Is there impact of the SARS-CoV-2 pandemic on steroidogenesis and fertility?

In December of 2019, several cases of unknown atypical respiratory diseases emerged in Wuhan, Hubei Province in China. After preliminary research, it was stated that the disease is transmittable between humans and was named COVID-19. Over the course of next months, it spread all over the world by air and sea transport and caused a global pandemic which affects life of everyone now-a-days. A large number of countries, have since been forced to take precautions such as curfews, lockdowns, wearing facemasks etc. Even with vaccines being produced in mass numbers, lack of targeted therapy continues to be a major problem. According to studies so far it seems that elderly people are more vulnerable to severe symptoms while children tend to by asymptomatic or have milder form the disease. In our review, we focused on gathering data about the virus itself, its characteristics, paths of transmission, and its effect on hormone production and secretion. In such, there is insufficient information in the literature worldwide, especially the ones that focus on the effect of COVID-19 on individual organs systems within the human body. Hence, the present evidence-based study focused on the possible effects of COVID-19 on adrenal gland and gonads i.e. on the process of steroidogenesis and fertility.

Biomechanical Testing of Additive Manufactured Proximal Humerus Fracture Fixation Plates.

Achieving satisfactory fracture fixation in osteoporotic patients with unstable proximal humerus fractures remains a major clinical challenge. Varus collapse is one of the more prominent complications that may lead to screw cutout. This aim of this study was to compare the fixation provided by conventional locking plates with novel design concepts that are only feasible through additive manufacturing (AM) techniques. In addition to reversed engineered implants, two novel implant designs with integrated struts were included in the study to provide medial support to humeral head. The medial strut was either solid or included a porous lattice structure intended to promote bone ingrowth. Biomechanical tests were performed using low density synthetic bones with simulated 3-part comminuted fractures. Nondestructive torsion and compression were performed, followed by increasing cyclic loading. The relative displacements between the bone fragments were determined using a 3D motion capture system. The AM manufactured implants with medial strut showed significant reduction of varus displacement during the increasing cyclic loading when compared to conventional designs. AM reversed-engineered locking plates showed similar mechanical behavior to conventional plates with identical geometry. This study demonstrates the feasibility and potential of employing alternative design via AM for fixation of unstable comminuted proximal humerus fractures to reduce fragment displacement.

Immunosuppression in liver tumors: opening the portal to effective immunotherapy.

We have recently witnessed substantial progress with immunotherapy for selected diseases. Checkpoint inhibitors and chimeric antigen receptor T (CAR-T) cells are among the most promising agents. Whereas much of the early success with CAR-T cells has been demonstrated with hematological malignancies, important barriers remain for the application of CAR-T cell therapies for the management of metastatic solid tumors. The challenges are particularly apparent when considering primary and metastatic tumors in the liver. At baseline, the intrahepatic space is immunosuppressive and this feature is exploited by malignant cells. Fortunately, our evolving understanding of liver immune cell biology is allowing the development of novel immunotherapeutic strategies for the treatment of liver tumors. Furthermore, the unique anatomic features of the liver make possible highly selective immunotherapeutic delivery approaches that may maximize antitumor efficacy while limiting off-target damage to healthy tissues. This review summarizes the immunobiology of the intrahepatic space and how this knowledge enables identification of hurdles and potential solutions to the barriers facing immunotherapy for liver tumors.

Tumor-associated GM-CSF overexpression induces immunoinhibitory molecules via STAT3 in myeloid-suppressor cells infiltrating liver metastases.

Assumptions that liver immune cells and immunosuppressive pathways are similar to their counterparts in other spaces have led to gaps in our understanding of intrahepatic neoplasm aggressiveness. Myeloid-derived suppressor cells (MDSCs) are potent inhibitors of antitumor immunity and pose a major obstacle to solid tumor treatment. Liver MDSCs (L-MDSCs) associated with liver metastases (LM) are particularly problematic by contributing to intrahepatic immunosuppression that promotes tumor progression. L-MDSCs have been reported to expand in response to granulocyte-macrophages colony-stimulating factor (GM-CSF) and suppress antitumor immunity in LM. To extend these findings, we examined mechanisms of intrahepatic immunosuppression exploited by L-MDSCs. We found that the majority of L-MDSCs co-expressed GM-CSF receptor (GM-CSF-R), indoleamine 2,3-dioxygenase (IDO) and programmed death ligand 1 (PD-L1), while demonstrating high levels of signal transducer and activator of transcription factor 3 (STAT3) activation. GM-CSF-secreting tumor cells induced STAT3 phosphorylation in L-MDSCs in addition to expression of IDO and PD-L1. GM-CSF or GM-CSF-R blockade markedly reduced L-MDSC IDO and PD-L1 expression, implicating tumor-derived GM-CSF in supporting L-MDSC-immunoinhibitory molecule expression. Small-molecule inhibitors of Janus-activated kinase 2 (JAK2) and STAT3 also dramatically diminished IDO and PD-L1 expression in L-MDSCs. We determined that STAT3 exerts transcriptional control over L-MDSC IDO and PD-L1 expression by binding to the IDO1 and PD-L1 promoters. Our data suggest that the GM-CSF/JAK2/STAT3 axis in L-MDSCs drives immunosuppression in a model of LM and blockade of this pathway may enable rescue of intrahepatic antitumor immunity.

On the Mechanism of Copper(I)-Catalyzed Azide-Alkyne Cycloaddition.

The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction regiospecifically produces 1,4-disubstituted-1,2,3-triazole molecules. This heterocycle formation chemistry has high tolerance to reaction conditions and substrate structures. Therefore, it has been practiced not only within, but also far beyond the area of heterocyclic chemistry. Herein, the mechanistic understanding of CuAAC is summarized, with a particular emphasis on the significance of copper/azide interactions. Our analysis concludes that the formation of the azide/copper(I) acetylide complex in the early stage of the reaction dictates the reaction rate. The subsequent triazole ring-formation step is fast and consequently possibly kinetically invisible. Therefore, structures of substrates and copper catalysts, as well as other reaction variables that are conducive to the formation of the copper/alkyne/azide ternary complex predisposed for cycloaddition would result in highly efficient CuAAC reactions. Specifically, terminal alkynes with relatively low pKa values and an inclination to engage in π-backbonding with copper(I), azides with ancillary copper-binding ligands (aka chelating azides), and copper catalysts that resist aggregation, balance redox activity with Lewis acidity, and allow for dinuclear cooperative catalysis are favored in CuAAC reactions. Brief discussions on the mechanistic aspects of internal alkyne-involved CuAAC reactions are also included, based on the relatively limited data that are available at this point.

Regional CAR-T cell infusions for peritoneal carcinomatosis are superior to systemic delivery.

Metastatic spread of colorectal cancer (CRC) to the peritoneal cavity is common and difficult to treat, with many patients dying from malignant bowel obstruction. Chimeric antigen receptor T cell (CAR-T) immunotherapy has shown great promise, and we previously reported murine and phase I clinical studies on regional intrahepatic CAR-T infusion for CRC liver metastases. We are now studying intraperitoneal (IP) delivery of CAR-Ts for peritoneal carcinomatosis. Regional IP infusion of CAR-T resulted in superior protection against carcinoembryonic antigen (CEA+) peritoneal tumors, when compared with systemically infused CAR-Ts. IP CAR-Ts also provided prolonged protection against IP tumor re-challenges and demonstrated an increase in effector memory phenotype over time. IP CAR-Ts provided protection against tumor growth at distant subcutaneous (SC) sites in association with increases in serum IFNγ levels. Given the challenges posed by immunoinhibitory pathways in solid tumors, we combined IP CAR-T treatment with suppressor cell targeting. High frequencies of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Treg) were found within the IP tumors, with MDSC expressing high levels of immunosuppressive PD-L1. Combinatorial IP CAR-T treatment with depleting antibodies against MDSC and Treg further improved efficacy against peritoneal metastases. Our data support further development of combinatorial IP CAR-T immunotherapy for peritoneal malignancies.

Temperature-modulated graphene oxide resistive humidity sensor for indoor air quality monitoring.

In this paper we present a temperature-modulated graphene oxide (GO) resistive humidity sensor that employs complementary-metal-oxide-semiconductor (CMOS) micro-electro-mechanical-system (MEMS) micro-hotplate technology for the monitoring and control of indoor air quality (IAQ). GO powder is obtained by chemical exfoliation, dispersed in water and deposited via ink-jet printing onto a low power micro-hotplate. Atomic force microscopy (AFM) and transmission electron microscopy (TEM) show the typical layered and wrinkled morphology of the GO. Raman spectroscopy, X-ray photoelectron spectroscopy (XPS) and Fourier transform infra-red (FTIR) spectroscopy indicate that the GO flakes possess a significant number of oxygen containing functional groups (epoxy, carbonyl, hydroxyl) extremely attractive for humidity detection. Electro-thermal characterisation of the micro-hotplates shows a thermal efficiency of 0.11 mW per °C, resulting in a sensor DC power consumption of only 2.75 mW at 50 °C. When operated in an isothermal mode, the sensor response is detrimentally affected by significant drift, hysteretic behaviour, slow response/recovery times and hence poor RH level discrimination. Conversely, a temperature modulation technique coupled with a differential readout methodology results in a significant reduction of the sensor drift, improved linear response with a sensitivity of 0.14 mV per %, resolution below 5%, and a maximum hysteresis of ±5%; response and recovery times equal to 189 ± 49 s and 89 ± 5 s, respectively. These performance parameters satisfy current IAQ monitoring requirements. We have thus demonstrated the effectiveness of integrating GO on a micro-hotplate CMOS-compatible platform enabling temperature modulation schemes to be easily applied in order to achieve compact, low power, low cost humidity IAQ monitoring.

Mask-less deposition of Au-SnO2 nanocomposites on CMOS MEMS platform for ethanol detection.

Here we report on the mask-less deposition of Au-SnO2 nanocomposites with a silicon-on-insulator (SOI) complementary metal oxide semiconductor (CMOS) micro electro mechanical system (MEMS) platform through the use of dip pen nanolithography (DPN) to create a low-cost ethanol sensor. MEMS technology is used in order to achieve low power consumption, by the employment of a membrane structure formed using deep reactive ion etching technique. The device consists of an embedded tungsten micro-heater with gold interdigitated electrodes on top of the SOI membrane. The tungsten micro-heater is used to raise the membrane temperature up to its operating temperature and the electrodes are used to measure the resistance of the nanocomposite sensing layer. The CMOS MEMS devices have high electro-thermal efficiency, with 8.2 °C temperature increase per mW power of consumption. The sensing material (Au-SnO2 nanocomposite) was synthesised starting from SnO nanoplates, then Au nanoparticles were attached chemically to the surface of SnO nanoplates, finally the mixture was heated at 700 °C in an oven in air for 4 h. This composite material was sonicated for 2 h in terpineol to make a viscous homogeneous slurry and then 'written' directly across the electrode area using the DPN technique without any mask. The devices were characterised by exposure to ethanol vapour in humid air in the concentration range of 100-1000 ppm. The sensitivity varied from 1.2 to 0.27 ppm(-1) for 100-1000 ppm of ethanol at 10% relative humid air. Selectivity measurements showed that the sensors were selective towards ethanol when they were exposed to acetone and toluene.

CMOS integration of inkjet-printed graphene for humidity sensing.

We report on the integration of inkjet-printed graphene with a CMOS micro-electro-mechanical-system (MEMS) microhotplate for humidity sensing. The graphene ink is produced via ultrasonic assisted liquid phase exfoliation in isopropyl alcohol (IPA) using polyvinyl pyrrolidone (PVP) polymer as the stabilizer. We formulate inks with different graphene concentrations, which are then deposited through inkjet printing over predefined interdigitated gold electrodes on a CMOS microhotplate. The graphene flakes form a percolating network to render the resultant graphene-PVP thin film conductive, which varies in presence of humidity due to swelling of the hygroscopic PVP host. When the sensors are exposed to relative humidity ranging from 10-80%, we observe significant changes in resistance with increasing sensitivity from the amount of graphene in the inks. Our sensors show excellent repeatability and stability, over a period of several weeks. The location specific deposition of functional graphene ink onto a low cost CMOS platform has the potential for high volume, economic manufacturing and application as a new generation of miniature, low power humidity sensors for the internet of things.

Diversity of killer cell immunoglobulin-like receptor genes in the Bengali population of northern West Bengal, India.

The Indian Subcontinent exhibits extensive diversity in its culture, religion, ethnicity and linguistic heritage, which symbolizes extensive genetic variations within the populations. The highly polymorphic Killer cell Immunoglobulin-like Receptor (KIR) family plays an important role in tracing genetic differentiation in human population. In this study, we aimed to analyse the KIR gene polymorphism in the Bengali population of northern West Bengal, India. To our knowledge, this is the first report on the KIR gene polymorphism in the Bengalis of West Bengal, India. Herein, we have studied the distribution of 14 KIR genes (KIR3DL1-3DL3, KIR2DL1-2DL5, KIR2DS1-2DS5 AND KIR3DS1) and two pseudogenes (KIR3DP1 and 2DP1) in the Bengalis. Apart from the framework genes (KIR2DL4, 3DL2, 3DL3 and 3DP1), which are present in all the individuals, the gene frequencies of other KIR genes varied between 0.34 and 0.88. Moreover, upon comparing the KIR polymorphism of the Bengalis with the available published data of other world populations, it has been found that the Indo-European-speaking Bengalis from the region share both Dravidian and Indo-Aryan gene pool with considerable influences of mongoloid and European descents. Furthermore, evidences from previously published data on human leucocyte antigen and Y-chromosome haplogroup diversity support the view. Our results will help to understand the genetic background of the Bengali population, in illustrating the population migration events in the eastern and north-eastern part of India, in explaining the extensive genetic admixture amongst the different linguistic groups of the region and also in KIR-related disease researches.

Non pitting edema, arthritis and ichthyosis; presenting manifestation of leprosy.

Leprosy is a chronic granulomatous infection caused by Mycobacterium leprae. Predominantly involving skin and nerves and having classic clinical description, the diagnosis may be clear-cut in majority of patients but may be challenging in others. Non-pitting edema, ichthyosis and arthritis are uncommon in leprosy and very rare in tuberculoid type where the diagnosis may be challenging unlike relatively clear-cut clinical picture in lepromatous type. Musculoskeletal manifestation is seen in 1-5% of cases and usually associated with reactional states where again the diagnosis sometimes becomes evident. High index of suspicion is therefore recommended in patients with unexplained systemic illness especially in endemic areas. Herein we report a young male with non pitting edema and symmetric peripheral arthritis involving all four limbs, and ichthyosis as presenting manifestation of borderline leprosy where the neuro-cutaneous manifestation developed two months after the said presenting features and in absence of a reactional state.

Community based mangrove management: a review on status and sustainability.

Community Based Mangrove Management (CBMM) has been advocated by both academia and governing agencies as a viable alternative for sustainably managing the ecologically important mangrove forests which are disappearing rapidly worldwide. Drawing insights from diverse sustainability issues, capabilities and performances of worldwide CBMM initiatives were examined in this paper. Higher numbers of CBMM initiatives were reported from South Asia and lesser from South America and Africa. Identification of the causes of degradation at a site and use-specific zonal replantations with respect to species associations were identified as major criteria of ecological sustainability. Regarding economic sustainability, transformation of potential uses of mangroves known by local communities into actual ones was found to be necessary. Proper disbursement of accrued benefits among community members irrespective of their socio-cultural status is also a major concern. Restructuring of CBMM institutions by ensuring participation of subsistence based users in decision-making and resource sharing have been identified as a prime determinant of institutional sustainability. However, limited number of studies on socio-political and institutional aspects as well as impacts of globalization induced socio-cultural transformations of communities on CBMM had been actually found. More focused researches on these aspects had been recommended for better community management of these highly stressed forests.

Pro-ulcer effects of resveratrol in mice with indomethacin-induced gastric ulcers are reversed by L-arginine.

BACKGROUND AND PURPOSE: Although resveratrol is currently being evaluated in pre-clinical studies as a potential cancer chemopreventive agent and cardiovascular stress-releasing compound, treatment with resveratrol severely delays healing of pre-existing gastric ulcers. Resveratrol treatment can also induce endothelial NOS (eNOS) expression. Here, we have attempted to modulate NO production via eNOS in order to alleviate the pro-ulcer effects of resveratrol. EXPERIMENTAL APPROACH: Gastric ulcers were induced in mice with a single dose of indomethacin. The effects of pretreatment with l-arginine on the pro-ulcer effects of resveratrol in these mice were then assessed. We measured ulcer damage scores (DS), myeloperoxidase (MPO) activity, generation of prostaglandin E(2) (PGE(2)) and NO, along with a gene expression study. KEY RESULTS: Resveratrol significantly aggravated damage from indomethacin-induced gastric ulcers, and delayed healing, as shown by increased DS and MPO activity. The mRNA for cyclooxygenase (COX)-1, but not that for COX-2, was inhibited by resveratrol treatment, with reduced synthesis of PGE(2) by gastric tissue. However, resveratrol treatment induced eNOS gene expression and shifted the eNOS/iNOS balance. l-Arginine given before resveratrol in mice with indomethacin-induced ulcers significantly increased tissue NO synthesis and improved ulcer healing. CONCLUSIONS AND IMPLICATIONS: Exogenous l-arginine increased NO formation via raised levels of eNOS induced by resveratrol and protected against the pro-ulcer effects of resveratrol. Therefore, l-arginine might be useful for alleviation of the pro-ulcer side effects of resveratrol in patients.

Restoration of impaired free radical generation and proinflammatory cytokines by MCP-1 in mycobacterial pathogenesis.

Mycobacterium tuberculosis exerts its pathogenic effects mainly via its cell wall glycolipid called Mannosylated Lipoarabinomannan (Man-LAM), which subverts the cellular inflammatory responses by the suppression of superoxide anion generation in earlier hours, and nitric oxide (NO) generation at later hours of pathogenic invasion. In this paper, we have shown the prophylactic effect of C-C chemokines, both in vitro and in vivo. Exogenous administration of C-C chemokines, particularly monocyte chemoattractant protein (MCP)-1, led to the induction of superoxide anion generation via the restoration of impaired protein kinase C (PKC) signalling in Man-LAM-treated macrophages. Monocyte chemoattractant protein-1 could also potently induce NO generation by upregulation of the proinflammatory cytokines tumour necrosis factor-alpha and interleukin-12 from Man-LAM-treated macrophages accompanied by inhibition of anti-inflammatory responses. Our in vivo observations clearly exhibited effective restoration of impaired PKC signalling as well as proinflammatory cytokine expression by MCP-1 in Man-LAM treated as well as M. tuberculosis H37Rv-infected C57BL/6 mice. We also observed, as direct evidence, that MCP-1 induced a significant reduction of the number of viable tubercle bacilli in the lungs and spleen of infected mice. Collectively, our findings strongly suggest the effectiveness of MCP-1 as a potent immunoprophylactic tool for controlling the mycobacterial establishment within the host.

Growth of carbon nanotubes on fully processed silicon-on-insulator CMOS substrates.

This paper describes the growth of Carbon Nanotubes (CNTs) both aligned and non-aligned on fully processed CMOS substrates containing high temperature tungsten metallization. While the growth method has been demonstrated in fabricating CNT gas sensitive layers for high temperatures SOI CMOS sensors, it can be employed in a variety of applications which require the use of CNTs or other nanomaterials with CMOS electronics. In our experiments we have grown CNTs both on SOI CMOS substrates and SOI CMOS microhotplates (suspended on membranes formed by post-CMOS deep RIE etching). The fully processed SOI substrates contain CMOS devices and circuits and additionally, some wafers contained high current LDMOSFETs and bipolar structures such as Lateral Insulated Gate Bipolar Transistors. All these devices were used as test structures to investigate the effect of additional post-CMOS processing such as CNT growth, membrane formation, high temperature annealing, etc. Electrical characterisation of the devices with CNTs were performed along with SEM and Raman spectroscopy. The CNTs were grown both at low and high temperatures, the former being compatible with Aluminium metallization while the latter being possible through the use of the high temperature CMOS metallization (Tungsten). In both cases we have found that there is no change in the electrical behaviour of the CMOS devices, circuits or the high current devices. A slight degradation of the thermal performance of the CMOS microhotplates was observed due to the extra heat dissipation path created by the CNT layers, but this is expected as CNTs exhibit a high thermal conductance. In addition we also observed that in the case of high temperature CNT growth a slight degradation in the manufacturing yield was observed. This is especially the case where large area membranes with a diameter in excess of 500 microns are used.

Impacts of climate change on the fate and behaviour of pesticides in surface and groundwater--A UK perspective.

Over the last two decades significant effort has been dedicated to understanding the fate and transport of pesticides in surface water and groundwater and to use this understanding in the development of environmental policy and regulation. However, there have been few studies that have investigated the relationships between pesticides and climate change, and where this work has been undertaken it has principally been in relation to the impacts of climate change on agricultural production rather than in the context of environmental protection. This study addresses that gap by reviewing how climate change may impact the fate and transport of pesticides in surface and groundwaters as a pre-cursor to quantitative studies. In order to structure the review, we have adopted a source-pathway-receptor approach where climate sensitivities of pesticide source terms, environmental pathways and receptors are reviewed. The main climate drivers for changing pesticide fate and behaviour are thought to be changes in rainfall seasonality and intensity and increased temperatures, but the effect of climate change on pesticide fate and transport is likely to be very variable and difficult to predict. In the long-term, indirect impacts, such as land-use change driven by changes in climate, may have a more significant effect on pesticides in surface and groundwaters than the direct impacts of climate change on pesticide fate and transport. The review focuses on climate change scenarios and case studies from the UK; however, the general conclusions can be applied more widely.

Activated sludge is a potential source for production of biodegradable plastics from wastewater.

Increased utilization of synthetic plastics caused severe environmental pollution due to their non-biodegradable nature. In the search for environmentally friendly materials to substitute for conventional plastics, different biodegradable plastics have been developed by microbial fermentations. However, limitations of these materials still exist due to high cost. This study aims at minimization of cost for the production of biodegradable plastics P(3HB) and minimization of environmental pollution. The waste biological sludge generated at wastewater treatment plants is used for the production of P(3HB) and wastewater is used as carbon source. Activated sludge was induced by controlling the carbon: nitrogen ratio to accumulate storage polymer. Initially polymer accumulation was studied by using different carbon and nitrogen sources. Maximum accumulation of polymer was observed with carbon source acetic acid and diammonium hydrogen phosphate (DAHP) as nitrogen source. Further studies were carried out to optimize the carbon: nitrogen ratios using acetic acid and DAHP. A maximum of 65.84% (w/w) P(3HB) production was obtained at C/N ratio of 50 within 96 hours of incubation.

Refractory schizophrenia, clozapine and epilepsy : management strategies.

This case of refractory schizophrenia in a 28 year old male showed significant improvement with clozapine. But therapeutic doses of clozapine were associated with generalised tonic clonic seizures (GTCS). Addition of sodium valproate allowed adequate control of schizophrenic symptoms as well as seizures. EEG abnormality correlated surprisingly well with development of GTCS and subsequent improvement with anticonvulsant. Factors that lead to seizure-vulnerability in clozapine treated patients are discussed.