Genome-wide data from medieval German Jews show that the Ashkenazi founder event pre-dated the 14th century.

We report genome-wide data from 33 Ashkenazi Jews (AJ), dated to the 14th century, obtained following a salvage excavation at the medieval Jewish cemetery of Erfurt, Germany. The Erfurt individuals are genetically similar to modern AJ, but they show more variability in Eastern European-related ancestry than modern AJ. A third of the Erfurt individuals carried a mitochondrial lineage common in modern AJ and eight carried pathogenic variants known to affect AJ today. These observations, together with high levels of runs of homozygosity, suggest that the Erfurt community had already experienced the major reduction in size that affected modern AJ. The Erfurt bottleneck was more severe, implying substructure in medieval AJ. Overall, our results suggest that the AJ founder event and the acquisition of the main sources of ancestry pre-dated the 14th century and highlight late medieval genetic heterogeneity no longer present in modern AJ.

Large-scale migration into Britain during the Middle to Late Bronze Age.

Present-day people from England and Wales have more ancestry derived from early European farmers (EEF) than did people of the Early Bronze Age1. To understand this, here we generated genome-wide data from 793 individuals, increasing data from the Middle to the Late Bronze Age and Iron Age in Britain by 12-fold, and western and central Europe by 3.5-fold. Between 1000 and 875 BC, EEF ancestry increased in southern Britain (England and Wales) but not northern Britain (Scotland) due to incorporation of migrants who arrived at this time and over previous centuries, and who were genetically most similar to ancient individuals from France. These migrants contributed about half the ancestry of people of England and Wales from the Iron Age, thereby creating a plausible vector for the spread of early Celtic languages into Britain. These patterns are part of a broader trend of EEF ancestry becoming more similar across central and western Europe in the Middle to the Late Bronze Age, coincident with archaeological evidence of intensified cultural exchange2-6. There was comparatively less gene flow from continental Europe during the Iron Age, and the independent genetic trajectory in Britain is also reflected in the rise of the allele conferring lactase persistence to approximately 50% by this time compared to approximately 7% in central Europe where it rose rapidly in frequency only a millennium later. This suggests that dairy products were used in qualitatively different ways in Britain and in central Europe over this period.

A positively selected FBN1 missense variant reduces height in Peruvian individuals.

On average, Peruvian individuals are among the shortest in the world1. Here we show that Native American ancestry is associated with reduced height in an ethnically diverse group of Peruvian individuals, and identify a population-specific, missense variant in the FBN1 gene (E1297G) that is significantly associated with lower height. Each copy of the minor allele (frequency of 4.7%) reduces height by 2.2 cm (4.4 cm in homozygous individuals). To our knowledge, this is the largest effect size known for a common height-associated variant. FBN1 encodes the extracellular matrix protein fibrillin 1, which is a major structural component of microfibrils. We observed less densely packed fibrillin-1-rich microfibrils with irregular edges in the skin of individuals who were homozygous for G1297 compared with individuals who were homozygous for E1297. Moreover, we show that the E1297G locus is under positive selection in non-African populations, and that the E1297 variant shows subtle evidence of positive selection specifically within the Peruvian population. This variant is also significantly more frequent in coastal Peruvian populations than in populations from the Andes or the Amazon, which suggests that short stature might be the result of adaptation to factors that are associated with the coastal environment in Peru.

The sensitivity of acute myeloid leukemia cells to cytarabine is increased by suppressing the expression of Heme oxygenase-1 and hypoxia-inducible factor 1-alpha.

BACKGROUND: Acute myeloid leukemia (AML), a malignancy Often resistant to common chemotherapy regimens (Cytarabine (Ara-c) + Daunorubicin (DNR)), is accompanied by frequent relapses. Many factors are involved in causing chemoresistance. Heme Oxygenase-1 (HO-1) and Hypoxia-Inducible Factor 1-alpha (HIF-1α) are two of the most well-known genes, reported to be overexpressed in AML and promote resistance against chemotherapy according to several studies. The main chemotherapy agent used for AML treatment is Ara-c. We hypothesized that simultaneous targeting of HO-1 and HIF-1α could sensitize AML cells to Ara-c. METHOD: In this study, we used our recently developed, Trans-Activator of Transcription (TAT) - Chitosan-Carboxymethyl Dextran (CCMD) - Poly Ethylene Glycol (PEG) - Nanoparticles (NPs), to deliver Ara-c along with siRNA molecules against the HO-1 and HIF-1α genes to AML primary cells (ex vivo) and cell lines including THP-1, KG-1, and HL-60 (in vitro). Subsequently, the effect of the single or combinational treatment on the growth, proliferation, apoptosis, and Reactive Oxygen Species (ROS) formation was evaluated. RESULTS: The designed NPs had a high potential in transfecting cells with siRNAs and drug. The results demonstrated that treatment of cells with Ara-c elevated the generation of ROS in the cells while decreasing the proliferation potential. Following the silencing of HO-1, the rate of apoptosis and ROS generation in response to Ara-c increased significantly. While proliferation and growth inhibition were considerably evident in HIF-1α-siRNA-transfected-AML cells compared to cells treated with free Ara-c. We found that the co-inhibition of genes could further sensitize AML cells to Ara-c treatment. CONCLUSIONS: As far as we are aware, this study is the first to simultaneously inhibit the HO-1 and HIF-1α genes in AML using NPs. It can be concluded that HO-1 causes chemoresistance by protecting cells from ROS damage. Whereas, HIF-1α mostly exerts prolific and direct anti-apoptotic effects. These findings imply that simultaneous inhibition of HO-1 and HIF-1α can overcome Ara-c resistance and help improve the prognosis of AML patients.

The prognostic and therapeutic potential of HO-1 in leukemia and MDS.

BACKGROUND: Heme oxygenase-1 (HO-1), a heme-degrading enzyme, is proven to have anti-apoptotic effects in several malignancies. In addition, HO-1 is reported to cause chemoresistance and increase cell survival. Growing evidence indicates that HO-1 contributes to the course of hematological malignancies as well. Here, the expression pattern, prognostic value, and the effect of HO-1 targeting in HMs are discussed. MAIN BODY: According to the recent literature, it was discovered that HO-1 is overexpressed in myelodysplastic syndromes (MDS), chronic myeloid leukemia (CML), acute myeloblastic leukemia (AML), and acute lymphoblastic leukemia (ALL) cells and is associated with high-risk disease. Furthermore, in addition to HO-1 expression by leukemic and MDS cells, CML, AML, and ALL leukemic stem cells express this protein as well, making it a potential target for eliminating minimal residual disease (MRD). Moreover, it was concluded that HO-1 induces tumor progression and prevents apoptosis through various pathways. CONCLUSION: HO-1 has great potential in determining the prognosis of leukemia and MDS patients. HO-1 induces resistance to several chemotherapeutic agents as well as tyrosine kinase inhibitors and following its inhibition, chemo-sensitivity increases. Moreover, the exact role of HO-1 in Chronic Lymphocytic Leukemia (CLL) is yet unknown. While findings illustrate that MDS and other leukemic patients could benefit from HO-1 targeting. Future studies can help broaden our knowledge regarding the role of HO-1 in MDS and leukemia. Video abstract.

Efficient method for the synthesis of novel methyl 4-cinnolinecarboxylate.

A new method is designed for the synthesis of some novel methyl 3-aryl/alkyl-4-cinnolinecarboxylate with developed a general Richter cyclization through diazotization strategy of commercially available 2-aryl/alkyl ethynyl aniline and methyl acetate. Most substrates were achieved in moderate to excellent yields in one-pot procedures under mild reaction conditions.

Long COVID syndrome-associated brain fog.

We investigated the frequency of brain fog in a large cohort of patients with documented coronavirus disease-2019 (COVID-19) who have survived the illness. We also scrutinized the potential risk factors associated with the development of brain fog. Adult patients (18-55 years of age), who were referred to the healthcare facilities anywhere in Fars province from February 19, 2020 to November 20, 2020 were included. All patients had a confirmed COVID-19 diagnosis. In a phone call, at least 3 months after their discharge from the hospital, we obtained their current information. A questionnaire was specifically designed for data collection. In total, 2696 patients had the inclusion criteria; 1680 (62.3%) people reported long COVID syndrome (LCS). LCS-associated brain fog was reported by 194 (7.2%) patients. Female sex (odds ratio [OR]: 1.4), respiratory problems at the onset (OR: 1.9), and intensive care unit (ICU) admission (OR: 1.7) were significantly associated with reporting chronic post-COVID "brain fog" by the patients. In this large population-based study, we report that chronic post-COVID "brain fog" has significant associations with sex (female), respiratory symptoms at the onset, and the severity of the illness (ICU admission).

Design of a new method for the synthesis of novel 2-aryl/alkyl-3H-indol-3-ones.

In this research, a mild, efficient, and general method has been developed to synthesize the new derivatives of 2-aryl/alkyl-3H-indol-3-ones in moderate to excellent yields. This method allowed the syntheses of these compounds via the three-component reaction of anhydride compound, sodium cyanide, and aniline derivatives using acetic anhydride as an organic catalyst in one-pot reactions. The advantages of this method include mild reaction conditions, simple procedures, and easy workup.

Inhibition of extracellular vesicle biogenesis in tumor cells: A possible way to reduce tumorigenesis.

Most eukaryotic cells secrete extracellular vesicles (EVs), which contribute to intracellular communication through transferring different biomolecules such as proteins, RNAs, and lipids to cells. Two main types of EVs are exosomes and microvesicles. Exosomes originate from multivesicular bodies, while microvesicles are shed from the plasma membrane. Mechanisms of exosomes and microvesicle biogenesis/trafficking are complex and many molecules are involved in their biogenesis and secretion. Tumor-derived EVs contain oncogenic molecules that promote tumor growth, metastasis, immune surveillance, angiogenesis, and chemoresistance. A growing body of evidence indicates various compounds can inhibit biogenesis and secretion of EVs from cells and several experiments were conducted to use EVs-inhibitors for understanding the biology of the cells or for understanding the pathology of several diseases like cancer. However, the nontargeting effects of drugs/inhibitors remain a concern. Our current knowledge of EVs biogenesis and their inhibition from tumor cells may provide an avenue for cancer management. In this review, we shed light on exosomes and microvesicles biogenesis, key roles of tumor-derived EVs, and discuss methods used to inhibition of EVs by different inhibitors.

Dietary patterns and risk of bladder cancer: a systematic review and meta-analysis.

BACKGROUND: Several studies have investigated the relationship between dietary patterns and the risk of bladder cancer (BC) in different regions including Europe, the United States, and Asia, with no conclusive evidence. A meta-analysis was undertaken to integrate the most recent information on the relationship between a data-driven Western diet (WD), the Mediterranean diet (MD), and dietary-inflammatory-index (DII) and the risk of BC. METHOD: We looked for published research into the relationship between dietary patterns and the incidence of BC in the PubMed/Medline, Cochrane Library, Web of Science, and Scopus databases up until February 2021. Using a multivariate random-effects model, we compared the highest and lowest categories of WD, MD and DII patterns and provided the relative risk (RR) or odds ratios (OR) and 95 percent confidence intervals (CIs) for the relevant relationships. RESULTS: The analysis comprised 12 papers that were found to be suitable after scanning the databases. Both case-control (OR 0.73, 95% CI: 0.52, 0.94; I2 = 49.9%, n = 2) and cohort studies (RR 0.93, 95% CI: 0.88, 0.97; I2 = 63%, n = 4) found a substantial inverse association between MD and BC. In addition, although cohort studies (RR 1.53, 95% CI 1.37, 1.70; I2 = 0%, n = 2) showed a direct association between WD and BC, case-control studies (OR 1.33, 95% CI 0.81, 1.88; I2 = 68.5%, n = 2) did not. In cohort studies, we found no significant association between DII and BC (RR 1.02, 95% CI 0.93, 1.12; I2 = 38.5%, n = 2). In case-control studies, however, a strong direct association between DII and BC was discovered (RR 2.04, 95% CI 1.23, 2.85; I2 = 0%, n = 2). CONCLUSION: The current meta-analysis showed that MD and WD have protective and detrimental effects on BC risk, respectively. No significant association between DII and the risk of BC was observed. More research is still needed to confirm the findings. Additional study is warranted to better understand the etiological mechanisms underlying how different dietary patterns affect BC. TRIAL REGISTRATION: Protocol registration number: CRD42020155353. Database for protocol registration: The international prospective register of systematic reviews database (PROSPERO). Data of registration: August 2020.

Tracing app technology: an ethical review in the COVID-19 era and directions for post-COVID-19.

We conducted a systematic literature review on the ethical considerations of the use of contact tracing app technology, which was extensively implemented during the COVID-19 pandemic. The rapid and extensive use of this technology during the COVID-19 pandemic, while benefiting the public well-being by providing information about people's mobility and movements to control the spread of the virus, raised several ethical concerns for the post-COVID-19 era. To investigate these concerns for the post-pandemic situation and provide direction for future events, we analyzed the current ethical frameworks, research, and case studies about the ethical usage of tracing app technology. The results suggest there are seven essential ethical considerations-privacy, security, acceptability, government surveillance, transparency, justice, and voluntariness-in the ethical use of contact tracing technology. In this paper, we explain and discuss these considerations and how they are needed for the ethical usage of this technology. The findings also highlight the importance of developing integrated guidelines and frameworks for implementation of such technology in the post- COVID-19 world. Supplementary Information: The online version contains supplementary material available at 10.1007/s10676-022-09659-6.

Putrescine-functionalized carbon quantum dot (put-CQD) nanoparticles effectively prime grapevine (Vitis vinifera cv. 'Sultana') against salt stress.

BACKGROUND: Salinity is an important global problem with destructive impacts on plants leading to different biochemical and metabolic changes in plants through induced oxidative stress that disturbs metabolism, growth, performance and productivity of plants. Given that putrescine (Put) and carbon quantum dots (CQDs), individually, have promising effects in different plant processes, the idea of their combination in a nano-structure "Put-CQD" lead to its synthesis to evaluate the potential exertion of synergistic effects. The current study aimed to investigate the application of newly-synthesized nanoparticles (NPs) consisting of CQDs and Put in grapevine (Vitis vinifera cv. 'Sultana') under salinity stress conditions. For this purpose, Put, CQDs and Put-CQD NPs at 5 and 10 mg L- 1 concentrations were applied as chemical priming agents in 'Sultana' grapevine 48 h prior salinity stress imposition (0 and 100 mM NaCl). RESULTS: Salinity significantly decreased (P ≤ 0.05) morphological parameters, photosynthetic pigments, chlorophyll fluorescence parameters and membrane stability index. In addition, salinity enhanced MDA, H2O2, proline content and antioxidant enzyme activity. Results revealed that Put-CQD NPs, particularly at 10 mg L- 1 concentration, alleviated the destructive impacts of salinity stress by improving leaf fresh and dry weights, K+ content, photosynthetic pigments, chlorophyll fluorescence and SPAD parameters, proline content, total phenolics and antioxidant enzymatic activities (CAT, APX, GP and SOD), while decreasing Na+ content, EL, MDA and H2O2 levels. CONCLUSION: To conclude, Put-CQD NPs represent an innovative priming treatment that could be effectively applied on grapevine to improve plant performance under salinity stress conditions.

Identifying the favored mutation in a positive selective sweep.

Most approaches that capture signatures of selective sweeps in population genomics data do not identify the specific mutation favored by selection. We present iSAFE (for "integrated selection of allele favored by evolution"), a method that enables researchers to accurately pinpoint the favored mutation in a large region (∼5 Mbp) by using a statistic derived solely from population genetics signals. iSAFE does not require knowledge of demography, the phenotype under selection, or functional annotations of mutations.

Thiomers of Chitosan and Cellulose: Effective Biosorbents for Detection, Removal and Recovery of Metal Ions from Aqueous Medium.

Removal of toxic metal ions using adsorbents is a well-known strategy for water treatment. While chitosan and cellulose can adsorb weakly some types of metals, incorporating thiols as metal chelating agents can improve their sorption behaviors significantly. Presented in this review are the various chemical modification strategies applicable for thiolation of chitosan and cellulose in the forms of mercaptans, xanthates and dithiocarbamates. Moreover, much attention has been paid to the specific strategies for controlling the thiolation degree and characterization approaches for establishing the structure-property relationship. Also, the kinetics and isotherm models that elucidate the adsorption processes and mechanisms induced by the thiomers have been explained. These thiomers have found great potentials in the applications associated with metal removal, metal recovery and metal detection.

Microbial Degradation Rates of Natural Bitumen.

Microorganisms are present in nearly every oil or bitumen sample originating from temperate reservoirs. Nevertheless, it is very difficult to obtain reliable estimates about microbial processes taking place in deep reservoirs, since metabolic rates are rather low and differ strongly during artificially cultivation. Here, we demonstrate the importance and impact of microorganisms entrapped in microscale water droplets for the overall biodegradation process in bitumen. To this end, we measured degradation rates of heavily biodegraded bitumen from the Pitch Lake (Trinidad and Tobago) using the novel technique of reverse stable isotope labeling, allowing precise measurements of comparatively low mineralization rates in the ng range in microcosms under close to natural conditions. Freshly taken bitumen samples were overlain with artificial brackish water and incubated for 945 days. Additionally, three-dimensional distribution of water droplets in bitumen was studied with computed tomography, revealing a water bitumen interface of 1134 cm2 per liter bitumen, resulting in an average mineralization rate of 9.4-38.6 mmol CO2 per liter bitumen and year. Furthermore, a stable and biofilm-forming microbial community established on the bitumen itself, mainly composed of fermenting and sulfate-reducing bacteria. Our results suggest that small water inclusions inside the bitumen substantially increase the bitumen-water interface and might have a major impact on the overall oil degradation process.

COVID-19 presentations and outcome in patients with epilepsy.

OBJECTIVE: To determine whether patients with epilepsy (PWE) are particularly over-represented in a very large cohort of patients with COVID-19. We also investigated whether COVID-19 is associated with a different clinical picture or a more severe course of illness in PWE (compared with others). METHODS: All consecutive patients who referred to and admitted at healthcare facilities anywhere in Fars province (located in the south of Iran with a population of 4,851,000 people) from February 19, 2020 until November 20, 2020 were included. RESULTS: A total of 37,968 patients were studied. Eighty-two patients (0.2%) had pre-existing epilepsy. Seizures were significantly more frequent among PWE as a presenting manifestation of COVID-19 compared with that in people without epilepsy (Odds Ratio = 27; p = 0.0001). Furthermore, PWE less often reported cough (significantly) and more often had gastrointestinal symptoms (vomiting and anorexia; as trends) compared with those in people without epilepsy. Patients with epilepsy were not differently likely to be intubated or admitted at ICUs. Case fatality rates were not different between the two groups [9.8% in PWE and 8.5% in people without epilepsy; p = 0.690]. CONCLUSION: Patients with epilepsy are not susceptible to contracting COVID-19 more than other individuals. Furthermore, COVID-19 in PWE is not associated with a more severe illness or a poorer prognosis. However, PWE and COVID-19 may present somewhat differently than others with such an illness. Why PWE less often present with cough and more often present with gastrointestinal symptoms is not clear yet and should be investigated and clarified in the future studies.

Formulation of a pH-sensitive cancer cell-targeted gene delivery system based on folate-chitosan conjugated nanoparticles.

In this study, we investigated the design and construct of a chitosan (CA)-based targeted gene delivery system and evaluated its function. To this end, CA-folic acid/pDNA (CA-FA/pDNA) nanoparticles were prepared in different formulations using the ion gelation method. All the synthesized nanoparticles were characterized using FTIR, TEM, SEM and DLS. Moreover, the effects of molecular weight (MW) of CA, DNA, and CA concentration were inspected on encapsulation efficiency (EE). The results showed that the EE of pDNA was directly proportional with MW of CA and CA concentration but was in an inverse proportion with DNA concentration. In addition, high MW of CA and low MW of CA nanoparticles showed lower and higher pDNA release in all pH ranges, respectively. It is concluded that the N/P ratio increase can cause controlled pDNA release.

Potential small-molecule drugs as available weapons to fight novel coronavirus (2019-nCoV): A review.

Since the new coronavirus known as 2019-nCoV (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) has widely spread in Wuhan, China, with severe pneumonia, scientists and physicians have made remarkable efforts to use various options such as monoclonal antibodies, peptides, vaccines, small-molecule drugs and interferon therapies to control, prevent or treatment infections of 2019-nCoV. However, no vaccine or drug has yet been confirmed to completely treat 2019-nCoV. In this review, we focus on the use of potential available small-molecule drug candidates for treating infections caused by 2019-nCoV.

Nano-based methods for novel coronavirus 2019 (2019-nCoV) diagnosis: A review.

Today, tremendous attention has been devoted to a new coronavirus, SARS-CoV-2 (2019-nCoV), due to severe effects on the global public in all over the world. Rapid and accurate diagnosis of 2019-nCoV are important for early treatment and cutting off epidemic transmission. In this regard, laboratory detection protocols, such as polymerase chain reaction (PCR) and computed tomography (CT) examination, have been utilized broadly for 2019-nCoV detection. Recently, nano-based methods for 2019-nCoV diagnoses are rapidly expanding and declaring comparable results with PCR and CT. In this review, recent advances in nano-based techniques have been highlighted and compared briefly with PCR and CT as well-known methods for 2019-nCoV detection.

COVID-19 in patients with Down syndrome.

PURPOSE: The aim of the current study was to determine whether COVID-19 is associated with a different presenting clinical picture or a more severe course of illness in people with Down syndrome (DS). METHODS: All consecutive patients who were admitted at healthcare facilities anywhere in Fars province (located in the south of Iran with a population of 4,851,000 people) from 19 February 2020 to 20 November 2020 were included. For every patient with DS, three age- and sex-matched patients with COVID-19 and without any underlying medical conditions were selected as controls. RESULTS: During the study period, 37,968 patients were hospitalized with a diagnosis of COVID-19. Eighteen patients had DS. Patients with DS were significantly more likely to be intubated [7 patients (39%)] compared with those without DS [3 patients (6%)]; p = 0.002. Patients with DS significantly more often died of COVID-19 compared with the controls [8 (44.4%) vs. 1 (1.9%); odds ratio: 24.37; 95% confidence interval 2.39-247.94; p = 0.007]. CONCLUSION: Patients with DS are among the high-risk populations with respect to severe COVID-19 and should receive the vaccine as soon as possible. Furthermore, they should receive more intensive care if they get hospitalized with the illness.