Seasonal variation in abundance and characteristics of microplastic in sewage sludge from major cities across the upper stretch of River Ganga, India.

Microplastic (MP) load in urban sewage sludge could vary annually in wastewater treatment plants (WWTPs) depending on seasonal precipitation and human activities. We investigated the seasonal dynamics in abundance and characterization of MP loading in WWTPs located in two cities across River Ganga, India's ecologically sensitive upper stretch. During a 12-month seasonal sampling (pre-monsoon, monsoon, and post-monsoon), sludge samples (n = 36) (primary sludge, PS; drying bed sludge, DBS) were collected and analyzed for load, polymer types, shape, colour, and size (20-1000 µm). Across the three seasons, MP concentrations (particles/kg) were found to be in the ranges of 93.4 ± 5.0 × 103-189.4 ± 11 × 103 in the PS and 39.6 ± 4.0 × 103-152.0 ± 7 × 103 in the DBS. The trend of MP loading was in the following order: monsoon > post-monsoon > pre-monsoon. The dominant MP size was 50-200 µm (36.22%) followed by 20-50 µm (27.65%), 200-500 µm (24.55%) and 500-1000 µm (11.58%). ATR-FTIR results revealed polypropylene, polyethylene terephthalate, polyvinyl chloride, and nylon dominating MP in sludge. This study highlights the importance of long-term monitoring of MP loading in sewage sludge to offer a more accurate estimate of MP contamination in sludge from WWTPs and develop a possible mechanism for its elimination to safeguard the environment.

Rigid Macrocycle Metal Complexes as CXCR4 Chemokine Receptor Antagonists: Influence of Ring Size.

Understanding the role of chemokine receptors in health and disease has been of increasing interest in recent years. Chemokine receptor CXCR4 has been extensively studied because of its defined role in immune cell trafficking, HIV infection, inflammatory diseases, and cancer progression. We have developed high affinity rigidified CXCR4 antagonists that incorporate metal ions to optimize the binding interactions with the aspartate side chains at the extracellular surface of the CXCR4 chemokine receptor and increase the residence time. Cross- and side-bridged tetraazamacrocylic complexes offer significant advantages over the non-bridged molecular structures in terms of receptor affinity, potential for radiolabelling, and use in therapeutic applications. Our investigation has been extended to the influence of the ring size on bridged tetraazamacrocyclic compounds with the addition of two novel chelators (bis-cross-bridged homocyclen and bis-cross-bridged cyclen) to compare to the bis-bridged cyclam, along with novel metal complexes formed with copper(II) or zinc(II). The in vitro biological assays showed that all of the zinc(II) complexes are high affinity antagonists with a marked increase in CXCR4 selectivity for the bis-cross-bridged cyclen complex, whereas the properties of the copper(II) complexes are highly dependent on metal ion geometry. X-ray crystal structural data and DFT computational studies allow for the rationalisation of the relative affinities and the aspartate residue interactions on the protein surface. Changing the ring size from 14-membered can increase the selectivity for the CXCR4 receptor whilst retaining potent inhibitory activity, improving the key pharmacological characteristics.

Myosteatosis and muscle loss impact liver transplant outcomes in male patients with hepatocellular carcinoma.

BACKGROUND: Sarcopenia is associated with unfavourable long-term survival in patients undergoing liver transplantation (LT) for hepatocellular carcinoma (HCC). However, the impact of myosteatosis and muscle loss on patient prognosis has not been investigated. METHODS: Seven hundred fifty-six HCC patients who received LT at 3 transplant centres were included. Computed tomography (CT) images of recipients were collected to measure skeletal muscle index (SMI) and skeletal muscle radiodensity (SMRA). The impact of myosteatosis on the prognosis of sarcopenic and non-sarcopenic patients was studied separately. Muscle status was evaluated based on the presence of sarcopenia and myosteatosis. The muscle loss of 342 males was calculated as the relative change of SMI between pre- and post-LT evaluations. Cox regression models were used to identify predictors of overall survival (OS) and recurrence-free survival (RFS). RESULTS: The study comprised 673 males and 83 females. The median follow-up time was 31 months (interquartile range, 19-43 months). Prior to LT, 267 (39.7%) and 187 (27.8%) males were defined as sarcopenic (low-SMI) and myosteatotic (low-SMRA), respectively. For sarcopenic recipients, the presence of myosteatosis was followed by a 23.6% decrease in 5 year OS (P < 0.001) and a 15.0% decrease in 5 year RFS (P = 0.014). Univariate and multivariate analyses revealed that muscle status was an independent predictor of OS [hazard ratio (HR), 1.569; 95% confidence interval (CI), 1.317-1.869; P < 0.001] and RFS (HR, 1.369; 95% CI, 1.182-1.586; P < 0.001). Postoperatively, a muscle loss >14.2% was an independent risk factor for poor OS (HR, 2.286; 95% CI, 1.358-3.849; P = 0.002) and RFS (HR, 2.219; 95% CI, 1.418-3.471; P < 0.001) in non-sarcopenic recipients (N = 209). CONCLUSIONS: Pre-transplant myosteatosis aggravated the adverse impact of sarcopenia on liver transplant outcomes in male HCC patients. Post-transplant muscle loss might assist in prognostic stratification of recipients without pre-existing sarcopenia, intriguing new insights into individualized management.

trans-IV restriction: a new configuration for metal bis-cyclam complexes as potent CXCR4 inhibitors.

The chemokine receptor CXCR4 is implicated in multiple diseases including inflammatory disorders, cancer growth and metastasis, and HIV/AIDS. CXCR4 targeting has been evaluated in treating cancer metastasis and therapy resistance. Cyclam derivatives, most notably AMD3100 (Plerixafor™), are a common motif in small molecule CXCR4 antagonists. However, AMD3100 has not been shown to be effective in cancer treatment as an individual agent. Configurational restriction and transition metal complex formation increases receptor binding affinity and residence time. In the present study, we have synthesized novel trans-IV locked cyclam-based CXCR4 inhibitors, a previously unexploited configuration, and demonstrated their higher affinity for CXCR4 binding and CXCL12-mediated signaling inhibition compared to AMD3100. These results pave the way for even more potent CXCR4 inhibitors that may provide significant efficacy in cancer therapy.

Patient Experiences after Intracorporeal Right Hemicolectomy: Evaluating Patient Reported Outcome Measures via Short Form-36.

OBJECTIVE: To identify the patient-reported outcome measures (PROMs) after intracorporal anastomosis (ICA) during laparoscopic right hemicolectomy. STUDY DESIGN: An observational study. Place and Duration of the Study: Department of General Surgery, Griffith Base Hospital, New South Wales, Australia, from August 2022 till February 2023. METHODOLOGY: Participants who underwent laparoscopic intracorporeal right hemicolectomy were included in this study. Patients requiring emergency procedures or with a history of psychiatric illness were excluded. The Short Form-36 (SF-36); a quality of life (QoL) questionnaire employed focusing on physical health-related domains post laparoscopic intracorporeal hemicolectomy. The relationship between QoL domains and operative outcomes specific to this anastomotic technique was also assessed. RESULTS: The SF-36 scores at six weeks and six months postoperation revealed shifts in the overall QoL following ICA. Notably, physical function showed significant improvement, while bodily pain remained a significant concern. The correlation analysis found operative blood loss and the length of the extraction site to be significantly correlated with postoperative physical role. CONCLUSION: The study determined that decreased operative blood loss and a shorter extraction site were associated with improved postoperative physical role. It showed the overall QoL improved within six months of the procedure, with the bodily pain domain still an area requiring attention. Understanding the impact of laparoscopic ICA on patient-reported outcomes may help in tailoring patient-cantred approaches and enhancing the overall quality of care. KEY WORDS: Intracorporeal, Right hemicolectomy, Patient-reported outcome measures, Colorectal anastomosis.

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Hepatocellular carcinoma (HCC) is one of the most common malignancies and is a major cause of cancer-related mortalities worldwide (Forner et al., 2018; He et al., 2023). Sarcopenia is a syndrome characterized by an accelerated loss of skeletal muscle (SM) mass that may be age-related or the result of malnutrition in cancer patients (Cruz-Jentoft and Sayer, 2019). Preoperative sarcopenia in HCC patients treated with hepatectomy or liver transplantation is an independent risk factor for poor survival (Voron et al., 2015; van Vugt et al., 2016). Previous studies have used various criteria to define sarcopenia, including muscle area and density. However, the lack of standardized diagnostic methods for sarcopenia limits their clinical use. In 2018, the European Working Group on Sarcopenia in Older People (EWGSOP) renewed a consensus on the definition of sarcopenia: low muscle strength, loss of muscle quantity, and poor physical performance (Cruz-Jentoft et al., 2019). Radiological imaging-based measurement of muscle quantity or mass is most commonly used to evaluate the degree of sarcopenia. The gold standard is to measure the SM and/or psoas muscle (PM) area using abdominal computed tomography (CT) at the third lumbar vertebra (L3), as it is linearly correlated to whole-body SM mass (van Vugt et al., 2016). According to a "North American Expert Opinion Statement on Sarcopenia," SM index (SMI) is the preferred measure of sarcopenia (Carey et al., 2019). The variability between morphometric muscle indexes revealed that they have different clinical relevance and are generally not applicable to broader populations (Esser et al., 2019).

Synthesis of ZnO and PEG-ZnO nanoparticles (NPs) with controlled size for biological evaluation.

The objective of this research was to produce the smallest possible ZnO nanoparticles through an adapted wet chemical process and subsequently, to fabricate a core-shell structure utilizing polyethylene glycol (PEG) as the shell component. The synthesis, size, and shape of the NPs were confirmed using advanced techniques. The resulting clustered NPs were round and had a size of 9.8 nm. Both plain and core-shell NPs were tested for their antibacterial properties against multi-drug resistant bacteria strains (E. cloacae, E. amnigenus, S. flexneri, S. odorifacae, Citrobacter, and E. coli), with concentrations of 500, 1000, and 1500 µg ml-1 used for testing. Both types of NPs demonstrated antibacterial activity against the tested pathogens, with the core-shell NPs being more effective. The synthesized NPs were biocompatible with human red blood cells, with a low level of hemolysis observed. The biocompatibility of the core-shell NPs was significantly enhanced by the presence of the PEG added as the shell. In addition, their effectiveness as photosensitizers for cancer treatment via photodynamic therapy (PDT) was evaluated. MTT assay was used to evaluate the cytotoxicity of ZnO and PEG-ZnO, and the results showed that these NPs were able to generate ROS inside tumor cells upon irradiation, leading to apoptosis and cell death, making them a promising candidate for PDT.

Insulin-induced gene 2 protects against hepatic ischemia-reperfusion injury via metabolic remodeling.

BACKGROUND: Hepatic ischemia-reperfusion (IR) injury is the primary reason for complications following hepatectomy and liver transplantation (LT). Insulin-induced gene 2 (Insig2) is one of several proteins that anchor the reticulum in the cytoplasm and is essential for metabolism and inflammatory responses. However, its function in IR injury remains ambiguous. METHODS: Insig2 global knock-out (KO) mice and mice with adeno-associated-virus8 (AAV8)-delivered Insig2 hepatocyte-specific overexpression were subjected to a 70% hepatic IR model. Liver injury was assessed by monitoring hepatic histology, inflammatory responses, and apoptosis. Hypoxia/reoxygenation stimulation (H/R) of primary hepatocytes and hypoxia model induced by cobalt chloride (CoCl2) were used for in vitro experiments. Multi-omics analysis of transcriptomics, proteomics, and metabolomics was used to investigate the molecular mechanisms underlying Insig2. RESULTS: Hepatic Insig2 expression was significantly reduced in clinical samples undergoing LT and the mouse IR model. Our findings showed that Insig2 depletion significantly aggravated IR-induced hepatic inflammation, cell death and injury, whereas Insig2 overexpression caused the opposite phenotypes. The results of in vitro H/R experiments were consistent with those in vivo. Mechanistically, multi-omics analysis revealed that Insig2 is associated with increased antioxidant pentose phosphate pathway (PPP) activity. The inhibition of glucose-6-phosphate-dehydrogenase (G6PD), a rate-limiting enzyme of PPP, rescued the protective effect of Insig2 overexpression, exacerbating liver injury. Finally, our findings indicated that mouse IR injury could be attenuated by developing a nanoparticle delivery system that enables liver-targeted delivery of substrate of PPP (glucose 6-phosphate). CONCLUSIONS: Insig2 has a protective function in liver IR by upregulating the PPP activity and remodeling glucose metabolism. The supplementary glucose 6-phosphate (G6P) salt may serve as a viable therapeutic target for alleviating hepatic IR.

Salicylic acid-related ribosomal protein CaSLP improves drought and Pst.DC3000 tolerance in pepper.

The ribosomal protein contains complex structures that belong to polypeptide glycoprotein family, which are involved in plant growth and responses to various stresses. In this study, we found that capsicum annuum 40S ribosomal protein SA-like (CaSLP) was extensively accumulated in the cell nucleus and cell membrane, and the expression level of CaSLP was up-regulated by Salicylic acid (SA) and drought treatment. Significantly fewer peppers plants could withstand drought stress after CaSLP gene knockout. The transient expression of CaSLP leads to drought tolerance in pepper, and Arabidopsis's ability to withstand drought stress was greatly improved by overexpressing the CaSLP gene. Exogenous application of SA during spraying season enhanced drought tolerance. CaSLP-knockdown pepper plants demonstrated a decreased resistance of Pseudomonas syringae PV.tomato (Pst) DC3000 (Pst.DC3000), whereas ectopic expression of CaSLP increased the Pst.DC3000 stress resistance in Arabidopsis. Yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) results showed that CaNAC035 physically interacts with CaSLP in the cell nucleus. CaNAC035 was identified as an upstream partner of the CaPR1 promoter and activated transcription. Collectively the findings demonstrated that CaSLP plays an essential role in the regulation of drought and Pst.DC3000 stress resistance.

SETD2 maintains nuclear lamina stability to safeguard the genome.

Histone methyltransferases play essential roles in the organization and function of chromatin. They are also frequently mutated in human diseases including cancer1. One such often mutated methyltransferase, SETD2, associates co-transcriptionally with RNA polymerase II and catalyzes histone H3 lysine 36 trimethylation (H3K36me3) - a modification that contributes to gene transcription, splicing, and DNA repair2. While studies on SETD2 have largely focused on the consequences of its catalytic activity, the non-catalytic functions of SETD2 are largely unknown. Here we report a catalysis-independent function of SETD2 in maintaining nuclear lamina stability and genome integrity. We found that SETD2, via its intrinsically disordered N-terminus, associates with nuclear lamina proteins including lamin A/C, lamin B1, and emerin. Depletion of SETD2, or deletion of its N-terminus, resulted in widespread nuclear morphology abnormalities and genome stability defects that were reminiscent of a defective nuclear lamina. Mechanistically, the N-terminus of SETD2 facilitates the association of the mitotic kinase CDK1 with lamins, thereby promoting lamin phosphorylation and depolymerization required for nuclear envelope disassembly during mitosis. Taken together, our findings reveal an unanticipated link between the N-terminus of SETD2 and nuclear lamina organization that may underlie how SETD2 acts as a tumor suppressor.

SETD2 safeguards the genome against isochromosome formation.

Isochromosomes are mirror-imaged chromosomes with simultaneous duplication and deletion of genetic material which may contain two centromeres to create isodicentric chromosomes. Although isochromosomes commonly occur in cancer and developmental disorders and promote genome instability, mechanisms that prevent isochromosomes are not well understood. We show here that the tumor suppressor and methyltransferase SETD2 is essential to prevent these errors. Using cellular and cytogenetic approaches, we demonstrate that loss of SETD2 or its epigenetic mark, histone H3 lysine 36 trimethylation (H3K36me3), results in the formation of isochromosomes as well as isodicentric and acentric chromosomes. These defects arise during DNA replication and are likely due to faulty homologous recombination by RAD52. These data provide a mechanism for isochromosome generation and demonstrate that SETD2 and H3K36me3 are essential to prevent the formation of this common mutable chromatin structure known to initiate a cascade of genomic instability in cancer.

BENDing with Polycomb in pluripotency and cancer.

Three recent publications on BEND3 firmly establish its role as a novel sequence-specific transcription factor that is essential for PRC2 recruitment and maintenance of pluripotency. Here, we briefly review our current understanding of the BEND3-PRC2 axis in the regulation of pluripotency and also explore the possibility of a similar connection in cancer.

Threshold switching in nickel-doped zinc oxide based memristor for artificial sensory applications.

Electronic devices featuring biomimetic behaviour as electronic synapses and neurons have motivated the emergence of a new era in information and humanoid robotics technologies. In the human body, a nociceptor is a unique sensory neuron receptor that is capable of detecting harmful signals, leading to the central nervous system initiating a motor response. Herein, a nickel-doped zinc oxide (NZO)/Au based memristor is fabricated for the first time and characterized for artificial nociceptor application. For this, the introduction of a nickel-doped zinc oxide (NZO) layer between P++-Si and Au electrodes is used to eliminate the surface effects of the NZO layer, resulting in improved volatile threshold switching performance. Depending on the intensity, duration, and repetition rate of the external stimuli, this newly created memristor exhibits various critical nociceptive functions, including threshold, relaxation, allodynia, and hyperalgesia. The electron trapping/detrapping to/from the traps in the NZO layer is responsible for these nociceptive properties. This kind of NZO-based device produces a multifunctional nociceptor performance that is essential for applications in artificial intelligence systems, such as neural integrated devices with nanometer-sized features.

All about the Benjamins: Efficacy of a modified triage protocol for trauma activation in geriatric patients.

BACKGROUND: The geriatric triage protocol at the study institution was modified from SBP <90 mmHg to SBP <110 mmHg and then to SBP <100 mmHg. The purpose of this study is to evaluate the impact of adjusting geriatric triage protocols on patient outcomes. METHODS: A single-center retrospective review was conducted on trauma patients 65 years or older. Three study periods with different geriatric specific trauma team activation (TTA) protocols (Group 1-SBP<90 mmHg; Group 2-SBP<110 mmHg; Group 3-SBP<100 mmHg) were compared. RESULTS: 2016 patients were included. There were no differences in mortality rates or need for trauma intervention (NFTI) rates among the three groups. The SBP <100 mmHg and SBP <110 mmHg groups had similar under-triage rates. The NFTI over-triage rate in the SBP <100 mmHg group was lower than the SBP <110 mmHg group. CONCLUSION: Using SBP <100 mmHg threshold for TTA criteria in geriatric trauma patients improves over-triage without leading to under-triage.

Hepatocellular carcinoma complicated with huge posterior pancreas head lymph node metastasis and primary renal carcinoma: A case report.

The incidence of hepatocellular carcinoma (HCC) associated with extrahepatic primary malignancy (EHPM) is extremely rare, especially for those that involve primary renal cell carcinoma (PRC). Here we present a case of a 66-year-old male who was diagnosed with HCC complicated with lymph node metastasis at posterior pancreas head and PRC. Biopsy results of the liver and the lymph node confirmed the diagnosis of HCC. The disease progressions of both HCC and PRC are controlled effectively following the initiation of comprehensive therapy including pembrolizumab, lenvatinib, radiotherapy, and transcatheter arterial chemo-embolization (TACE). Ultimately, the patient had successfully access to surgery and complete response (CR) of all the tumors were achieved after surgery.

Long-lasting brain fog is related with severity clusters of symptoms in COVID-19 patients

BACKGROUND: COVID-19 patients may experience Long-lasting symptoms from weeks to even months. AIM: To evaluate long-term cognitive impairment based on the severity of symptoms of COVID-19 infection in a primary health system setting. Material and Methods: From a database of 363 patients, 83 cases aged 47 ± 15 years, (58% females) were selected from June to August 2020. In patients who survived the virus, 24 infection-related symptoms were collected to create three severity clusters (mild, moderate, and severe). The follow-up time was at least seven months. Comparing the first two clusters with the severe cluster, the existence of brain fog and risk factors (obesity, hypertension, diabetes, chronic lung disease, and hypothyroidism) were analyzed. RESULTS: Thirty-one patients (37%) had persistent symptoms lasting up to 240 days. Fifty-one patients (61%) experienced brain fog. Concentration was affected by symptom severity (odds ratio [OR] 3.63, 95% confidence interval [CI] 1.26-10.46, p = 0.02). Short- or long-term memory loss was not affected. Moreover, symptom severity was related to brain fog (OR 3.16, 95% CI 1.05-9.51, p = 0.04). Patients with persistent symptoms had a concentration impairment associated with severity patterns (OR 24.3, 95% CI 1.73-340.11, p = 0.03). Conclusions: Brain fog is associated with symptom severity in COVID-19 survivors and lasts for more than eight months.

ANTECEDENTES: Los pacientes que han tenido COVID-19 pueden experimentar síntomas persistentes que duran semanas a meses. OBJETIVO: Evaluar el deterioro cognitivo a largo plazo en función de la severidad de los síntomas de la infección por COVID-19, en un escenario de sistema primario de salud. Material y Métodos: De una base de datos de 363 pacientes se seleccionaron 83 casos de 47 ± 15 años (58% mujeres), de junio-agosto de 2020. Se recopilaron 24 síntomas relacionados con la infección, creando tres grupos (leve, moderado y severo), en pacientes que padecieron y sobreviven al virus. El tiempo de seguimiento fue de al menos siete meses. La existencia de niebla cerebral y de factores de riesgo (obesidad, hipertensión, diabetes, enfermedad pulmonar crónica e hipotiroidismo) se comparó los dos grupos de severidad más bajos con el nivel superior. RESULTADOS: Treinta y un pacientes (37%) tuvieron síntomas prolongados con una duración de hasta 240 días. Cincuenta y un pacientes (61%) mostraron niebla cerebral. El deterioro de la concentración fue afectado por la severidad (Razón de riesgo (RR) = 3,63, Intervalos de confianza (IC) 95%: 1,26-10,46, p = 0,02). La pérdida de memoria a corto o largo plazo no fue afectada. El grupo con mayor severidad se asoció a niebla cerebral (RR = 3,16, IC95%: 1,05-9,51, p = 0,04). Los portadores de síntomas prolongados tuvieron una alteración de la concentración asociado a severidad (RR: 3,16, IC95%: 1,05-9,51, p= 0,04). Conclusiones: La niebla cerebral está relacionada con la severidad de los síntomas en supervivientes de COVID-19 permaneciendo por más de ocho meses.

A patent review of pharmaceutical and therapeutic applications of oxadiazole derivatives for the treatment of chronic diseases (2013-2021).

INTRODUCTION: Oxadiazole is a unique class of heterocycle, possessing numerous important biomedical and therapeutic applications, such as anti-bacterial, anti-cancer, anti-inflammatory, inhibitors for diverse enzymes, receptor modulators, and neuroprotective properties. The rapid development in the field of oxadiazole-containing structures is confirmed by the development of numerous clinical drugs, such as doxazosin, nesapidil, pleconaril, fasiplon, ataluren, zibotentan, and prenoxdiazine as selected examples. AREAS COVERED: This review provides a comprehensive overview of the range of biological applications of oxadiazole-containing drugs in a range of patents from 2013 to 2021. The information was collected from available data sources including SciFinder, Reaxys, MedLine, and Chemical Abstracts. EXPERT OPINION: Oxadiazole is an established class of compounds with fascinating biological properties. The importance of oxadiazoles can be recognized by their enormous application in a wide spectrum of medicinal chemistry from anticancer, lantibiotics, and antidiabetics to their use in agriculture and neuroprotection. For instance, the oxadiazole-based compounds have shown the ability to modulate a variety of receptors including the M4 receptor agonists, S1P1 receptor modulators, SSTR5 antagonists, orexin type-2 receptor agonists, liver X receptor agonists, and many more. This testifies to the special features associated with the oxadiazole scaffold, making it a significant pharmacophore.

Patient characteristics and diagnostic tests associated with syncopal falls: A Southwestern surgical congress multicenter study.

BACKGROUND: Patients suspected of syncope frequently undergo laboratory and imaging studies to determine the etiology of the syncope. Variability exists in these workups across institutions. The purpose of this study was to evaluate the utilization and diagnostic yield of these workups and the patient characteristics associated with syncopal falls. METHODS: A multi-institutional retrospective review was performed on adult patients admitted after a fall between 1/2017-12/2018. Syncopal falls were compared to non-syncopal falls. RESULTS: 4478 patients were included. There were 795 (18%) patients with a syncopal fall. Electrocardiogram, troponin, echocardiogram, CT angiography (CTA), and carotid ultrasound were more frequently tested in syncope patients compared to non-syncope patients. Syncope patients had higher rates of positive telemetry/Holter monitoring, CTAs, and electroencephalograms. CONCLUSION: Patients who sustain syncopal falls frequently undergo diagnostic testing without a higher yield to determine the etiology of syncope.