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This article presents the first edition of an Old-Babylonian acrographic vocabulary excavated in the city of Ur. Although fragmentary and poorly preserved, this text provides interesting new aspects for the understanding of the so-called „dialects“ of Sumerian and of bilingual language teaching in general, and identifies lurû(m) „(man with a) thin/croaky voice“ as a (person with a) speech defect described as „Emesal“. In addition, it contains entries of business terminology known from the north Babylonian „Sippar Phrasebook“, the Old Babylonian „Forerunner“ of canonical Ura 1 and 2.

With this case report we support our medical hypothesis that metreleptin treatment ameliorates starvation related emotional, cognitive and behavioral symptomatology of anorexia nervosa (AN) and show for the first time strong effects in a male patient with AN. A 15.9 year old adolescent with severe AN of eight-month duration was treated off-label with metreleptin. Hyperactivity was assessed with accelerometry. Visual analogue scales (VAS), validated self- and clinician rating scales and lab results tracked changes from baseline to end of the 24-day dosing period and a five-month follow-up. Substantial improvements of mood and eating disorder related cognitions and hyperactivity set in after two days of treatment. During dosing, sub-physiological testosterone and TT3 levels normalized; clinically libido reemerged. Weight did not increase substantially during the dosing period. During follow-up target weight was attained; mood did not deteriorate; hyperactivity ceased. The results substantiate the strong effects seen in female cases and underscore the need for a double-blind placebo-controlled trial to confirm the observed strong, multiple and rapid onset beneficial effects of metreleptin in AN. Supplementary Information The online version contains supplementary material available at 10.1007/s00787-021-01778-7.

Background While observational studies revealed an inverse association between serum 25(OH)vitamin D (25(OH)D) and the risk of attention deficit/hyperactivity disorder (ADHD), the causality of this relationship remains unclear. Methods We conducted a bidirectional two-sample Mendelian Randomization (MR) study to examine whether 25(OH)D has an effect on the risk to develop ADHD or vice versa. Information on single nucleotide polymorphisms (SNP) associated with serum 25(OH)D was obtained from a genome-wide association study (GWAS) considering phenotype data from 79,366 individuals of European ancestry. Data on risk for ADHD were derived from a GWAS analysis with 20,183 individuals diagnosed with ADHD and 35,191 controls. For our analysis, we considered effect sizes based on the European participants (19,099 cases and 34,194 controls). Results Single SNP analyses showed a causal effect of vitamin D on ADHD risk for only one SNP (rs12785878, p = 0.024). The overall MR estimates did not reveal a causal effect of 25(OH)D on risk for ADHD. In the reverse analysis, neither any single nor the multi-SNP MR analyses showed a causal effect of ADHD on 25(OH)D. Conclusion Results from this two-sample MR study did not confirm a causal effect of 25(OH)D on ADHD or vice versa. Accordingly, our study does not provide evidence that improving 25(OH)D via supplementation could reduce the risk of developing ADHD.

Purpose The COVID-19 pandemic and public measures have a direct impact on the nutrition situation; studies show changes in food consumption, eating behavior or body weight but complex pattern analyses of changes rarely exist. Methods During the first German lockdown, a web-based survey was conducted among adults. It included 33 questions about changes in food intake, eating habits and physical activity, as well as anthropometrics and sociodemographic factors. Patterns of change were calculated based on changes in food intake and eating habits using two-step cluster analysis. To identify influencing factors for assignment to the patterns of change, binary logistic regression analyses were performed. Results Data from 2103 participants (81% female, 40 ± 14 years) were considered for analysis. Increased stockpiling, cooking, and variation in preparation was reported by 50–70%. The constant pattern (C-P, 36%) reported little change besides the above. The health-oriented pattern (HO-P; 37%) reported eating more healthy foods, avoiding unhealthy foods, and eating less and less frequently. The emotional-driven pattern (ED-P; 28%) exhibits higher influence of emotions on eating behavior, less avoidance of unhealthy foods, and increased consumption of sweets, pastries, and alcohol. The odds of changing eating behavior either to HO-P or ED-P were higher in women, people with migration background, younger participants, and increased with BMI categories. Conclusion Both, the ED-P and HO-P, exhibit distinctive reactions in eating habits and food intake when dealing with a distressing experience. In subgroups, these may lead to disturbances in eating behavior and increase the risk for eating disorders and obesity.

Background In Sub-Saharan African countries, rapid urbanization and increasing socio-economic status are associated with a transition to decreased physical activity (PA). A more sedentary lifestyle is linked to increased body fat leading to increments in leptin levels. Since rodent and human studies in high-income countries have shown that starvation-induced hypoleptinemia triggers high PA, efforts are warranted to pursue the hypothesis that low leptin levels in lean children of low- and middle-income countries (LMIC) are also associated with high PA. Methods In this cross-sectional study, we assessed seven-day PA with triaxial accelerometry (ActiGraph GT3X) among 223 primary school children (9 to 12 years of age) in rural Tanzania. Moderate-to-vigorous PA (MVPA) and total accelerometer counts per day were outcome variables. Leptin was determined using enzyme linked immunosorbent assay tests from dried blood spots. Anthropometric assessments were conducted and food insecurity and socio-demographic data were gathered using semi-structured interviews. Results In this sample of school children in rural Tanzania, leptin concentrations (median: 0.91 ng/mL, P25: 0.55, P75: 1.69), body mass index z-scores (median: -1.35, P25: -1.93, P75: -0.82), and height-for-age-z-scores (median: -1.16, P25: -1.96, P75: -0.61) were low. In contrast, PA levels were high with a median MVPA time of 119 min/day. Linear regression confirmed that leptin levels were negatively associated with MVPA (beta: -18.1; 95%CI: -29.7; -6.5; p = 0.002) and total accelerometer counts (beta: -90,256; 95%CI: -154,146; -26,365; p = 0.006). Children residing in areas with better infrastructure had lower MVPA levels (p p = 0.062) than children residing in areas only reachable via dirt roads. Conclusion Our cross-sectional field study is the first that supports the hypothesis of low leptin levels as a potential endocrine trigger of high PA in lean children of a LMIC. We observed early signs of a PA transition towards a less active lifestyle in a subgroup residing in areas with better infrastructure that concomitantly tended to have higher leptin concentrations. Considering that area-dependent PA differences were more pronounced among girls than boys, whereas differences in leptin levels were less pronounced, not only biological, but also external factors explain PA transition.

Zusammenfassung In der Debatte um die Digitalisierung der Arbeitswelt adressieren empirische Forschungsarbeiten Veränderungen von Arbeitsmärkten, Arbeitsplätzen, Berufen, Tätigkeitsprofilen und Tätigkeiten in verschiedenen Settings. Ein Überblick über Verfahren zur Messung von Auswirkungen der Digitalisierung auf die Arbeitswelt fehlt bislang. Der Beitrag untersucht anhand eines systematischen Literaturreviews Methoden zur Wirkungsmessung digitalisierter Arbeit in empirischen Studien. Zentrale Fragen adressieren die Konzeptualisierung und Operationalisierung von Digitalisierung im Arbeitskontext sowie die methodische Konzeption von Wirkungsanalysen. Die in das Review eingeschlossenen Studien konzentrieren sich auf arbeitsmarkt- sowie branchenbezogene Untersuchungen. Die Ergebnisse zeigen eine breite Spanne von eingesetzten Methoden auf, die qualitative sowie quantitative Untersuchungen einschließt und von retrospektiven Wirkungsmessungen bis hin zu prospektiven Wirkungsprojektionen reicht. Die Weiterentwicklung von Instrumenten zur Wirkungsmessung digitalisierter Arbeitswelten kann von einer stärkeren Konzentration auf Wirkungsdynamiken sowie themenzentrierte Analysen, beispielsweise zum (informellen) Erwerb digitaler Kompetenzen, profitieren.

The Textual Criticism of Sumerian Literature. By Paul Delnero. The Journal of Cuneiform Studies Supplemental Series, vol. 3. Boston: American Schools of Oriental Research, 2012. Pp. viii + 230. $89.95. [Distributed by ISD, Bristol, Conn.]

Purpose Lifestyle scores which combine single factors such as diet, activity, or sleep duration showed associations with cognitive decline in adults. However, the role of a favourable lifestyle in younger age and the build-up of cognitive reserve is less clear, which is why we investigated longitudinal associations between a lifestyle score in childhood and adolescence and fluid intelligence obtained on average 6 years later. Methods In the DONALD cohort, a lifestyle score of 0 to 4 points including healthy diet and duration of moderate-to-vigorous physical activity, sedentary behaviour and sleep was repeatedly assessed in participants aged 5 and 19 years. Data on fluid intelligence were assessed via a German version of the culture fair intelligence test (CFT), using CFT 1-R in children 8.5 years of age or younger (n = 62) or CFT 20-R in participants older than 8.5 years (n = 192). Multivariable linear regression models were used to investigate prospective associations between the lifestyle score and the fluid intelligence score. Results Mean lifestyle score of all participants was 2.2 (0.7–4) points. A one-point increase in the lifestyle score was associated with a higher fluid intelligence score (4.8 points [0.3–7.3], p = 0.0343) for participants completing the CFT 20-R. Furthermore, each additional hour of sedentary behaviour was associated with a lower fluid intelligence score (− 3.0 points [− 5.7 to − 0.3], p = 0.0313). For younger participants (CFT 1-R), no association was found in any analysis (p > 0.05). Conclusion A healthy lifestyle was positively associated with fluid intelligence, whereby sedentary behaviour itself seemed to play a prominent role.

Digitale Technologien in der Altenpflege versprechen einen Fortschritt fur Teilhabe, Versorgungs- und Arbeitsqualitat. Doch in der betrieblichen Praxis zeigt sich, dass Digitalisierungsprojekte nicht selten ein hetzendes ,Muddling Through‘, mehr Zeitdruck und neue Improvisationserfordernisse der Beschaftigten zur Folge haben. Partizipative Gestaltungsstrategien werden durch unterschiedliche betriebliche Innovationskulturen, Zeitverwendungskonkurrenzen, fehlende strategische Perspektiven oder durch konfliktbehaftete betriebliche Arbeitsbeziehungen zusatzlich erschwert. Der Beitrag stellt mit der „Lernreise“ ein Instrument vor, mit dem sich Fuhrungskrafte, Beschaftigte und betriebliche Interessenvertretungen gemeinsam Innovationsperspektiven und Gestaltungskapazitaten fur einen sinnvollen Technikeinsatz erschliesen konnen. Dies leistet, wie im Projekt DIALOGSPLUS gezeigt werden konnte, einen Beitrag zur Erhohung der subjektiven und betrieblichen Innovationsfahigkeit und -bereitschaft.

Ethnopharmacological relevance Impaired glucose tolerance and diabetes mellitus have become major health issues even in non-industrialized countries. As access to clinical management is often poor, dietary interventions and alternative medicines are required. For bitter gourd, Momordica charantia L . , antidiabetic properties have been claimed. Aim of the study The main objective of the intervention study was to assess antidiabetic effects of daily bitter gourd consumption of 2.5 g powder over the course of eight weeks among prediabetic individuals. Materials and methods In a randomized placebo-controlled single blinded clinical trial, 52 individuals with prediabetes were studied after consuming a bitter gourd or a cucumber juice. For reducing the impact of between subject differences in the study population, a crossover design was chosen with eight weeks for each study period and four weeks washout in between. Fasting plasma glucose was chosen as the primary outcome variable. Results Comparing the different exposures, the CROS analysis (t=−2.23, p =0.031, r=0.326) revealed a significant difference in the change of FPG of 0.31 mmol/L (5.6 mg/dL) with a trend (R 2 =0,42387). The number of 44 finally complete data sets achieved a power of 0.82, with a medium-to-large effect size (Cohen's d 0.62). The effect was also proven by a general linear mixed model (estimate 0.31; SE: 0.12; p: 0.01; 95%CI: 0.08; 0.54). Not all participants responded, but the higher the initial blood glucose levels were, the more pronounced the effect was. No serious adverse effects were observed. Conclusions Bitter gourd supplementation appeared to have benefits in lowering elevated fasting plasma glucose in prediabetes. The findings should be replicated in other intervention studies to further investigate glucose lowering effects and the opportunity to use bitter gourd for dietary self-management, especially in places where access to professional medical care is not easily assured.

PURPOSE Chronic inflammation, even at subclinical levels, is associated with adverse long-term outcome. PATIENTS AND METHODS In this prospective, observational study, 66 critically ill patients surviving to hospital discharge were included. C-reactive protein (CRP) levels were determined at hospital discharge, 1, 2, and 6 weeks after hospital discharge. All the patients were repeatedly screened for adverse events resulting in rehospitalization or death for 1.5 years. RESULTS After hospital discharge, over two-thirds of the patients exhibited elevated CRP levels (>2.0 mg/L). During the first week, CRP decreased compared with hospital discharge (P

This article offers a first edition of BM 23820+23831, a manuscript of a previously unknown Old Babylonian Sumerian poem on the relationship between the goddess Innana and king Išme-Dagan of Isin. The king is initially depicted as a humiliated supplicant who suffers under Innana’s wrath, until the intervention of his personal god restores Innana’s favour. A mythological catalogue lists other individuals and places who offended the goddess and were destroyed by her in retribution.

The development of vaccine components or recombinant therapeutics critically depends on sustained expression of the corresponding transgene. This study aimed to determine the contribution of intragenic CpG content to expression efficiency in transiently and stably transfected mammalian cells. Based upon a humanized version of green fluorescent protein (GFP) containing 60 CpGs within its coding sequence, a CpG-depleted variant of the GFP reporter was established by carefully modulating the codon usage. Interestingly, GFP reporter activity and detectable protein amounts in stably transfected CHO and 293 cells were significantly decreased upon CpG depletion and independent from promoter usage (CMV, EF1 alpha). The reduction in protein expression associated with CpG depletion was likewise observed for other unrelated reporter genes and was clearly reflected by a decline in mRNA copy numbers rather than translational efficiency. Moreover, decreased mRNA levels were neither due to nuclear export restrictions nor alternative splicing or mRNA instability. Rather, the intragenic CpG content influenced de novo transcriptional activity thus implying a common transcription-based mechanism of gene regulation via CpGs. Increased high CpG transcription correlated with changed nucleosomal positions in vitro albeit histone density at the two genes did not change in vivo as monitored by ChIP.

The transframe protein p6*, also referred to as TFP-p6pol, is one of the least-characterized gene products in human immunodeficiency virus type 1 (HIV-1), consistently raising controversial discussions on its main function in the viral life cycle. p6* is located at the amino terminus of the Pol moiety within the Gag-Pol precursor, which is synthesized following a programmed ribosomal −1 frameshift during translation (Fig. ​(Fig.1).1). In contrast, the Gag precursor is generated by conventional translation at a 20-fold-higher rate (summarized in reference 13). The characterization of recombinant p6* protein by nuclear magnetic resonance analysis revealed a highly flexible structure (3), suggesting that p6* might serve as an adjustable hinge within the large Gag-Pol precursor to facilitate folding of the bulky protein domains during viral assembly. Proper folding of the embedded homodimeric protease (PR) is an essential prerequisite for full activity following sequential autocleavage from the full-length Gag-Pol polyprotein (summarized in reference 13). Indeed, the p6* residues have been demonstrated to stabilize the PR dimer and dictate the folding propensities of PR precursors, thereby influencing the rate of PR maturation (6, 10, 21). Interestingly, the autoprocessing of a truncated Gag-PR precursor was clearly accelerated when the p6* sequence was deleted, leading to the proposal that the active site of the PR might be less accessible in the presence of p6* (26). Further observations that p6* itself is sequentially cleaved by the PR (1, 7, 22, 23, 24, 30, 31, 32, 41) strengthened the hypothesis that the transframe protein contributes to spatiotemporal activation of the PR. Indeed, we and others have previously shown that the PR needs to be released from the flanking p6* residues to be capable of completing all virus-associated processing steps (24, 27, 36). The potential of p6* to regulate PR activity has been further corroborated by our finding that recombinant p6* protein comprising a free accessible carboxyl terminus is a potent inhibitor of the mature PR in vitro (28). Apart from the carboxyl-terminal tetrapeptide mainly contributing to the observed inhibition, the amino-terminal octapeptide of p6* (TFP) has been reported to inhibit PR activity in vitro (21). FIG. 1. Gag and Gag-Pol polyproteins encoded by NL4-3 (NL) and AL proviruses. (A) Schematic representation of the Gag and Gag-Pol polyprotein precursors. The p6* domain within Gag-Pol is highlighted in black, and the p1-p6gag region inserted in the Gag-Pol ... The fact that p6* has a substantial size of 55 to 72 amino acids, depending on the isolate, raises the question of whether the transframe protein exerts other functions apart from PR regulation. In this regard, p6* has also been proposed to be a possible binding partner of the viral Nef protein, the major pathogenicity factor during HIV infection (9). However, the target site within p6* for Nef interaction has not been mapped so far. Although it is completely overlapped by the p1-p6gag domains, the p6* sequence offers much room for natural polymorphisms (5). Furthermore, amino acid insertions or duplications, as well as deletions of up to 13 residues, in p6* sequences of infectious isolates have been reported, some of which are associated with viral drug resistance (4, 29, 35, 38). We have recently shown that nonconservative substitutions of up to 70% of the p6* residues in a provirus clone did not abolish viral growth or infectivity in various cell lines, suggesting that the central p6* region is widely dispensable for viral in vitro replication (19, 27). Unlike the variable center, the p6* amino terminus is highly conserved owing to the overlapping p1gag sequence (14) and the RNA frameshift signal composed of a heptanucleotide slippery site (UUUUUUA) and a 3′ pseudoknot structure (11). This complex sequence context imposes major restrictions on mutational analysis of the p6* amino terminus in the viral background (24). To allow for a more in-depth functional analysis of the conserved p6* residues in the viral context, we have established a novel NL4-3-based provirus with p1-p6gag and p6* reading frames uncoupled via a dislocated frameshift site. Thereby, we could demonstrate that neither the deletion of the bulk of p6* nor the insertion of a short unrelated sequence significantly affected replication and infectivity of the virus in different cell cultures. However, the insertion of a five times larger green fluorescent protein (GFP)-encoding sequence into the p6* reading frame was associated with a clear loss of particle production and infectivity. Therefore, we conclude that p6* is a spacer protein of limited length which is widely dispensable for viral replication in vitro.

The HIV-1 transframe protein p6⁎ known to modulate HIV-1 protease activation has been suggested to interact with the viral pathogenicity factor Nef. However, a potential interaction site in p6⁎ has not been mapped so far. To evaluate effects of p6⁎ modification on viral replication in light of Nef function, clustered substitutions were introduced into the central p6⁎ region of the infectious provirus NL4-3 and virus growth and composition of the various mutants was analyzed in different cell cultures in the presence or absence of Nef. Whereas clustered p6⁎ substitutions did neither affect particle incorporation of Nef, nor precursor maturation or viral infectivity, a simultaneous substitution of 40 of the total 56 p6⁎ residues significantly diminished viral infectivity and replication in a Nef-independent manner. Furthermore, this extended modification was not capable of rescuing the negative effects of a transdominant Nef mutant on particle production suggesting that the proposed target for Nef interaction in Gag-Pol is located outside the modified p6⁎ region. In sum these data strongly argue against a functional connection of the central p6⁎ region and Nef during viral life cycle.

The human immunodeficiency virus type 1 (HIV-1) protease (PR) has recently been shown to be inhibited by its propeptide p6* in vitro. As p6* itself is a PR substrate, the primary goal of this study was to determine the importance of p6* cleavage for HIV-1 maturation and infectivity. For that purpose, short peptide variants mimicking proposed cleavage sites within and flanking p6* were designed and analyzed for qualitative and quantitative hydrolysis in vitro. Proviral clones comprising the selected cleavage site mutations were established and analyzed for Gag and Pol processing, virus maturation, and infectivity in cultured cells. Amino-terminal cleavage site mutation caused aberrant processing of nucleocapsid proteins and delayed replication kinetics. Blocking the internal cleavage site resulted in the utilization of a flanking site at a significantly decreased hydrolysis rate in vitro, which however did not affect Gag-Pol processing and viral replication. Although mutations blocking cleavage at the p6* carboxyl terminus yielded noninfectious virions exhibiting severe Gag processing defects, mutations retarding hydrolysis of this cleavage site neither seemed to impact viral infectivity and propagation in cultured cells nor seemed to interfere with overall maturation of released viruses. Interestingly, these mutants were shown to be clearly disadvantaged when challenged with wild-type virus in a dual competition assay. In sum, we conclude that p6* cleavage is absolutely essential to allow complete activation of the PR and subsequent processing of the viral precursors.

Virus-like particles (VLPs) are highly organised spheres that self-assemble from virus-derived structural antigens. These stable and versatile subviral particles possess excellent adjuvant properties capable of inducing innate and cognate immune responses. Commercialised VLP-based vaccines have been successful in protecting humans from hepatitis B virus (HBV) and human papillomavirus (HPV) infection and are currently explored for their potential to combat other infectious diseases and cancer. Much insight into VLP-mediated immune stimulation and optimised VLP design has been gained from human immunodeficiency virus (HIV)-derived VLPs presenting promising components of current AIDS vaccine approaches. Owing to their unique features, VLPs and virosomes, the in vitro-reconstituted VLP counterparts, have recently gained ground in the field of nanobiotechnology as organic templates for the development of new biomaterials.

We have previously shown that Rev-dependent expression of HIV-1 Gag from CMV immediate early promoter critically depends on the AU-rich codon bias of the gag gene. Here, we demonstrate that adaptation of the green fluorescent protein (GFP) reporter gene to HIV codon bias is sufficient to turn this hivGFP RNA into a quasi-lentiviral message following the rules of late lentiviral gene expression. Accordingly, GFP expression was significantly decreased in transfected cells strictly correlating with reduced RNA levels. In the presence of the HIV 5′ major splice donor, the hivGFP RNAs were stabilized in the nucleus and efficiently exported to the cytoplasm following fusion of the 3′ Rev-responsive element (RRE) and coexpression of HIV-1 Rev. This Rev-dependent translocation was specifically inhibited by leptomycin B suggesting export via the CRM1-dependent pathway used by late lentiviral transcripts. In conclusion, this quasi-lentiviral reporter system may provide a new platform for developing sensitive Rev screening assays.

Introduction of Fruits and Vegetables into Children’sDiets in the Iringa Region, TanzaniaUndernutrition is still a major problem among chil-dren under the age of 5 years in developing countries[1], often occurring during the weaning period, whichis recommended by World Health Organization tostart after 6 months of exclusive breastfeeding[2, 3]. However, little is known about the introduc-tion time and consumption frequency of complemen-tary foods in Tanzania. Therefore, an explorativestudy was conducted in the Iringa Region ofTanzania’s Southern Highlands during the dryseason in August and September 2008. Participantswere recruited by a systematic sampling procedureconsisting of 124 rural and urban mothers and heryoungest child between the age of 6 months and5 years. Mothers were interviewed with structuredand open-ended questionnaires. Children’s dietaryintakes were assessed using a single 24-h dietaryrecall [4], of which a dietary diversity score (DDS)[5] and a food variety score (FVS) according toDrewnowski et al. [6] were calculated. Children’sheights and weights were measured with a portablewooden stadiometer (Shorr Productions ofMaryland, USA) and a digital scale (Seca 862, SecaGmbH & Co KG, Hamburg, Germany), respectively.ENA-software using WHO Child Growth Standards2005 [7] was applied to determine the nutritionalstatus. Data of nine children were incomplete andexcluded of the statistical analysis [SPSS version17.0 (SPSS Inc., Chicago, IL, USA)]. The medianchild’s age was 19 months (Table 1). Children wereintroduced to grain-based complementary foods,fruits and vegetables at a median age of4.0 (0.1/12), 6.0 (1/17) and 8.0 (2/24) months, respect-ively, with no statistical differences between the ruraland urban area. A total of 76% of children wereintroduced to complementary foods earlier than thefirst 6 months of life. Notably, the introduction wasstill later than in other developing and developedcountries [8–13]. However, 51% were given solidsbefore reaching the age of 4 months, increasingtheir risk of diarrhoea. Regarding vegetables,30% of children were not given any before reachingthe age of 12 months increasing their risk of develop-ing micronutrient deficiencies. The mean DDS was5 while children were primarily fed starchy foods,such as maize, plain rice, cassava and sweet potatoes(Fig. 1). Regarding vegetables, they ate traditionalvegetables adapted to local agricultural conditionsand incorporated into the family’s diet. The medianand mean FVS was 11 and higher than the mean FVSof 5.5 found in a South African study [14], but com-parable to the mean value of 10 found amongGuatemalan infants [15]. The observed stunting rateof 41% was similar to the rate of 38% found by theTanzanian Demographic and Health Survey 2004–05(TDHS) [16]. Both weights and heights of childrenwere positively correlated with the number of fruitand vegetable types consumed as well as DDSand FVS. These findings indicate that a higher foodvariety has positive impacts on weight andheight development of children, although thisimpact is not fully understood. Conclusively, furtherinvestigations on the impact of young children’sdiets on their growth, health and development areneeded.C

Angiotensin converting enzyme inhibitors (ACE-I) are a mainstay for the treatment of heart failure, and of diabetic microalbuminuria. Recently ACE-I have been found to decrease plasma levels of circulating vascular cell adhesion molecule-1 (cVCAM-1) in patients with congestive heart failure. As increased cVCAM-1 levels are pathognomonic for diabetics with microangiopathy, we investigated the effects of ACE-I on plasma levels of cVCAM-1, intercellular adhesion molecule (cICAM-1), and cE-selectin in microalbuminuric diabetics. In addition, the effects of ACE-I on plasma levels of plasminogen activator inhibitor (PAI-1) and of tissue plasminogen activator (TPA) were studied. Fosinopril (10 mg/day) was administered over 12 weeks to 11 microalbuminuric patients with non-insulin-dependent diabetes mellitus (NIDDM). As expected, baseline plasma concentrations of cE-selectin, cICAM-1, and cVCAM-1 were markedly higher in patients than in healthy control subjects (n = 82; P.001). PAI-1 levels in NIDDM were similar to those in control subjects, whereas TPA levels were about 25% lower in patients than in control subjects (P = .013). Serum levels of cVCAM-1 decreased by -19% (CI: -25% to -13%) after treatment with fosinopril (P = .003) and were no longer different from those of the control group. In contrast, plasma levels of cE-selectin, cICAM-1, PAI-1, and TPA were unaffected. As expected microalbuminuria decreased by -44% (CI: -65 to -22; P = .004). In conclusion, fosinopril lowered cVCAM-1 levels along with microalbuminuria in NIDDM. This may represent a novel mechanism of action of ACE-I in diabetes-associated endothelial dysfunction. Whether decreased VCAM-1 expression is responsible for the observed reduction in microalbuminuria, deserves further investigation.

Type 2 diabetes is a growing health problem worldwide that is particularly severe in India and China. In these areas, bitter gourd (Momordica charantia) is a popular vegetable which is traditionally known to have health beneficial effects not only, but mainly, on diabetes. Bitter gourd could be a cheap possibility to help the poor in these and other countries to control their blood glucose levels. This review describes anti-diabetic effects of bitter gourd reported in the literature and discusses what still needs to be clarified for developing an evidence-based and safe use of the bitter gourd for diabetes. Analyses of bioactive compounds have shown that bitter gourd is rich in nutrients and phytochemicals of which some have anti-diabetic effects. Juices, powders, extracts, and isolated compounds have been tested in vitro and in vivo. Bitter gourd increases insulin secretion of the pancreas, decreases intestinal glucose uptake, and increases uptake and utilization of glucose in peripheral tissues. Although human studies with type 2 diabetics are weak in their design and/or results, some of the studies do indicate anti-diabetic effects in patients and safety for bitter gourd treatment in humans. In the future, well designed studies with rodents will help to understand what kind of bitter gourd variety, dosage, preparation, and duration of administration is optimal. Such results will help to design human studies which are necessary to prove the effectiveness of bitter gourd in patients.

Autologous expression of recombinant human proteins in human cells for biomedical research and product development is often hampered by low expression yields limiting subsequent structural and functional analyses. Following RNA and codon optimization, 50 candidate genes representing five classes of human proteins – transcription factors, ribosomal and polymerase subunits, protein kinases, membrane proteins and immunomodulators – all showed reliable, and 86% even elevated expression. Analysis of three representative examples showed no detrimental effect on protein solubility while unaltered functionality was demonstrated for JNK1, JNK3 and CDC2 using optimized constructs. Molecular analysis of a sequence-optimized transgene revealed positive effects at transcriptional, translational, and mRNA stability levels. Since improved expression was consistent in HEK293T, CHO and insect cells, it was not restricted to distinct mammalian cell systems. Additionally, optimized genes represent powerful tools in functional genomics, as demonstrated by the successful rescue of an siRNA-mediated knockdown using a sequence-optimized counterpart. This is the first large-scale study addressing the influence of multiparameter optimization on autologous human protein expression.

Trans-dominant human immunodeficiency virus type 1 (HIV-1) Gag derivatives have been shown to efficiently inhibit late steps of HIV-1 replication in vitro by interfering with Gag precursor assembly, thus ranking among the interesting candidates for gene therapy approaches. However, efficient antiviral activities of corresponding transgenes are likely to be counteracted in particular by cell-mediated host immune responses toward the transgene-expressing cells. To decrease this potential immunogenicity, a 24-amino acid Gly-Ala (GA) stretch derived from Epstein-Barr virus nuclear antigen-1 (EBNA1) and known to overcome proteasomal degradation was fused to a trans-dominant Gag variant (sgD1). To determine the capacity of this fusion polypeptide to repress viral replication, PM-1 cells were transduced with sgD1 and GAsgD1 transgenes, using retroviral gene transfer. Challenge of stably transfected permissive cell lines with various viral strains indicated that N-terminal GA fusion even enhanced the inhibitory properties of sgD1. Further studies revealed that the GA stretch increased protein stability by blocking proteasomal degradation of Gag proteins. Immunization of BALB/c mice with a DNA vaccine vector expressing sgD1 induced substantial Gag-specific immune responses that were, however, clearly diminished in the presence of GA. Furthermore, recognition of cells expressing the GA-fused transgene by CD8(+) T cells was drastically reduced, both in vitro and in vivo, resulting in prolonged survival of the transduced cells in recipient mice.

Structural data support a model where – following proteolytic cleavage – the amino-terminal domain of human immunodeficiency virus type 1 (HIV-1) capsid protein refolds into a β-hairpin/helix tertiary structure that is stabilized by a buried salt bridge forming between the positively charged primary imino group of a proline residue and the negatively charged carboxyl group of a conserved aspartate. In order to evaluate the contribution of either side-chain length or charge to the formation of infectious virus capsids, aspartate 183 was substituted for glutamate or asparagine in the viral context. It was found that both modifications abolished infectivity of the corresponding viruses in permissive T lymphocytes, although none of particle assembly and release, RNA encapsidation, incorporation of Env glycoproteins and packaging of cyclophilin A were impaired. However, whereas biophysical analyses of mutant virions yielded wild-type-like particle sizes and densities, electron microscopy revealed aberrant core morphologies that could be attributed to either increased (D183N) or reduced (D183E) capsid stability. Although the two amino acid substitutions had opposing effects upon core stability, both mutants were shown to exhibit a severe block in early reverse transcription, underscoring the importance of correct salt-bridge formation for early steps of virus replication.

From the seeds of Dodonaea viscosa a chromatographically pure saponin ester mixture consisting of dodonosides A and B was isolated using DCCC and preparative TLC. The structures of the two compounds were determined by 1 H NMR, 13 C NMR, FAB MS and GC/MS. Both have R 1 -barrigenol as the aglycone and possess an α- L -arabinofuranosyl (1 → 2 or 3)-[β- D -galactopyranosyl (1 → 2 or 3)]-β- D -glucuronopyranose moiety linked to the 3β-hydroxy group. They are esterified at C-21 and C-22 with 2,3-dimethyloxiran-2-carboxylic acid and 2-methylbutyric acid in dodonoside A and 2,3-dimethyloxiran-2-carboxylic acid and angelic acid in dodonoside B. The saponin mixture exerts antiexudative, phagocytosis-enhancing and molluscicidal activity.

The human immunodeficiency virus type-1 (HIV-1) transframe domain p6* is located between the nucleocapsid protein (NC) and the protease (PR) within the Gag-Pol precursor. This flexible, 68-amino-acid HIV-1 p6* domain has been suggested to negatively interfere with HIV PR activity in vitro proposing a contribution of either the C-terminal p6* tetrapeptide, internal cryptic PR cleavage sites, or a zymogen-related mechanism to a regulated PR activation. To assess these hypotheses in the viral context, a series of recombinant HX10-based provirus constructs has been established with clustered amino acid substitutions throughout the entire p6* coding sequence. Comparative analysis of the mutant proviral clones in different cell culture systems revealed that mutations within the well-conserved amino-terminal p6* region modified the Gag/Gag-Pol ratio and thus resulted in the release of viruses with impaired infectivity. Clustered amino acid substitutions destroying (i) the predicted cryptic PR cleavage sites or (ii) homologies to the pepsinogen propeptide did not influence viral replication in cell culture, whereas substitutions of the carboxyl-terminal p6* residues 62 to 68 altering proper release of the mature PR from the Gag-Pol precursor drastically reduced viral infectivity. Thus, the critical contribution of p6* and overlapping cis-acting sequence elements to timely regulated virus maturation and infectivity is closely linked to precise ribosomal frameshifting and proper N-terminal release of the viral PR from the Gag-Pol precursor, clearly disproving the hypothesis that sequence motifs in the central part of p6* modulate PR activation and viral infectivity.