Home Manufacture of Drugs: An Online Investigation and a Toxicological Reality Check of Online Discussions on Drug Chemistry

Emerging trends in market dynamics and the use of new psychoactive substances are both a public health concern and a complex regulatory issue. One novel area of investigation is the availability of homemade opioids, amphetamines and dissociatives, and the potential fueling of interest in clandestine home manufacture of drugs via the Internet. We illustrate here how online communal folk pharmacology of homemade drugs on drug website forums may actually inform home manufacture practices or contribute to the reduction of harms associated with this practice. Discrepancies between online information around purification and making homemade drugs safer, and the synthesis of the same substances in a proper laboratory environment, exist. Moderation and shutdown of synthesis queries and discussions online are grounded in drug websites adhering to harm-reduction principles by facilitating discussions around purification of homemade drugs only. Drug discussion forums should consider reevaluating their policies on chemistry discussions in aiming to reach people who cannot or will not refrain from cooking their own drugs with credible information that may contribute to reductions in the harms associated with this practice. © 2017 Taylor & Francis Group, LL

Mass measurements near the rr-process path using the Canadian Penning Trap mass spectrometer

The masses of 40 neutron-rich nuclides from Z = 51 to 64 were measured at an average precision of $\delta m/m= 10^{-7}$ using the Canadian Penning Trap mass spectrometer at Argonne National Laboratory. The measurements, of fission fragments from a $^{252}$Cf spontaneous fission source in a helium gas catcher, approach the predicted path of the astrophysical $r$ process. Where overlap exists, this data set is largely consistent with previous measurements from Penning traps, storage rings, and reaction energetics, but large systematic deviations are apparent in $\beta$-endpoint measurements. Differences in mass excess from the 2003 Atomic Mass Evaluation of up to 400 keV are seen, as well as systematic disagreement with various mass models.Comment: 15 pages, 16 figures. v2 updated, published in Physical Review

TMSB4Y is a Candidate Tumor Suppressor on the Y Chromosome and is Deleted in Male Breast Cancer.

Male breast cancer comprises less than 1% of breast cancer diagnoses. Although estrogen exposure has been causally linked to the development of female breast cancers, the etiology of male breast cancer is unclear. Here, we show via fluorescence in situ hybridization (FISH) and droplet digital PCR (ddPCR) that the Y chromosome was clonally lost at a frequency of ~16% (5/31) in two independent cohorts of male breast cancer patients. We also show somatic loss of the Y chromosome gene TMSB4Y in a male breast tumor, confirming prior reports of loss at this locus in male breast cancers. To further understand the function of TMSB4Y, we created inducible cell lines of TMSB4Y in the female human breast epithelial cell line MCF-10A. Expression of TMSB4Y resulted in aberrant cellular morphology and reduced cell proliferation, with a corresponding reduction in the fraction of metaphase cells. We further show that TMSB4Y interacts directly with β-actin, the main component of the actin cytoskeleton and a cell cycle modulator. Taken together, our results suggest that clonal loss of the Y chromosome may contribute to male breast carcinogenesis, and that the TMSB4Y gene has tumor suppressor properties

Electron Tomography of the Contact between T Cells and SIV/HIV-1: Implications for Viral Entry

The envelope glycoproteins of primate lentiviruses, including human and simian immunodeficiency viruses (HIV and SIV), are heterodimers of a transmembrane glycoprotein (usually gp41), and a surface glycoprotein (gp120), which binds CD4 on target cells to initiate viral entry. We have used electron tomography to determine the three-dimensional architectures of purified SIV virions in isolation and in contact with CD4+ target cells. The trimeric viral envelope glycoprotein surface spikes are heterogeneous in appearance and typically ∼120 Å long and ∼120 Å wide at the distal end. Docking of SIV or HIV-1 on the T cell surface occurs via a neck-shaped contact region that is ∼400 Å wide and consistently consists of a closely spaced cluster of five to seven rod-shaped features, each ∼100 Å long and ∼100 Å wide. This distinctive structure is not observed when viruses are incubated with T lymphocytes in the presence of anti-CD4 antibodies, the CCR5 antagonist TAK779, or the peptide entry inhibitor SIVmac251 C34. For virions bound to cells, few trimers were observed away from this cluster at the virion–cell interface, even in cases where virus preparations showing as many as 70 envelope glycoprotein trimers per virus particle were used. This contact zone, which we term the “entry claw”, provides a spatial context to understand the molecular mechanisms of viral entry. Determination of the molecular composition and structure of the entry claw may facilitate the identification of improved drugs for the inhibition of HIV-1 entry

β-delayed neutron spectroscopy using trapped radioactive ions

A novel technique for β-delayed neutron spectroscopy has been demonstrated using trapped ions. The neutron-energy spectrum is reconstructed by measuring the time of flight of the nuclear recoil following neutron emission, thereby avoiding all the challenges associated with neutron detection, such as backgrounds from scattered neutrons and γ rays and complicated detector-response functions. I+137 ions delivered from a Cf252 source were confined in a linear Paul trap surrounded by radiation detectors, and the β-delayed neutron-energy spectrum and branching ratio were determined by detecting the β- and recoil ions in coincidence. Systematic effects were explored by determining the branching ratio three ways. Improvements to achieve higher detection efficiency, better energy resolution, and a lower neutron-energy threshold are proposed. © 2013 American Physical Society

Tensor interaction limit derived from the α-β-ν̄ correlation in trapped Li8 ions

A measurement of the α-β-ν̄ angular correlation in the Gamow-Teller decay Li8→Be*8+ν̄+β, Be*8→ α+α has been performed using ions confined in a linear Paul trap surrounded by silicon detectors. The energy difference spectrum of the α particles emitted along and opposite the direction of the β particle is consistent with the standard model prediction and places a limit of 3.1% (95.5% confidence level) on any tensor contribution to the decay. From this result, the amplitude of any tensor component CT relative to that of the dominant axial-vector component CA of the electroweak interaction is limited to |CT/CA|\u3c0.18 (95.5% confidence level). This experimental approach is facilitated by several favorable features of the Li8 β decay and has different systematic effects than the previous β-ν̄ correlation results for a pure Gamow-Teller transition obtained from studying He6 β decay. © 2013 American Physical Society

Limit on Tensor Currents from Li 8 β Decay

In the standard model, the weak interaction is formulated with a purely vector-axial-vector (V-A) structure. Without restriction on the chirality of the neutrino, the most general limits on tensor currents from nuclear β decay are dominated by a single measurement of the β-ν¯ correlation in He6 β decay dating back over a half century. In the present work, the β-ν¯-α correlation in the β decay of Li8 and subsequent α-particle breakup of the Be8∗ daughter was measured. The results are consistent with a purely V-A interaction and in the case of couplings to right-handed neutrinos (CT=-CT′) limits the tensor fraction to |CT/CA|2\u3c0.011 (95.5% C.L.). The measurement confirms the He6 result using a different nuclear system and employing modern ion-trapping techniques subject to different systematic uncertainties

Phenotypic and Functional Properties of Helios+ Regulatory T Cells

Helios, an Ikaros family transcription factor, is preferentially expressed at the mRNA and protein level in regulatory T cells. Helios expression previously appeared to be restricted to thymic-derived Treg. Consistent with recent data, we show here that Helios expression is inducible in vitro under certain conditions. To understand phenotypic and functional differences between Helios+ and Helios− Treg, we profiled cell-surface markers of FoxP3+ Treg using unmanipulated splenocytes. We found that CD103 and GITR are expressed at high levels on a subset of Helios+ Treg and that a Helios+ Treg population could be significantly enriched by FACS sorting using these two markers. Quantitative real-time PCR (qPCR) analysis revealed increased TGF-β message in Helios+ Treg, consistent with the possibility that this population possesses enhanced regulatory potential. In tumor-bearing mice, we found that Helios+ Treg were relatively over-represented in the tumor-mass, and BrdU studies showed that, in vivo, Helios+ Treg proliferated more than Helios− Treg. We hypothesized that Helios-enriched Treg might exert increased suppressive effects. Using in vitro suppression assays, we show that Treg function correlates with the absolute number of Helios+ cells in culture. Taken together, these data show that Helios+ Treg represent a functional subset with associated CD103 and GITR expression

Production of radioactive ion beams using the in-flight technique

Reactions with a heavy projectile incident on a light target can be used for the efficient in-flight production of secondary radioactive beams. An overview of this technique is given using data on 17F beams produced via the p(17O, 17F)n and d(16O, 17F)n reactions. With primary 16,17O beam currents of 100 pnA, intensities of up to 2×106 17F/s on target were achieved. Using this beam, the p(17F, α) 14O reaction was measured

Hotspot SF3B1 mutations induce metabolic reprogramming and vulnerability to serine deprivation.

Cancer-associated mutations in the spliceosome gene SF3B1 create a neomorphic protein that produces aberrant mRNA splicing in hundreds of genes, but the ensuing biologic and therapeutic consequences of this missplicing are not well understood. Here we have provided evidence that aberrant splicing by mutant SF3B1 altered the transcriptome, proteome, and metabolome of human cells, leading to missplicing-associated downregulation of metabolic genes, decreased mitochondrial respiration, and suppression of the serine synthesis pathway. We also found that mutant SF3B1 induces vulnerability to deprivation of the nonessential amino acid serine, which was mediated by missplicing-associated downregulation of the serine synthesis pathway enzyme PHGDH. This vulnerability was manifest both in vitro and in vivo, as dietary restriction of serine and glycine in mice was able to inhibit the growth of SF3B1MUT xenografts. These findings describe a role for SF3B1 mutations in altered energy metabolism, and they offer a new therapeutic strategy against SF3B1MUT cancers