoptotic regulator Bcl-x to regulate tumor cell apoptosis during treatment. Genetic inactivation of RBM10 diminished EGFR inhibitor–mediated apoptosis by decreasing the ratio of (proapoptotic) Bcl-xS to (antiapoptotic) Bcl-xL isoforms of Bcl-x. RBM10 deficiency was a biomarker of poor response to EGFR inhibitor treatment in clinical samples. Coinhibition of Bcl-xL and mutant EGFR overcame the resistance induced by RBM10 deficiency. This study sheds light on the role of co-occurring genetic alterations and on the effect of splicing factor deficiency on the modulation of sensitivity to targeted kinase inhibitor cancer therapy.

Background: Singapore General Hospital (SGH) is the largest acute tertiary-care hospital in Singapore. Healthcare workers (HCWs) are at risk of acquiring COVID-19 in both the community and workplaces. SGH has a robust exposure management process including prompt contact tracing, immediate ring fencing, lock down of affected cubicles or single room isolation for patient contacts, and home isolation orders for staff contacts of COVID-19 cases during the containment phase of the pandemic. Contacts were also placed on enhanced surveillance with PCR testing on days 1 and 4 as well as daily antigen rapid tests (ARTs) for 10 days after exposure. Here, we describe the characteristic of HCWs with COVID-19 during the third wave of the COVID-19 pandemic. Methods: This retrospective observational study included all SGH HCWs who acquired COVID-19 during the third wave (ie, the 18-week period from September 1 to December 31, 2021) of the COVID-19 pandemic. Univariate analysis was used to compare characteristics of work-associated infection (WAI) and community-acquired infection (CAI) among HCWs. Results: Among a workforce of >10,000 at SGH, 335 HCWs acquired COVID-19 during study period. CAI (exposure to known clusters or household contact) accounted for 111 HCW infections (33.1%). Also, 48 HCWs (14.3%) had a WAI (ie, acquired at their work places where there was no patient contact). Among WAsI, only 5 HCWs had hospital-acquired infection (confirmed by phylogenetic analysis). The sources of exposure for the remaining 176 HCWs were unknown. Weekly incidence of COVID-19 among HCWs was comparable to the epidemiology curve of all cases in Singapore (Fig. 1 and 2). The mean age of HCWs with COVID-19 was 39.6 years, and most were women. At the time of positive SARS-CoV-2 PCR test, 223 HCWs were symptomatic, and 67 (20.0%) of them had comorbidities. Only 16 HCWs (4.8%) required hospitalization, and all recovered fully with no mortality (Table 1). Being female was associated with community COVID-19 acquisition (OR, 4.6, P Conclusions: During the thrid wave of the COVID-19 pandemic, a higher percentage of HCWs at SGH acquired the infection from the community than from the workplace. Safe management measures, such as universal masking, social distancing, and robust exposure management processes including prompt contact tracing and environmental disinfection, can reduce the risk of COVID-19 in the hospital work environment.

Intratumoural heterogeneity is a feature of liver cancer. Here, the authors demonstrate that heterogeneity exists at the immune cell level in liver cancer and show that tumours with high intratumoural immune heterogeneity demonstrated an immune suppressive microenvironment, which was associated with tumour evolution and a poor prognosis.

Introduction: Alzheimer's disease (AD) will become a prominent public health issue in the future given its cognitively debilitating nature. As the advent of global ageing society is expected, AD may bring tremendous socioeconomical costs if current diagnosis methods stay put. In this article, we performed a systematic review of a recent (less than 10 years) ultrasensitive technology, the immunomagnetic reduction (IMR), which shows promising potential of early diagnosis of AD. Methods: We searched the Pubmed and Embase databases for studies that included keywords “early-stage Alzheimer's disease” and “immunomagnetic signal reduction.” Results: After full-text review, a total of 7 studies were included for final analysis. Most included studies have reported on Aβ40, Aβ42, t-tau, and levels of these biomarkers in the plasma of early AD patients comparing those in the healthy population. The ranges of the mean Aβ40 levels are as follows: 59.2 to 60.9 for control groups and 36.9 to 39.5 pg/mL for AD. Aβ42 and t-tau concentrations are both markedly lower than Aβ40, Aβ42 at 15.5 to 16.1 for control groups and 17.9 to 19 pg/mL for AD; t-tau levels were 13.5 to 14.3 for control groups and 39.4 to 46.7 pg/mL for AD. There is a significant increasing level of plasma Aβ42 by IMR assays in early AD patients across nearly all the included studies. There is a possible relationship between plasma levels of IMR AD biomarkers and (1) degree of hippocampal atrophy using magnetic resonance imaging, and (2) amount of brain amyloid accumulation using positron emission tomography. Conclusion: IMR assay is an ultrasensitivity technique that is useful for detection of early AD, which can provide benefits on understanding the disease progression of AD and encourage early medical invention for AD patients.

Abstract The RIG‐I pathway can be activated by RNA containing 5′ triphosphate, leading to type I interferon release and immune activation. Hence, RIG‐I agonists have been used to induce immune responses against cancer as potential immunotherapy. However, delivery of 5′ triphosphorylated RNA molecules as RIG‐I agonists to tumour cells in vivo is challenging due to the susceptibility of these molecules to degradation. In this study, we demonstrate the use of extracellular vesicles (EVs) from red blood cells (RBCs), which are highly amenable for RNA loading and taken up robustly by cancer cells, for RIG‐I agonist delivery. We evaluate the anti‐cancer activity of two novel RIG‐I agonists, the immunomodulatory RNA (immRNA) with a unique secondary structure for efficient RIG‐I activation, and a 5′ triphosphorylated antisense oligonucleotide with dual function of RIG‐I activation and miR‐125b inhibition (3p‐125b‐ASO). We find that RBCEV‐delivered immRNA and 3p‐125b‐ASO trigger the RIG‐I pathway, and induce cell death in both mouse and human breast cancer cells. Furthermore, we observe a significant suppression of tumour growth coupled with increased immune cell infiltration mediated by the activation of RIG‐I cascade after multiple intratumoral injections of RBCEVs loaded with immRNA or 3p‐125b‐ASO. Targeted delivery of immRNA using RBCEVs with EGFR‐binding nanobody administrated via intrapulmonary delivery facilitates the accumulation of RBCEVs in metastatic cancer cells, leading to potent tumour‐specific CD8+ T cells immune response. This contributes to prominent suppression of breast cancer metastasis in the lung. Hence, this study provides a new strategy for efficient RIG‐I agonist delivery using RBCEVs for immunotherapy against cancer and cancer metastasis.

Hydraulic turbines contribute to 60% of renewable energy in the world; however, they also entail some adverse effects on the aquatic ecology system. One such effect is their excessive noise and vibration. To minimize this effect, one of the most effective and feasible solutions is to modify the design of the turbine rotor blade by introducing a skew. In this study, two 0.3-meter tidal turbines with 0-degree (no-skewness) and positive 90-degree skewness made of stainless steel 316L were designed and printed using a 3-D printing powder bed fusion technique. These rotors were then tested at the Emerson Cavitation Tunnel (ECT) at Newcastle University, UK, and the variation in the skewness of the blades of the turbines as a function of the power coefficient on a given tip speed ratio (TSR) value was ascertained. Results showed that the highly skewed rotor had significantly lower drag and torque fluctuations, with a slight decrease in efficiency compared to the non-skewed one, which warrants further investigation on the effect of added skew to reduce vibration and noise. Numerical simulations were also performed for verification and validation of the experimental tests, using the H45 dynamometer at the ECT. A comprehensive software code for propellers and tidal turbines, ROTORYSICS, was used to examine the cavitation effect of the two rotors; a comparison was made for both, with and without cavitation. The results indicate that for a high immersion depth of tidal turbine rotors, cavitation rarely occurs, but for hydrokinetic turbines that are installed on dams in rivers and falls, cavitation could be a serious concern. It was concluded that the 0-degree skewed rotor is more hydrodynamically efficient than the 90-degree skewed rotor.

Atopic dermatitis (AD) is a systemic inflammatory disorder. However, the relationship between severity of AD and metabolic and atopic conditions is not well studied. The aim of this study was to elucidate the relationship between severity of AD and comorbidities, such as metabolic conditions (increased body mass index, hypertension, hyperlipidaemia, and type II diabetes mellitus) and other atopic manifestations (allergic rhinitis, asthma and food allergies). A retrospective population-based national study of a cohort of young adult males conscripted into military service in Singapore over a 5-year period was performed, utilizing military electronic medical records. A dose-dependent effect was found between the association of comorbidities and severity of AD. Metabolic and atopic conditions were significantly correlated with having moderate-to-severe AD. An association of metabolic and atopic conditions with severity of adult AD was found, which suggests that chronic severe AD may result in increased disease burden and morbidity.

Spinal and bulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of polyglutamine region in the androgen receptor. To gain insights into mechanisms of SBMA, four wild-type and five SBMA iPSC lines were differentiated to spinal motor neurons (sMNs) with high efficiency. SBMA sMNs showed neurite defects, reduced sMN survival and decreased protein synthesis levels. Microarray analysis revealed a dysregulation in various neuronal-related signalling pathways in SBMA sMNs. Strikingly, FAM135B a novel gene of unknown function, was found drastically downregulated in SBMA sMNs. Knockdown of FAM135B in wild-type sMNs reduced their survival and contributed to neurite defects, similar to SBMA sMNs, suggesting a functional role of FAM135B in SBMA. The degenerative phenotypes and dysregulated genes revealed could be potential therapeutic targets for SBMA.

Growing concerns like depleting mineral resources, increased materials wastage, and structural light-weighting requirements due to emission control regulations drive the development of sustainable metal matrix composites. Al and Mg based alloys with relatively lower melting temperatures qualify for recycling applications and hence are considered as the matrix material for developing sustainable composites. The recent trend also explores various industrial by-products and agricultural wastes as green reinforcements, and this article presents insights on the properties of Al and Mg based sustainable metal matrix composites with special emphasis on green reinforcements and processing methods.

EGFR mutant lung adenocarcinoma (LUAD) exhibit diverse clinical outcomes in response to targeted therapies. Here the authors show that these LUADs involve a complex genomic landscape with high intratumor heterogeneity, providing insights into the evolutionary trajectory of oncogene-driven LUAD and potential mediators of EGFR TKI resistance.

A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-21556-y.

Subungual squamous cell carcinoma is a rare entity and difficult to diagnose as its clinical presentation may resemble benign conditions. This case report highlights the need to maintain a high clinical index of suspicion, and recommends a practical approach for subungual conditions. Dermoscopy and a biopsy for histology are important adjuncts to clinch the diagnosis.

miRNAs can function either as proto-oncogenes or tumour suppressors in several cancers; however their function in tumour initiating cells is unclear. Here, Zhang et al. show that tumour initiating cell-specific miR-1246 and miR-1290 promote lung cancer initiation and metastasis and could serve as prognostic markers.

Robots have been reportedly seen serving food in several restaurants in many parts of the world. New ventures have been deploying mechanical partners which promote the growth in service robotics. However, robots are considerably incompetent when it comes to beverage and soup delivery. The physical challenge behind the clumsy motion of these machines is found to be its jerky motion control. Jerk control solutions are widely studied in a constrained environment but not well introduced in dynamic environments. In this paper, we will begin by examining developed kinematics solutions, open-source packages from Robot Operating System and the constraints of motion planning. The proposed solution in this paper provides a quick system response with jerk limits using spline velocity profiles. The solution will introduce the concepts of a state machine design that enables the robot to behave and move reactively; effectively balancing its desired velocity and position without spilling a drop of customer satisfaction. Experiments have proven that robots can move at higher velocity without any crashing, spilling, or docking issues. The smooth velocity control proposed will improve the capabilities of waiter robot and service operations in restaurants.

During the development of the central nervous system, the proliferation of neural progenitors and differentiation of neurons and glia are tightly regulated by different transcription factors and signaling cascades, such as the Wnt and Shh pathways. This process takes place in cooperation with several microRNAs, some of which evolutionarily conserved in vertebrates, from teleosts to mammals. We focused our attention on miR-7, as its role in the regulation of cell signaling during neural development is still unclear. Specifically, we used human stem cell cultures and whole zebrafish embryos to study, in vitro and in vivo, the role of miR-7 in the development of dopaminergic (DA) neurons, a cell type primarily affected in Parkinson’s disease. We demonstrated that the zebrafish homologue of miR-7 (miR-7a) is expressed in the forebrain during the development of DA neurons. Moreover, we identified 143 target genes downregulated by miR-7, including the neural fate markers TCF4 and TCF12, as well as the Wnt pathway effector TCF7L2. We then demonstrated that miR-7 negatively regulates the proliferation of DA-progenitors by inhibiting Wnt/β-catenin signaling in zebrafish embryos. In parallel, miR-7 positively regulates Shh signaling, thus controlling the balance between oligodendroglial and DA neuronal cell fates. In summary, this study identifies a new molecular cross-talk between Wnt and Shh signaling pathways during the development of DA-neurons. Being mediated by a microRNA, this mechanism represents a promising target in cell differentiation therapies for Parkinson’s disease.

The parasite Toxoplasma gondii causes an opportunistic infection, that is, particularly severe in immunocompromised patients, infants, and neonates. Current antiparasitic drugs are teratogenic and cause hypersensitivity-based toxic side effects especially during prolonged treatment. Furthermore, the recent emergence of drug-resistant toxoplasmosis has reduced the therapeutic impact of such drugs. In an effort to develop recombinant antibodies as a therapeutic alternative, a panel of affinity-matured, T. gondii tachyzoite-specific single-chain variable fragment (scFv) antibodies was selected by phage display and bioinformatic analysis. Further affinity optimization was attempted by introducing point mutations at hotspots within light chain complementarity-determining region 2. This strategy yielded four mutated scFv sequences and a parental scFv that were used to produce five mouse–human chimeric IgGs in Nicotiana benthamiana plants, with yields of 33–72 mg/kg of plant tissue. Immunological analysis confirmed the specific binding of these plant-derived antibodies to T. gondii tachyzoites, and in vitro efficacy was demonstrated by their ability to inhibit the invasion of human fibroblasts and impair parasite infectivity. These novel recombinant antibodies could therefore be suitable for the development of plant-derived immunotherapeutic interventions against toxoplasmosis.

Microwave energy can be used for the processing of a wide variety of materials. It is used most commonly for the heating of food and has been increasingly applied for processing of polymers; ceramics; metals; minerals and composites. The use of microwave energy allows rapid and volumetric heating where heat is generated from within the material instead of via radiative heat transfer from external heating elements. This paper aims to provide a review on the use of energy efficient and environment friendly microwave energy route to synthesize magnesium based materials reinforced with various types of metallic and ceramic reinforcements. Magnesium composites are extremely attractive for weight critical applications in automotive; aerospace; electronics and transportation sectors. The magnesium composites were prepared using blend—compact—microwave sintering—extrusion methodology. Microwave sintering allowed a significant reduction of 80% in both processing time and energy consumption over conventional sintering without any detrimental effect on the properties of the synthesized magnesium composites. Physical; microstructure and mechanical properties of microwave sintered magnesium composites will also be discussed and compared with magnesium composites processed by conventional liquid and solid processing techniques.

While, the genomic landscape of early stage, treatment naïve lung adenocarcinomas (LUADs) has been described quite elaborately in recent literature, the genomic profile of late stage, drug resistant tumors remains largely unknown. Further, most of the published studies are based on smoker dominated Caucasian cohorts and EGFR-mutant LUAD remains under-represented in them. Despite response rates of upto 70% to EGFR tyrosine kinase inhibitors (TKIs), resistance ensues in most of these EGFR-mutant patients, limiting responses to a median of 10-12 months. Thus, to better understand the evolution of these tumors in context of drug resistance, we perform a comparative analysis of the mutational and copy number landscape of early stage, treatment naïve vs late stage, resistant tumors. Whole exome sequencing was performed on: (i) 100 tumor sectors from 24 early stage, treatment naïve EGFR-mutant LUAD cases. (ii) 81 biopsies from 58 late stage, TKI and chemotherapy resistant cases. Copy number analysis using SNP arrays was performed for a subset of these patients. The significantly higher mutation burden in the late stage, drug resistant tumors elucidated a driver mutation landscape beyond just recurrent TP53 mutations, which was dominated by PIK3CA (14%), RB1 (10%), NF1 (7%) and other rare mutations in EGFR (in 5/58 cases), many of which co-occurred with the T790M mutation. Functional studies validated the oncogenicity of some of these rare mutations in the PI3K/AKT1 pathway. The copy number landscape revealed pervasive, truncal genome doubling events in both cohorts (~80% cases). While comparable fraction of genome was affected by overall copy number gains or losses (copy change >=1) across the two cohorts (49.2% vs 46.3%, P=0.51), significantly higher fraction of genome was affected by amplifications (copy change >=2; 8.7% vs 5%, P=0.02) and loss of heterozygosity (LOH; 33.1% vs 20.6%, P=0.003) in the drug resistant tumors compared to the treatment naive tumors. In summary, our study reveals (i) increased mutation and driver burden with co-occurring resistance mutations and (ii) higher fraction of genome with amplifications and LOH in the drug resistant cohort, suggesting ways in which genomic landscape of EGFR-mutant LUAD evolves, potentially making them more tolerant to drug treatment.

Alternative lengthening of telomeres (ALT) supports telomere maintenance in 10-15% of cancers, thus representing a compelling target for therapy. By performing anti-cancer compound library screen on isogenic cell lines and using extrachromosomal telomeric C-circles, as a bona fide marker of ALT activity, we identify a receptor tyrosine kinase inhibitor ponatinib that deregulates ALT mechanisms, induces telomeric dysfunction, reduced ALT-associated telomere synthesis, and targets, in vivo, ALT-positive cells. Using RNA-sequencing and quantitative phosphoproteomic analyses, combined with C-circle level assessment, we find an ABL1-JNK-JUN signalling circuit to be inhibited by ponatinib and to have a role in suppressing telomeric C-circles. Furthermore, transcriptome and interactome analyses suggest a role of JUN in DNA damage repair. These results are corroborated by synergistic drug interactions between ponatinib and either DNA synthesis or repair inhibitors, such as triciribine. Taken together, we describe here a signalling pathway impacting ALT which can be targeted by a clinically approved drug.

The transcription factor B-Myb is present in all proliferating cells, and in mice engineered to remove this gene, embryos die in utero just after implantation due to inner cell mass defects. This lethal phenotype has generally been attributed to a proliferation defect in the cell cycle phase of G1.In the present study, we show that the major cell cycle defect in murine embryonic stem (mES) cells occurs in G2/M. Specifically, knockdown of B-Myb by short-hairpin RNAs results in delayed transit through G2/M, severe mitotic spindle and centrosome defects, and in polyploidy. Moreover, many euploid mES cells that are transiently deficient in B-Myb become aneuploid and can no longer be considered viable. Knockdown of B-Myb in mES cells also decreases Oct4 RNA and protein abundance, while over-expression of B-MYB modestly up-regulates pou5f1 gene expression. The coordinated changes in B-Myb and Oct4 expression are due, at least partly, to the ability of B-Myb to directly modulate pou5f1 gene promoter activity in vitro. Ultimately, the loss of B-Myb and associated loss of Oct4 lead to an increase in early markers of differentiation prior to the activation of caspase-mediated programmed cell death.Appropriate B-Myb expression is critical to the maintenance of chromosomally stable and pluripotent ES cells, but its absence promotes chromosomal instability that results in either aneuploidy or differentiation-associated cell death.