On the classification of a small imbalanced cytogenetic image database

Solving a multiclass classification task using a small imbalanced database of patterns of high dimension is difficult due to the curse-of-dimensionality and the bias of the training toward the majority classes. Such a problem has arisen while diagnosing genetic abnormalities by classifying a small database of fluorescence in situ hybridization signals of types having different frequencies of occurrence. We propose and experimentally study using the cytogenetic domain two solutions to the problem. The first is hierarchical decomposition of the classification task, where each hierarchy level is designed to tackle a simpler problem which is represented by classes that are approximately balanced. The second solution is balancing the data by up-sampling the minority classes accompanied by dimensionality reduction. Implemented by the naive Bayesian classifier or the multilayer perceptron neural network, both solutions have diminished the problem and contributed to accuracy improvement. In addition, the experiments suggest that coping with the smallness of the data is more beneficial than dealing with its imbalance     

Sources of variability in copula duration of Mediterranean Fruit Flies

Previous studies have reported considerable variation in copula duration in the Mediterranean Fruit Fly (medfly), Ceratitis capitata Weidemann (Diptera: Tephritidae). Presently, however, this variation is largely unexplained. In this study we measure copula duration in two medfly strains used in applied research in Israel and examine how much of the variation in copula duration is due to the strain, age, the time of day the mating begins and the relative size of the mating pair. We found the following: flies of a strain reared in the laboratory since 1976 (Vienna) copulated for longer than flies of a strain collected in 1969 and periodically refreshed with wild males (Sade); older flies copulated for longer than young flies; and pairs in which males were smaller than females copulated for longer than pairs in which males were larger or the sexes were more evenly size-matched. The time of day the mating commenced (morning vs afternoon) had no effect. We discuss potential mechanisms underlying these variations in medfly copula duration.     

Sediment biogeochemistry in an East African mangrove forest (Gazi Bay, Kenya)

The biogeochemistry of mangrove sediments was investigated in several mangrove forest communities in Gazi Bay, a coastal lagoon in Kenya, Africa. Carbon dioxide fluxes, sediment median grain sizes, sedimentary organic carbon, nitrogen and phosphorus contents and pore-water characteristics (ammonium, nitrate, sulfate and chloride) could be related to forest type. Mangrove sediments have pH values that range from 3.5 to 8.3 due to the limited buffer capacity of these sediments and intense acidifying processes such as aerobic degradation of organic matter, oxidation of reduced components, ammonium uptake by roots and root respiration. The mangrove sediments are nitrogen-rich compared to mangrove litter, as a result of microbial nitrogen retention, uptake and fixation, and import of nitrogen-rich material. It appears that mangrove sediments in Gazi Bay act as a nutrient and carbon sink rather than as a source for adjacent seagrass and reef ecosystems.     

Protein unfolding is not a prerequisite for endoplasmic reticulum-to-cytosol dislocation

We examined the effects of protein folding on endoplasmic reticulum (ER)-to-cytosol transport (dislocation) by exploiting the well-characterized dihydrofolate reductase (DHFR) domain. DHFR retains the capacity to bind folate analogues in the lumen of microsomes and in the ER of intact cells, upon which it acquires a conformation resistant to proteinase K digestion. Here we show that a Class I major histocompatibility complex heavy chain fused to DHFR is still recognized by the human cytomegalovirus-encoded glycoproteins US2 and US11, resulting in dislocation of the fusion protein from the ER in vitro and in vivo. A folded state of the DHFR domain does not impair dislocation of Class I MHC heavy chains in vitro or in living cells. In fact, a slight acceleration of the dislocation of DHFR heavy chain fusion was observed in vitro in the presence of a folate analogue. These results suggest that one or more of the channels used for dislocation can accommodate polypeptides that contain a tightly folded domain of considerable size. Our data raise the possibility that the Sec61 channel can be modified to accommodate a folded DHFR domain for dislocation, but not for translocation into the ER, or that a channel altogether distinct from Sec61 is used for dislocation.     

Structure of the regulatory subunit of acetohydroxyacid synthase isozyme III from Escherichia coli

The enzyme acetohydroxyacid synthase (AHAS) catalyses the first common step in the biosynthesis of the three branched-chain amino acids. Enzymes in the AHAS family generally consist of regulatory and catalytic subunits. Here, we describe the first crystal structure of an AHAS regulatory subunit, the ilvH polypeptide, determined at a resolution of 1.75 A. IlvH is the regulatory subunit of one of three AHAS isozymes expressed in Escherichia coli, AHAS III. The protein is a dimer, with two beta alpha beta beta alpha beta ferredoxin domains in each monomer. The two N-terminal domains assemble to form an ACT domain structure remarkably close to the one predicted by us on the basis of the regulatory domain of 3-phosphoglycerate dehydrogenase (3PGDH). The two C-terminal domains combine so that their beta-sheets are roughly positioned back-to-back and perpendicular to the extended beta-sheet of the N-terminal ACT domain. On the basis of the properties of mutants and a comparison with 3PGDH, the effector (valine) binding sites can be located tentatively in two symmetrically related positions in the interface between a pair of N-terminal domains. The properties of mutants of the ilvH polypeptide outside the putative effector-binding site provide further insight into the functioning of the holoenzyme. The results of this study open avenues for further studies aimed at understanding the mechanism of regulation of AHAS by small-molecule effectors.     

Six Month In Situ High-Resolution Carbonate Chemistry and Temperature Study on a Coral Reef Flat Reveals Asynchronous pH and Temperature Anomalies

Understanding the temporal dynamics of present thermal and pH exposure on coral reefs is crucial for elucidating reef response to future global change. Diel ranges in temperature and carbonate chemistry parameters coupled with seasonal changes in the mean conditions define periods during the year when a reef habitat is exposed to anomalous thermal and/or pH exposure. Anomalous conditions are defined as values that exceed an empirically estimated threshold for each variable. We present a 200-day time series from June through December 2010 of carbonate chemistry and environmental parameters measured on the Heron Island reef flat. These data reveal that aragonite saturation state, pH, and pCO₂ were primarily modulated by biologically-driven changes in dissolved organic carbon (DIC) and total alkalinity (TA), rather than salinity and temperature. The largest diel temperature ranges occurred in austral spring, in October (1.5 – 6.6°C) and lowest diel ranges (0.9 – 3.2°C) were observed in July, at the peak of winter. We observed large diel total pH variability, with a maximum range of 7.7 – 8.5 total pH units, with minimum diel average pH values occurring during spring and maximum during fall. As with many other reefs, the nighttime pH minima on the reef flat were far lower than pH values predicted for the open ocean by 2100. DIC and TA both increased from June (end of Fall) to December (end of Spring). Using this high-resolution dataset, we developed exposure metrics of pH and temperature individually for intensity, duration, and severity of low pH and high temperature events, as well as a combined metric. Periods of anomalous temperature and pH exposure were asynchronous on the Heron Island reef flat, which underlines the importance of understanding the dynamics of co-occurrence of multiple stressors on coastal ecosystems.     

The Earliest Lead Object in the Levant

In the deepest section of a large complex cave in the northern Negev desert, Israel, a bi-conical lead object was found logged onto a wooden shaft. Associated material remains and radiocarbon dating of the shaft place the object within the Late Chalcolithic period, at the late 5^th millennium BCE. Based on chemical and lead isotope analysis, we show that this unique object was made of almost pure metallic lead, likely smelted from lead ores originating in the Taurus range in Anatolia. Either the finished object, or the raw material, was brought to the southern Levant, adding another major component to the already-rich Late Chalcolithic metallurgical corpus known to-date. The paper also discusses possible uses of the object, suggesting that it may have been used as a spindle whorl, at least towards its deposition.     

Enrichment of oxygen heavy isotopes during photosynthesis in phytoplankton

Some of the oxygen produced during oxygenic photosynthesis is consumed but little is known about the extent of the processes involved. We measured the ¹⁷O/¹⁶O and ¹⁸O/¹⁶O ratios in O₂ produced by certain marine and freshwater phytoplankton representing important groups of primary producers. When the cells were performing photosynthesis under very low dissolved oxygen concentrations (<3 μM), we observed significant enrichment in both ¹⁸O and ¹⁷O with respect to the substrate water. The difference in δ¹⁸O between O₂ and water was about 4.5, 3, 5.5, and 7‰ in the diatom Phaeodactylum tricornutum, Nannochloropsis sp. (Eustigmatophyceae), the coccolithophore Emiliania huxleyi and the green alga Chlamydomonas reinhardtii, respectively. The difference in δ¹⁷O was about 0.52 that of δ¹⁸O. As explained, the observed enrichments most probably stem from considerable oxygen consumption during photosynthesis even when major O₂-consuming reactions such as photorespiration were minimized. These enrichments increased linearly with rising O₂ levels but with different δ¹⁷O/δ¹⁸O slopes for the various organisms, suggesting engagements of different O₂-consuming reactions with rising O₂ levels. Consumption of O₂ may be important for energy dissipation during photosynthesis. The isotope enrichment observed here, not accounted for in earlier assessments, closes an important gap in our understanding of the difference between the isotopic compositions of atmospheric oxygen and that of seawater, i.e., the Dole effect.     

Aminoalkylcarbamoylphosphonates reduce TNFα release from activated immune cells

Some carbamoylphosphonates (CPOs) inhibit matrix metalloproteinases (MMPs). Although MMPs are involved in inflammatory processes, the anti-inflammatory activity of CPOs has not been reported. In this context we compared the biological activity of the three aminoCPOs, PYR-CPO, PIP-CPO and cis-ACCP. We were particularly interested in their capability to modulate the secretion of tumor necrosis factor alpha (TNFα). LPS-activated mouse peritoneal macrophages and LPS-activated mouse splenocytes were used to explore this question. It was found that the aminoCPOs were able to reduce TNFα secretion to a level equivalent to the reduction caused by the steroid drug budesonide (BUD). The reduction in TNFα levels was neither accompanied by cytotoxicity, nor did it inhibit cell proliferation. To explicate whether the aminoCPOs affect TNFα processing by TNFα-converting enzyme (TACE), TACE inhibitory properties of the three molecules was tested in vitro. Only PIP-CPO exerted TACE inhibitory activity at therapeutic (non-cytotoxic) concentrations, indicating on its potential to serve as an anti-inflammatory agent by reducing TNFα secretion.     

Phase 1 Safety and Immunogenicity Evaluation of ADVAX,a Multigenic,DNA-Based Clade C/B' HIV-1 Candidate Vaccine

Background

We conducted a Phase I dose escalation trial of ADVAX, a DNA-based candidate HIV-1 vaccine expressing Clade C/B'' env, gag, pol, nef, and tat genes. Sequences were derived from a prevalent circulating recombinant form in Yunnan, China, an area of high HIV-1 incidence. The objective was to evaluate the safety and immunogenicity of ADVAX in human volunteers.

Methodology/Principal Findings

ADVAX or placebo was administered intramuscularly at months 0, 1 and 3 to 45 healthy volunteers not at high risk for HIV-1. Three dosage levels [0.2 mg (low), 1.0 mg (mid), and 4.0 mg (high)] were tested. Twelve volunteers in each dosage group were assigned to receive ADVAX and three to receive placebo in a double-blind design. Subjects were followed for local and systemic reactogenicity, adverse events, and clinical laboratory parameters. Study follow up was 18 months. Humoral immunogenicity was evaluated by anti-gp120 binding ELISA. Cellular immunogenicity was assessed by a validated IFNγ ELISpot assay and intracellular cytokine staining. ADVAX was safe and well-tolerated, with no vaccine-related serious adverse events. Local and systemic reactogenicity events were reported by 64% and 42% of vaccine recipients, respectively. The majority of events were mild. The IFNγ ELISpot response rates to any HIV antigen were 0/9 (0%) in the placebo group, 3/12 (25%) in the low-dosage group, 4/12 (33%) in the mid-dosage group, and 2/12 (17%) in the high-dosage group. Overall, responses were generally transient and occurred to each gene product, although volunteers responded to single antigens only. Binding antibodies to gp120 were not detected in any volunteers, and HIV seroconversion did not occur.

Conclusions/Significance

ADVAX delivered intramuscularly is safe, well-tolerated, and elicits modest but transient cellular immune responses.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00249106","term_id":"NCT00249106"}}NCT00249106