Nivolumab as Second-Line Therapy Improves Survival in Patients with Unresectable Hepatocellular Carcinoma.

BACKGROUND: Limited data exists for the efficacy and outcomes of nivolumab as a second-line treatment for unresectable hepatocellular carcinoma (uHCC). We aimed to assess the efficacy and safety of nivolumab in patients with uHCC who experienced disease progression during sorafenib treatment. METHODS: In this retrospective, observational, multicenter study, adult Child-Turcotte-Pugh A/7B patients with uHCC who tolerated sorafenib therapy but showed disease progression switched to second-line intravenous nivolumab (n = 42). A similar number of consecutive, unselected patients who were maintained on sorafenib therapy, regardless of tumoral response or progression, served as historical controls (n = 38). The primary endpoint was overall survival (OS, defined as the time from starting sorafenib in either group up to death due to any cause) and analyzed by intention-to-treat. RESULTS: The mean age of the overall cohort was 72.4 ± 10.1 years, of whom 87.5% were males and 58.8% had underlying viral etiology. Patients in the two cohorts were similar, except those who received nivolumab had more co-morbidities (70.0% vs. 15.4%), ECOG-2 status (21.4% vs. 15.8%), BCLC stage C (81.0% vs. 47.4%), and extravascular invasion (54.4% vs. 21.8%) (p < 0.05 for all). More patients in the nivolumab arm were Child-Turcotte-Pugh B (35.7% vs. 21.1%, p = 0.15). Median OS was 22.2 months (95% CI: 8.9-49.8) on second-line nivolumab and 11.0 months (95% CI: 3.6-18.4) on sorafenib alone (HR 1.93; 95% CI: 1.1-3.3, p = 0.014). Median OS after starting nivolumab was 10.2 months, and time-to-progression was 4.9 months (95% CI: 3.2-6.3). CONCLUSION: Nivolumab is an effective second-line treatment option in patients with uHCC who progress on sorafenib, with significantly improved OS. These early real-life data offer encouraging results, similar to those shown in Phase I/IIa clinical trials. Further investigations are warranted for the use of nivolumab as a monotherapy.

Biosynthesis of copper nanoparticles using Solenostemma argel and their effect on enhancing salt tolerance in barley plants.

The distinctive characteristics of nanoparticles and their potential applications have been given considerable attention by scientists across different fields, particularly agriculture. However, there has been limited effort to assess the impact of copper nanoparticles (CuNPs) in modulating physiological and biochemical processes in response to salt-induced stress. This study aimed to synthesize CuNPs biologically using Solenostemma argel extract and determine their effects on morphophysiological parameters and antioxidant defense system of barley (Hordeum vulgare) under salt stress. The biosynthesized CuNPs were characterized by (UV-vis spectroscopy with Surface Plasmon Resonance at 320 nm, the crystalline nature of the formed NPs was verified via XRD, the FTIR recorded the presence of the functional groups, while TEM was confirmed the shape (spherical) and the sizes (9 to 18 nm) of biosynthesized CuNPs. Seeds of barley plants were grown in plastic pots and exposed to different levels of salt (0, 100 and 200 mM NaCl). Our findings revealed that the supplementation of CuNPs (0, 25 and 50 mg/L) to salinized barley significantly mitigate the negative impacts of salt stress and enhanced the plant growth-related parameters. High salinity level enhanced the oxidative damage by raising the concentrations of osmolytes (soluble protein, soluble sugar, and proline), malondialdehyde (MDA) and hydrogen peroxide (H2O2). In addition, increasing the activities of enzymatic antioxidants, total phenol, and flavonoids. Interestingly, exposing CuNPs on salt-stressed plants enhanced the plant-growth characteristics, photosynthetic pigments, and gas exchange parameters. Furthermore, CuNPs counteracted oxidative damage by lowering the accumulation of osmolytes, H2O2, MDA, total phenol, and flavonoids, while simultaneously enhancing the activities of antioxidant enzymes. In conclusion, the application of biosynthesized CuNPs presents a promising approach and sustainable strategy to enhance plant resistance to salinity stress, surpassing conventional methods in terms of environmental balance.

The first assessment of marine litter on somalian coast: The case of Liido Beach, mogadishu.

This paper presents the first assessment of marine litter in the Mogadishu coastal area of Somalia. Samples were collected monthly using 100 m × 40 m transect and classified following OSPAR Marine Litter Survey Guide while litter sources were identified using Ocean Conservancy Marine Debris Index. The results showed a total of 119873 items consisting of plastics (89.47%), clothing items (7.53%), and others (3.00%) recovered from Liido Beach. Litter density ranged from 2.19 items/m2 to 14.18 items/m2 with a mean of 6.25 items/m2 and Clean Coast Index (CCI) suggesting that Liido Beach is extremely dirty (>20 items/m2). In addition, the primary sources of marine litter at the beach are local recreational and shoreline activities (54.12%), and dumping (36.61%). The dominance of plastic litter on the beach poses potential threats to marine biodiversity in the Somalia coastal area and the West Indian Ocean. It is recommended that effective strategies and solutions to mitigate litter on the beach and other coastal areas in Somalia should be developed and compensated with public education and awareness campaigns across the country.

Knowledge and attitude on the role of lifestyle modifications in the management of diabetes in Jeddah, Saudi Arabia.

BACKGROUND: Public knowledge about the role of lifestyle in managing type two diabetes (T2D) is an essential preventive strategy. Despite efforts in public awareness, the prevalence continues to rise, with the majority relying on the availability of effective therapeutics, underestimating the role of healthy lifestyle changes. This study aims to assess public awareness of the impact of lifestyle modification in managing T2D in a major metropolitan city in Saudi Arabia, which will help inform the health management authority in the country on the level of public awareness and advise on the development of educational programs. METHODS: An observational cross-sectional survey study comprising 16 knowledge and 6 attitude questions was conducted among the population over 18 years old using online survey. After validation, the online self-developed questionnaire was distributed through social media. RESULTS: The knowledge and attitude scores were similar between males and females. Participants with a family member or friend with T2D demonstrated higher knowledge scores. However, the attitude scores did not differ significantly based on family or friend relationships. CONCLUSION: The knowledge and attitude on the role of lifestyle modifications in preventing and managing T2D is moderate, implying an opportunity for innovative strategies to raise public knowledge and attitude.

UPLC/ESI/MS profiling of red algae Galaxaura rugosa extracts and its activity against malaria mosquito vector, Anopheles pharoensis, with reference to Danio rerio and Daphnia magna as bioindicators.

BACKGROUND: Anopheles pharoensis has a major role in transmitting several human diseases, especially malaria, in Egypt?. Controlling Anopheles is considered as an effective strategy to eliminate the spread of malaria worldwide. Galaxaura rugosa is a species of red algae found in tropical to subtropical marine environments. The presence of G. rugosa is indicative of the ecosystem's overall health. The current work aims to investigate UPLC/ESI/MS profile of G. rugosa methanol and petroleum ether extracts and its activity against An. pharoensis and non-target organisms, Danio rerio and Daphnia magna. METHODS: Galaxaura rugosa specimens have been identified using DNA barcoding for the COI gene and verified as G. rugosa. The UPLC/ESI/MS profiling of G. rugosa collected from Egypt was described. The larvicidal and repellent activities of G. rugosa methanol and petroleum ether extracts against An. pharoensis were evaluated, as well as the toxicity of tested extracts on non-target organisms, Dan. rerio and Dap. magna. RESULTS: The UPLC/ESI/MS analysis of methanol and petroleum ether extracts led to the tentative identification of 57 compounds belonging to different phytochemical classes, including flavonoids, tannins, phenolic acids, phenyl propanoids. Larval mortality was recorded at 93.33% and 90.67% at 80 and 35 ppm of methanol and petroleum ether extracts, respectively, while pupal mortality recorded 44.44 and 22.48% at 35 and 30 ppm, respectively. Larval duration was recorded at 5.31 and 5.64 days by methanol and petroleum ether extracts at 80 and 35 ppm, respectively. A decrease in acetylcholinesterase (AChE) level and a promotion in Glutathione-S-transferase (GST) level of An. pharoensis 3rd instar larvae were recorded by tested extracts. The petroleum ether extract was more effective against An. pharoensis starved females than methanol extract. Also, tested extracts recorded LC50 of 1988.8, 1365.1, and 11.65, 14.36 µg/mL against Dan. rerio, and Dap. magna, respectively. CONCLUSIONS: Using red algae derivatives in An. pharoensis control could reduce costs and environmental impact and be harmless to humans and other non-target organisms.

Improving the Outcome of Patients With Heart Failure: Assessment of Iron Deficiency and Intravenous Iron Replacement.

Background Iron deficiency (ID) has been shown to be a significant co-morbidity in patients with heart failure (HF), independent of their anaemia status. Correction of ID has been shown to improve quality of life, recurrent heart failure hospitalizations and morbidity. A quality improvement project was designed to improve the assessment and treatment of iron deficiency in HF patients in our tertiary care centre. Methods and results An initial baseline dataset was collected, followed by two cycles of interventions to help improve the care of HF patients admitted to our hospital over a two-month period. The Plan-Do-Study-Act (PDSA) cycle approach was applied, with the first intervention involving raising awareness of the importance and need to assess the iron status of HF patients through education provided to doctors, nurses and patients. Furthermore, information leaflets were produced and disseminated across the medical wards and through social media forums. The post-intervention datasets were collected and compared to the baseline outcomes. Baseline data showed that only four (20%) of heart failure patients had their iron status checked. Following the interventions, screening for ID increased to 80% (16), of which 85% (11) of those who identified as iron deficient received intravenous iron replacement. Conclusion The project was successful in improving the practice of screening for iron deficiency and intravenous replacement of iron in patients with HF.

Echocardiographic Assessment of the Left Ventricle in Young Prehypertensive Nigerians.

BACKGROUND:  Prehypertension is associated with an increased risk of cardiovascular morbidity and mortality. This risk could partly be explained by the early compromise in left ventricular (LV) structure and function. This study investigated the LV geometry and function in young black prehypertensive subjects. METHODS AND RESULTS: This cross-sectional descriptive study was conducted at the Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria. Echocardiography-derived LV geometry and function were assessed using standardized methods. Prehypertensive subjects had higher mean systolic blood pressure (BP) (130.78 ± 3.57 mmHg vs 111.42 ± 3.54 mmHg, P<0.001), diastolic BP (79.32 ± 4.13 mmHg vs 66.39 ± 4.42 mmHg, P<0.001), body mass index (BMI) (26.24 ± 3.45 kg/m2 vs 22.20 ± 2.21 kg/m2, P<0.001), waist circumference (WC) (86.93 ± 8.73 cm vs 76.73 ± 6.66 cm, P<0.001), fasting blood glucose (FBG) (93.84 ± 7.28 mg/dl vs 90.08 ± 6.26 mg/dl, P<0.001), and dyslipidemia (21.5% vs 6%. P<0.001) compared to normotensive subjects. LV mass index (LVMI) was greater in prehypertensive subjects compared to normotensive subjects {male (106.84 ± 12.34 g/m2 vs 76.07 ± 10.25 g/m2, P<0.001); female (92.06 ± 8.80 g/m2 vs 66.53 ± 7.21 g/m2, P<0.001)}, with abnormal LV geometry recorded in 17.5%. Linear regression analysis showed that waist circumference, systolic BP, serum creatinine level, and urea level were determinants of LVMI. The prevalence of LV diastolic dysfunction was higher in prehypertensive subjects than in normotensive subjects (14.5% vs. 0.5%, P<0.001), with systolic BP {odds ratio (OR) 0.928, confidence interval (CI) 0.834 - 0.969; P=0.016)} and diastolic BP (OR 0.832, CI 0.722 - 0.958; P=0.011) being independent predictors. CONCLUSION:  This study showed that prehypertension in young Black subjects was associated with altered LV geometry and impaired diastolic function, and these changes demonstrated linear progression with increasing systolic BP.

Improving the Production of Secondary Metabolites via the Application of Biogenic Zinc Oxide Nanoparticles in the Calli of Delonix elata: A Potential Medicinal Plant.

The implementation of nanotechnology in the field of plant tissue culture has demonstrated an interesting impact on in vitro plant growth and development. Furthermore, the plant tissue culture accompanying nanoparticles has been showed to be a reliable alternative for the biosynthesis of secondary metabolites. Herein, the effectiveness of zinc oxide nanoparticles (ZnONPs) on the growth of Delonix elata calli, as well as their phytochemical profiles, were investigated. Delonix elata seeds were collected and germinated, and then the plant species was determined based on the PCR product sequence of ITS1 and ITS4 primers. Afterward, the calli derived from Delonix elata seedlings were subjected to 0, 10, 20, 30, 40, and 50 mg/L of ZnONPs. The ZnONPs were biologically synthesized using the Ricinus communis aqueous leaf extract, which acts as a capping and reducing agent, and zinc nitrate solution. The nanostructures of the biogenic ZnONPs were confirmed using different techniques like UV-visible spectroscopy (UV), zeta potential measurement, Fourier transform infrared spectra (FTIR), X-ray diffraction (XRD), and scanning electron microscopy (SEM). Adding 30 mg/L of ZnONPs to the MS media (containing 2.5 µM 2,4-D and 1 µM BAP) resulted in the highest callus fresh weight (5.65 g) compared to the control and other ZnONP treatments. Similarly, more phenolic accumulation (358.85 µg/g DW) and flavonoid (112.88 µg/g DW) contents were achieved at 30 mg/L. Furthermore, the high-performance liquid chromatography (HPLC) analysis showed significant increments in gallic acid, quercetin, hesperidin, and rutin in all treated ZnONP calli compared to the control. On the other hand, the gas chromatography and mass spectroscopy (GC-MS) analysis of the calli extracts revealed that nine phytochemical compounds were common among all extracts. Moreover, the most predominant compound found in calli treated with 20, 30, 40, and 50 mg/L of ZnONPs was bis(2-ethylhexyl) phthalate, with percentage areas of 27.33, 38.68, 22.66, and 17.98%, respectively. The predominant compounds in the control and in calli treated with 10 mg/L of ZnONPs were octadecanoic acid, 2-propenyl ester and heptanoic acid. In conclusion, in this study, green ZnONPs exerted beneficial effects on Delonix elata calli and improved their production of bioactive compounds, especially at a dose of 30 mg/L.

Structural and geomorphological study of Bradost, Chinara, Shireen and Sare Musa anticlines, Iraqi Kurdistan Region.

The Bradost and Chinara mountains are two well-known geomorphic features in the Iraqi Kurdistan Region (IKR), forming two anticlines, besides Shireen and Sare Musa anticlines, which are located north of the Bradost anticline, all four anticlines trend NW - SE. The four anticlines are dissected by the Greater Zab River that swings along its course within the anticlines due to tens of very old landslides and/or plunges. The four studied anticlines are dissected by different thrust faults, which extend for a few kilometers. The thrust faults trend NW - SE; however, locally they deflect from the main trend. The Lower Jurassic rocks are the oldest exposed rocks in the studied area, whereas the rocks of the Bekhme Formation form the carapace of the Bradost and Chinara anticlines. Different structural and geomorphological features were interpreted from satellite images and those which are accessible were checked in the field, all of them indicate the four anticlines exhibit lateral growth. We have measured different aspects to elucidate the type of folds. The four anticlines are Detachment folds, with shallow decollement, which ranges in depth between (100-250) m.

Biosynthesis of Silver Nanoparticles and Exploring Their Potential of Reducing the Contamination of the In Vitro Culture Media and Inducing the Callus Growth of Rumex nervosus Explants.

Among biological methods, green synthesis of the nanomaterials using plant extracts was shown to be an environmentally friendly, economical, and simple approach. In the current study, the biogenic synthesis of silver nanoparticles (AgNPs) was achieved using the leaf extract of Hibiscus tiliaceus, in order to prevent the contamination of the tissue culture media and induce callus growth. The nanostructures of the fabricated AgNPs were characterized using UV-visible spectroscopy, Fourier transform infra-red spectra (FTIR), X-ray diffraction (XRD), transmission electron microscopy (TEM), zeta size, and zeta potential techniques. Our results indicate that The UV-vis spectrum of AgNPs exhibited an absorption band at 415 nm. The FTIR analysis identified the functional groups which could involve in the reduction of silver ions to AgNPs, this was also confirmed by the (hkl) diffraction peaks in the XRD diffractogram. Moreover, the TEM analysis showed a spherical nanoparticle with a size ranging from 21 and 26 nm. Thereafter, the potential antibacterial and antifungal activity of the biogenic AgNPs was evaluated against Bacillus pumilus and Alternaria alternata which were isolated from the in vitro culture media and identified based on 16S rDNA and ITS rDNA sequences, respectively. The results showed that the AgNPs significantly inhibited the growth of Alternaria alternata and Bacillus pumilus at all applied concentrations (5, 10, 20 and 40 mg/L). Compared to the control more fungal radial growth reduction (42.59%,) and bacterial inhibition (98.12%) were registered in the plates containing high doses of AgNPs (40 mg/L). Using Rumex nervosus explants, the biosynthesized AgNPs were tested for their impact to promote callus growth. The obtained results showed a significant effect of AgNPs on callus fresh weight at all applied doses. Moreover, AgNPs treatments showed a polymorphism of 12.5% which was detected by RAPD markers. In summary, the results revealed that AgNPs (40 mg/L) can be effectively added to the in vitro culture media for reducing microbial contamination and improving callus growth while greatly maintaining its genetic stability.

Effect of Green Synthesized ZnO-NPs on Growth, Antioxidant System Response and Bioactive Compound Accumulation in Echinops macrochaetus, a Potential Medicinal Plant, and Assessment of Genome Size (2C DNA Content).

Echinops macrochaetus is a medicinal plant that can be used to cure various diseases. In the present study, plant-mediated zinc oxide nanoparticles (ZnO-NPs) were synthesized using an aqueous leaf extract of the medicinal plant Heliotropium bacciferum and characterized using various techniques. E. macrochaetus was collected from the wild and identified using the internal transcribed spacer sequence of nrDNA (ITS-nrDNA), which showed the closeness to its related genus in a phylogenetic tree. The effect of synthesized biogenic ZnO-NPs was studied on E. macrochaetus in a growth chamber for growth, bioactive compound enhancement and antioxidant system response. The irrigation of plants at a low concentration of ZnO-NPs (T1 = 10 mg/L) induced more growth in terms of biomass, chlorophyll content (273.11 µg/g FW) and carotenoid content (135.61 µg/g FW) than the control and other treatments (T2-20 mg/L and T3-40 mg/L). However, the application of a high concentration of ZnO-NPs (20 and 40 mg/L) increased the level of antioxidant enzymes (SOD, APX and GR), total crude and soluble protein, proline and TBARS contents. The accumulations of the compounds quercetin-3-ß-D-glucoside, luteolin 7-rutinoside and p-coumaric acid were greater in the leaf compared to the shoot and root. A minor variation was observed in genome size in treated plants as compared to the control group. Overall, this study revealed the stimulatory effect of phytomediated ZnO-NPs, which act as bio-stimulants/nano-fertilizers as revealed by more biomass and the higher production of phytochemical compounds in different parts of the E. macrochaetus.

Selective modulation of monocyte and neutrophil responses with activated protein C in preterm infants.

BACKGROUND: Inflammation is associated with many disorders of preterm infants including periventricular leukomalacia, chronic lung disease, and necrotizing enterocolitis. Activated protein c (APC) has shown positive immunomodulatory effects. OBJECTIVES: We aimed to study neutrophil and monocyte function in response to lipopolysaccharide (LPS) and APC stimulation ex vivo in preterm infants <32 weeks gestation over the first week of life compared to neonatal and adult controls. METHODS: Peripheral blood was taken on day 1, 3, and 7 and stimulated with LPS in the absence or presence of APC. Expression of toll-like receptor 4 (TLR4) and CD11b and reactive oxygen intermediate (ROI) release from neutrophils and monocytes was examined by flow cytometry. RESULTS: LPS induced neutrophil ROI in adults and preterm infants and was significantly reduced by APC. Baseline and LPS-induced monocyte ROI production in preterm neonates was increased compared to adult and term controls. Neutrophil TLR4 baseline expression was higher in term controls compared to preterm infants. CONCLUSION: Increased systemic ROI release in preterm infants may mediate tissue damage, ROI was reduced by APC. However, due to the high risk of hemorrhage further examination of APC mutant forms with anti-inflammatory but decreased anticoagulant properties is merited.

Biogenic silver nanoparticles improve bioactive compounds in medicinal plant Juniperus procera in vitro.

Bioactive compounds of medicinal plants present as natural ingredients provide health benefits beyond the basic nutritional value of these products. However, the availability of bioactive compounds in the current natural sources is limited. Hence, the induction of bioactive compound production from medicinal plants through nanoparticles (NPs) might play a vital role in industrially important medicinal compounds. Therefore, this study aimed to synthesize silver nanoparticles (AgNPs) biologically and to investigate their effect on phytochemical compound production from the callus of Juniperus procera. AgNPs were synthesized biologically using aqueous leaf extract of Phoenix dactylifera, which acted as a reducing and capping agent, and silver nitrate solution. The formation of AgNPs has been confirmed through different analytical techniques such as UV-Visible spectroscopy (UV), Fourier-transform infrared spectroscopy (FTIR), dynamic light scattering (DLS), and scanning electron microscope (SEM). The impact of different concentrations (0.0, 5, 20, and 50 mg/L) of AgNPs on enzymatic and non-enzymatic antioxidants of the callus of J. procera was investigated. The obtained results showed a significant effect of AgNPs on biomass accumulation and non-enzymatic antioxidants (phenol, tannin, and flavonoid content). Additionally, total protein content and superoxide dismutase (SOD) activity were increased in response to AgNPs. Furthermore, bioactive compounds like gallic acid, tannic acid, coumarin, hesperidin, rutin, quercetin, and ferruginol were chromatographically separated and quantified using high-performance liquid chromatography (HPLC) with reference standards. These compounds were increased significantly in response to AgNPs treatments. We concluded that AgNPs could be a promising elicitor for improving the production of phytochemical compounds in medicinal plants. This work can serve asa good model for improving the production of bioactive compounds from medicinal plants in vitro. This molecular investigation should be done to understand better the metabolic mechanism leading to bioactive compound production scaling.

Precision Determination of the Neutral Weak Form Factor of

We report a precise measurement of the parity-violating (PV) asymmetry A_{PV} in the elastic scattering of longitudinally polarized electrons from ^{48}Ca. We measure A_{PV}=2668±106(stat)±40(syst) parts per billion, leading to an extraction of the neutral weak form factor F_{W}(q=0.8733 fm^{-1})=0.1304±0.0052(stat)±0.0020(syst) and the charge minus the weak form factor F_{ch}-F_{W}=0.0277±0.0055. The resulting neutron skin thickness R_{n}-R_{p}=0.121±0.026(exp)±0.024(model) fm is relatively thin yet consistent with many model calculations. The combined CREX and PREX results will have implications for future energy density functional calculations and on the density dependence of the symmetry energy of nuclear matter.

Assessment of the Impacts of Green Synthesized Silver Nanoparticles on Maerua oblongifolia Shoots under In Vitro Salt Stress.

Salinity is one of the major abiotic stresses that affect the plant's growth and development. Recently, the contribution of nanoparticles (NPs) to ameliorating salinity stresses has become the new field of interest for scientists due to their special physiochemical properties in the biological system. This study is designed to examine the effects of biosynthesized silver nanoparticles (AgNPs) spherical in shape (size range between 9 and 30 nm) on morphophysiological characteristics and the antioxidant defense system of in vitro raised Maerua oblongifolia under four levels of salt stress (0, 50, 100, and 200 mM NaCl). Our findings reveal that the application of AgNPs (0, 10, 20, and 30 mg/L) to M. oblongifolia shoots significantly alleviates the adverse effects of salt stress and ameliorates plant developmental-related parameters and defense systems. High salinity elevates the oxidative damage by over-accumulation of the levels of total soluble sugars, proline, hydrogen peroxide (H2O2), and malondialdehyde (MDA). In addition, enhancing the activity of the antioxidant enzymes, total phenolic, and flavonoid content over the control. Interestingly, the application of AgNPs to salinized plants improved the growth traits and photosynthetic pigment production and caused higher enhancement in antioxidant enzyme activities. Furthermore, mitigating the oxidative damage by lowering the accumulation of proline, soluble sugars, H2O2, MDA, and total phenolic and flavonoid contents in salt-stressed plants. In general, AgNPs augmented the growth of M. oblongifolia shoots under saline conditions through different strategies; thus, AgNPs can be used as an appropriate eco-friendly approach that enhances salinity tolerance in plants.

Corrigendum: Genome-Wide Identification and Expression Profiling of Germin-Like Proteins Reveal Their Role in Regulating Abiotic Stress Response in Potato.

[This corrects the article DOI: 10.3389/fpls.2021.831140.].

Artemisinin inhibits neutrophil and macrophage chemotaxis, cytokine production and NET release.

Immune cell chemotaxis to the sites of pathogen invasion is critical for fighting infection, but in life-threatening conditions such as sepsis and Covid-19, excess activation of the innate immune system is thought to cause a damaging invasion of immune cells into tissues and a consequent excessive release of cytokines, chemokines and neutrophil extracellular traps (NETs). In these circumstances, tempering excessive activation of the innate immune system may, paradoxically, promote recovery. Here we identify the antimalarial compound artemisinin as a potent and selective inhibitor of neutrophil and macrophage chemotaxis induced by a range of chemotactic agents. Artemisinin released calcium from intracellular stores in a similar way to thapsigargin, a known inhibitor of the Sarco/Endoplasmic Reticulum Calcium ATPase pump (SERCA), but unlike thapsigargin, artemisinin blocks only the SERCA3 isoform. Inhibition of SERCA3 by artemisinin was irreversible and was inhibited by iron chelation, suggesting iron-catalysed alkylation of a specific cysteine residue in SERCA3 as the mechanism by which artemisinin inhibits neutrophil motility. In murine infection models, artemisinin potently suppressed neutrophil invasion into both peritoneum and lung in vivo and inhibited the release of cytokines/chemokines and NETs. This work suggests that artemisinin may have value as a therapy in conditions such as sepsis and Covid-19 in which over-activation of the innate immune system causes tissue injury that can lead to death.

Determinants of weight, psychological status, food contemplation and lifestyle changes in patients with obesity during the COVID-19 lockdown: a nationwide survey using multiple correspondence analysis.

INTRODUCTION: The corona virus disease 2019 (COVID-19) pandemic forced most of the Italian population into lockdown from 11 March to 18 May 2020. A nationwide survey of Italian Clinical Nutrition and Dietetic Services (Obesity Centers or OCs) was carried out to assess the impact of lockdown restrictions on the physical and mental wellbeing of patients with obesity (PWO) who had follow-up appointments postponed due to lockdown restrictions and to compare determinants of weight gain before and after the pandemic. METHODS: We designed a structured 77-item questionnaire covering employment status, diet, physical activity and psychological aspects, that was disseminated through follow-up calls and online between 2 May and 25 June 2020. Data were analyzed by multiple correspondence analysis (MCA) and multiple linear regression. RESULTS: A total of 1,232 PWO from 26 OCs completed the questionnaires (72% female, mean age 50.2 ± 14.2 years; mean BMI 34.7 ± 7.6 kg/m2; 41% obesity class II to III). During the lockdown, 48.8% gained, 27.1% lost, while the remainder (24.1%) maintained their weight. The mean weight change was +2.3 ± 4.8 kg (in weight gainers: +4.0 ± 2.4 kg; +4.2% ± 5.4%). Approximately 37% of participants experienced increased emotional difficulties, mostly fear and dissatisfaction. Sixty-one percent reduced their physical activity (PA) and 55% experienced a change in sleep quality/quantity. The lack of online contact (37.5%) with the OC during lockdown strongly correlated with weight gain (p < 0.001). Using MCA, two main clusters were identified: those with unchanged or even improved lifestyles during lockdown (Cluster 1) and those with worse lifestyles during the same time (Cluster 2). The latter includes unemployed people experiencing depression, boredom, dissatisfaction and increased food contemplation and weight gain. Within Cluster 2, homemakers reported gaining weight and experiencing anger due to home confinement. CONCLUSIONS: Among Italian PWO, work status, emotional dysregulation, and lack of online communication with OCs were determinants of weight gain during the lockdown period.

Atypical Centriolar Composition Correlates with Internal Fertilization in Fish.

The sperm competition theory, as proposed by Geoff Parker, predicts that sperm evolve through a cascade of changes. As an example, internal fertilization is followed by sperm morphology diversification. However, little is known about the evolution of internal sperm structures. The centriole has an ancient and evolutionarily conserved canonical structure with signature 9-fold, radially symmetric microtubules that form the cell's centrosomes, cilia, and flagella. Most animal spermatozoa have two centrioles, one of which forms the spermatozoan flagellum. Both are delivered to the egg and constitute the embryo's first two centrosomes. The spermatozoa of mammals and insects only have one recognizable centriole with a canonical structure. A second sperm centriole with an atypical structure was recently reported in both animal groups and which, prior to this, eluded discovery by standard techniques and criteria. Because the ancestors of both mammals and insects reproduced by internal fertilization, we hypothesized that the transition from two centrioles with canonical composition in ancestral sperm to an atypical centriolar composition characterized by only one canonical centriole evolved preferentially after internal fertilization. We examined fish because of the diversity of species available to test this hypothesis−as some species reproduce via internal and others via external fertilization−and because their spermatozoan ultrastructure has been extensively studied. Our literature search reports on 277 fish species. Species reported with atypical centriolar composition are specifically enriched among internal fertilizers compared to external fertilizers (7/34, 20.6% versus 2/243, 0.80%; p < 0.00001, odds ratio = 32.4) and represent phylogenetically unrelated fish. Atypical centrioles are present in the internal fertilizers of the subfamily Poeciliinae. Therefore, internally fertilizing fish preferentially and independently evolved spermatozoa with atypical centriolar composition multiple times, agreeing with Parker's cascade theory.

Reduced α-galactosidase A activity in zebrafish (Danio rerio) mirrors distinct features of Fabry nephropathy phenotype.

Fabry disease (FD) is a rare genetic lysosomal storage disorder, resulting from partial or complete lack of alpha-galactosidase A (α-GAL) enzyme, leading to systemic accumulation of substrate glycosphingolipids with a broad range of tissue damage. Current in vivo models are laborious, expensive, and fail to adequately mirror the complex FD physiopathology. To address these issues, we developed an innovative FD model in zebrafish. Zebrafish GLA gene encoding α-GAL enzyme presents a high (>70%) homology with its human counterpart, and the corresponding protein has a similar tissue distribution, as evaluated by immunohistochemistry. Moreover, a similar enzymatic activity in different life stages could be demonstrated. By using CRISPR/Cas9 technology, we generated a mutant zebrafish with decreased GLA gene expression, and decreased expression of the specific gene product in the kidney. Mutant animals showed higher plasma creatinine levels and proteinuria. Transmission electron microscopy (TEM) studies documented an increased podocyte foot process width (FPW) in mutant, as compared to wild type zebrafish. This zebrafish model reliably mirrors distinct features of human FD and could be advantageously used for the identification of novel biomarkers and for an effective screening of innovative therapeutic approaches.