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Hoarding disorder is characterized by an accumulation of possessions due to excessive acquisition of or difficulty discarding possessions, regardless of their actual value and is estimated to affect 2-6% of the population. Animal hoarding, a distinct subset of hoarding disorder, has a significant public health impact on the humans involved, as well as animal welfare. Individuals exhibit self-neglect, apathy, social withdrawal and object hoarding; living within squalid, deteriorated, structurally unsafe and uninhabitable premises, alongside neglected animals. Cases are complex, costly and impact on a range of responding service providers. Effective case management is poorly understood and researched, with published literature in England particularly sparse. Improving understanding of the characteristics of these cases is the first step in informed case management. This research is the first exploration of the characteristics of animal hoarders in England and the areas where cases were located. Information about prosecutions involving large numbers of animals that were reported in the media was systematically obtained. This identified 66 cases between January 2015 and December 2020. Geospatial analysis exploring characteristics of locations where animal hoarding cases are also reported. Findings were broadly consistent with the international literature in that females (64%), those living alone (71%) and those with a mean age of 49 were well represented. Cats (61.5%) and dogs (60%) were the most commonly hoarded species. There was a mean of 44 animals per case and dead or animals requiring euthanasia found in 53% of cases. Key characteristics of the areas where cases were found highlight urban, densely populated, and high levels of deprivation being the most represented. Evidence of recidivism was evident in 39% of cases, suggesting that prosecution is not an effective rehabilitator. Animal hoarding raises serious implications for Public Health Services, and the lack of current effective case management strategies are discussed., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Wilkinson, Schoultz, King, Neave and Bailey.)

The IKK-NFκB complex is a key signaling node that facilitates activation of gene expression in response to extracellular signals. The kinase IKKβ and the transcription factor RELA have been targeted by covalent modifiers that bind to surface exposed cysteine residues. A common feature in well characterized covalent modifiers of RELA and IKKβ is the Michael acceptor containing α-methylene-γ-butyrolactone functionality. Through synthesis and evaluation of a focused set of α-methylene-γ-butyrolactone containing spirocyclic dimers (SpiDs) we identified SpiD3 as an anticancer agent with low nanomolar potency. Using cell-free and cell-based studies we show that SpiD3 is a covalent modifier that generates stable RELA containing high molecular weight complexes. SpiD3 inhibits TNFα-induced IκBα phosphorylation resulting in the blockade of RELA nuclear translocation. SpiD3 induces apoptosis, inhibits colony formation and migration of cancer cells. The NCI-60 cell line screen revealed that SpiD3 potently inhibits growth of leukemia cell lines, making it a suitable pre-therapeutic lead for hematological malignancies., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Activation of inhibitor of nuclear factor NF-κB kinase subunit-β (IKKβ), characterized by phosphorylation of activation loop serine residues 177 and 181, has been implicated in the early onset of cancer. On the other hand, tissue-specific IKKβ knockout in Kras mutation-driven mouse models stalled the disease in the precancerous stage. In this study, we used cell line models, tumor growth studies, and patient samples to assess the role of IKKβ and its activation in cancer. We also conducted a hit-to-lead optimization study that led to the identification of 39-100 as a selective mitogen-activated protein kinase kinase kinase (MAP3K) 1 inhibitor. We show that IKKβ is not required for growth of Kras mutant pancreatic cancer (PC) cells but is critical for PC tumor growth in mice. We also observed elevated basal levels of activated IKKβ in PC cell lines, PC patient-derived tumors, and liver metastases, implicating it in disease onset and progression. Optimization of an ATP noncompetitive IKKβ inhibitor resulted in the identification of 39-100, an orally bioavailable inhibitor with improved potency and pharmacokinetic properties. The compound 39-100 did not inhibit IKKβ but inhibited the IKKβ kinase MAP3K1 with low-micromolar potency. MAP3K1-mediated IKKβ phosphorylation was inhibited by 39-100, thus we termed it IKKβ activation modulator (IKAM) 1. In PC models, IKAM-1 reduced activated IKKβ levels, inhibited tumor growth, and reduced metastasis. Our findings suggests that MAP3K1-mediated IKKβ activation contributes to KRAS mutation-associated PC growth and IKAM-1 is a viable pretherapeutic lead that targets this pathway.

Cyclin-dependent kinase 9 (CDK9) is a member of the cyclin-dependent kinase (CDK) family which is involved in transcriptional regulation of several genes, including the oncogene Myc, and is a validated target for pancreatic cancer. Here we report the development of an aminopyrazole based proteolysis targeting chimera (PROTAC 2) that selectively degrades CDK9 (DC 50  = 158 ± 6 nM). Mass spectrometry-based kinome profiling shows PROTAC 2 selectively degrades CDK9 in MiaPaCa2 cells and sensitizes them to Venetoclax mediated growth inhibition., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Neuropeptides comprise the largest class of neural and neuroendocrine signaling molecules. Vertebrate tachykinins (TKs) and the structurally-related invertebrate tachykinin-related peptides (TRPs) together form the largest neuropeptide superfamily, with a number of conserved neural and neuroendocrine functions across species. Arthropods, including crustaceans, have provided many insights into neuropeptide signaling and function. Crustacean tachykinin-related peptide occurs in endocrine organs and cells and in two of the major crustacean CNS components, the supraoesophageal ganglion ("brain") and the stomatogastric nervous system. However, little is known about TRP sources in the remaining major CNS component, the thoracic ganglion mass (TGM). To gain further insight into the function of this peptide, we aimed to identify intrinsic TRP sources in the TGM of the Jonah crab, Cancer borealis. We first adapted a clearing protocol to improve TRP immunoreactivity specifically in the TGM, which is a dense, fused mass of multiple ganglia in short-bodied crustaceans such as Cancer species of crabs. We verified that the clearing protocol avoided distortion of cell body morphology yet increased visibility of TRP immunoreactivity. Using confocal microscopy, we found TRP-immunoreactive (TRP-IR) axon tracts running the length of the TGM, TRP-IR neuropil in all ganglia, and approximately 110 TRP-IR somata distributed throughout the TGM, within and between ganglia. These somata likely represent both neural and neuroendocrine sources of TRP. Thus, there are many potential intrinsic sources of TRP in the TGM that are positioned to regulate behaviors such as food intake, locomotion, respiration, and reproduction., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A diverse series of 1,2,4-oxadiazoles based substituted compounds were designed, synthesized and evaluated as anticancer agents targeting carbonic anhydrase IX (CAIX). Initial structure-activity analysis suggested that the thiazole/thiophene-sulfonamide conjugates of 1,2,4-oxadiazoles exhibited potent anticancer activities with low μM potencies. Compound OX12 exhibited antiproliferative activity (IC 50  = 11.1 µM) along with appreciable inhibition potential for tumor-associated CAIX (IC 50  = 4.23 µM) isoform. Therefore, OX12 was structurally optimized and its SAR oriented derivatives (OX17-27) were synthesized and evaluated. This iteration resulted in compound OX27 with an almost two-fold increase in antiproliferative effect (IC 50  = 6.0 µM) comparable to the clinical drug doxorubicin and significantly higher potency against CAIX (IC 50  = 0.74 µM). Additionally, OX27 treatment decreases the expression of CAIX, induces apoptosis and ROS production, inhibited colony formation and migration of colon cancer cells. Our studies provide preclinical rational for the further optimization of identified OX27 as a suitable lead for the possible treatment of CRC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Developing small molecules that indirectly regulate Mcl-1 function has attracted a lot of attention in recent years. Here, we report the discovery of an aminopyrazole, 2-([1,1'-biphenyl]-4-yl)- N -(5-cyclobutyl-1 H -pyrazol-3-yl)acetamide (analog 24), which selectively inhibited cyclin-dependent kinase (CDK) 5 over CDK2 in cancer cell lines. We also show that analog 24 reduced Mcl-1 levels in a concentration-dependent manner in cancer cell lines. Using a panel of doxycycline inducible cell lines, we show that CDK5 inhibitor 24 selectively modulates Mcl-1 function while the CDK4/6 inhibitor 6-acetyl-8-cyclopentyl-5-methyl-2-(5-(piperazin-1-yl)pyridin-2-ylamino)pyrido[2,3-day]pyrimidin-7(8 H )-one does not. Previous studies using RNA interference and CRISPR showed that concurrent elimination of Bcl-xL and Mcl-1 resulted in induction of apoptosis. In pancreatic cancer cell lines, we show that either CDK5 knockdown or expression of a dominant negative CDK5 results in synergistic induction of apoptosis. Moreover, concurrent pharmacological perturbation of Mcl-1 and Bcl-xL in pancreatic cancer cell lines using a CDK5 inhibitor analog 24 that reduced Mcl-1 levels and 4-(4-{[2-(4-chlorophenyl)-5,5-dimethyl-1-cyclohexen-1-yl]methyl}-1-piperazinyl)- N -[(4-{[(2 R )-4-(4-morpholinyl)-1-(phenylsulfanyl)-2-butanyl]amino}-3-[(trifluoromethyl)sulfonyl]phenyl)sulfonyl] benzamide (navitoclax), a Bcl-2/Bcl-xL/Bcl-w inhibitor, resulted in synergistic inhibition of cell growth and induction of apoptosis. In conclusion, we demonstrate targeting CDK5 will sensitize pancreatic cancers to Bcl-2 protein inhibitors. SIGNIFICANCE STATEMENT: Mcl-1 is stabilized by CDK5-mediated phosphorylation in pancreatic ductal adenocarcinoma, resulting in the deregulation of the apoptotic pathway. Thus, genetic or pharmacological targeting of CDK5 sensitizes pancreatic cancers to Bcl-2 inhibitors, such as navitoclax., (Copyright © 2019 by The Author(s).)

Development of selective kinase inhibitors that target the ATP binding site continues to be a challenge largely due to similar binding pockets. Palbociclib is a cyclin-dependent kinase inhibitor that targets the ATP binding site of CDK4 and CDK6 with similar potency. The enzymatic function associated with the kinase can be effectively probed using kinase inhibitors however the kinase-independent functions cannot. Herein, we report a palbociclib based PROTAC that selectively degrades CDK6 while sparing the homolog CDK4. We used competition studies to characterize the binding and mechanism of CDK6 degradation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Parenteral Nutrition (PN) provides life sustaining support where gastrointestinal nutrition is inadequate due to disease or prematurity. Intravenous lipid emulsions (IVLEs) form a staple part of PN. Whilst the physical stability of IVLE's is relatively well known and quantified, chemical stability is an area where little testing has occurred. We report a new sensitive method for the monitoring of selected triglycerides present within two IVLEs and the detection and quantification of the peroxidation product 4-hydroxynonenal (HNE) using HPLC with in-line UV and charged aerosol detection (CAD). IVLEs used included the soy-bean oil based emulsion Intralipid ® 20% and SMOFlipid ® 20% (Fresenius Kabi UK), based on soy-bean, olive, fish oil and medium chain triglycerides. Assay validation gave R 2 values of ≥0.99 for all selected triglyceride peaks and 4-hydroxynonenal. Inter and intra-day repeatability gave RSD values < 7.2% for CAD detection, achieving a precise and repeatable method. HNE was confirmed through internal standardisation of the HPLC method. Selected triglycerides were identified using ESI-MS with MicroTOF. This novel method permits the chemical stability of IVLEs to be quantified and monitored in respect to lipid peroxidation during storage prior to delivery to the patient, ensuring the optimal safety of IVLEs in a clinical setting., (Copyright © 2018 European Society for Clinical Nutrition and Metabolism. Published by Elsevier Ltd. All rights reserved.)

Objectives: Axillary ultrasound with fine needle aspiration (AXUSFNA) in early-stage breast cancer has required reappraisal. ACOSOG Z-0011 and after mapping of the axilla: radiotherapy or surgery have shown that women with limited nodal disease at sentinel lymph node biopsy got no survival advantage with completion axillary node dissection. We hypothesize that AXUSFNA may be sufficiently accurate for staging for some patients and sentinel lymph node biopsy need not be performed. We define the false negative rate (FNR) of AXUSFNA in different subsets of patients., Materials and Methods: This retrospective cohort study included node positive patients who also underwent AXUSFNA between 1/2006 and 12/2010 followed by axillary surgery. The FNR was calculated for the entire group and for subgroups determined by tumor, nodal, and ultrasound findings., Results: Out of ∼700 AXUSFNA patients, 128 node positive patients were included in the study. The overall AXUSFNA FNR was 35.9% (95% confidence interval, 28.1%-44.6%). There was a significantly higher FNR with smaller tumors and presence of ductal carcinoma in situ on multivariate analysis. On ultrasound, benign-appearing nodes had a higher FNR than indeterminate nodes (78.9% vs. 60.9%, P=0.2) and significantly higher than suspicious nodes (78.9% vs. 2.9%, P<0.0001)., Conclusions: In our cohort, the FNR for AXUSFNA was comparable with the rate of residual disease in the control arms of Z-0011 (27.4%) and after mapping of the axilla: radiotherapy or surgery (33%). However, our analysis suggests that we may be able to identify more appropriate patients for AXUSFNA and halve the FNR. As primary tumor characteristics and genomics drive systemic therapeutic recommendations, there may be an ongoing role for AXUSFNA in axillary staging.

African lungfish Protopterus annectens can produce rotational movements around the joint between the pelvis and the pelvic fin, allowing these animals to walk across benthic substrates. In tetrapods, limb rotation at the hip joint is a common feature of substrate-based locomotion. For sprawling tetrapods, rotation can involve nine or more muscles, which are often robust and span multiple joints. In contrast, P. annectens uses a modest morphology of two fan-shaped muscles, the pelvic fin protractor and retractor, to accomplish this movement. We hypothesized that functional subdivision, coupled with their broad insertions on the femur, allows each of these muscles to pull on the limb from multiple directions and provides a mechanism for fin rotation. To test this hypothesis, we examined the muscle activity at three locations in both the protractor and the retractor muscles during walking. Electromyograms show differences in the timing of muscle activation between dorsal and ventral regions of each muscle, suggesting that each muscle is functionally subdivided once. The subdivisions demonstrate sequential onsets of muscle activity and overlap of activity between regions, which are also features of limb control in tetrapods. These data indicate that subdivisions of protractor and retractor muscles impart functional complexity to a morphologically simple system, and suggest a mechanism that allows lungfish to produce a tetrapod-like walking gait with only two muscles. As one of few extant sarcopterygian fishes, P. annectens may provide important functional data to inform interpretation of limb movement of fossil relatives., (© 2014. Published by The Company of Biologists Ltd.)

The West African lungfish (Protopterus annectens) performs benthic, pelvic fin-driven locomotion with gaits common to tetrapods, the sister group of the lungfishes. Features of P. annectens movement are similar to those of modern tetrapods and include use of the distal region of the pelvic fin as a “foot,” use of the fin to lift the body above the substrate and rotation of the fin around the joint with the pelvis. In contrast to these similarities in movement, the pelvic fins of P. annectens are long, slender structures that are superficially very different from tetrapod limbs. Here, we describe the musculoskeletal anatomy of the pelvis and pelvic fins of P. annectens with dissection, magnetic resonance imaging, histology and 3D-reconstruction methods. We found that the pelvis is embedded in the hypaxial muscle by a median rostral and two dorsolateral skeletal projections. The protractor and retractor muscles at the base of the pelvic fin are fan-shaped muscles that cup the femur. The skeletal elements of the fin are serially repeating cartilage cylinders. Along the length of the fin, repeating truncated cones of muscles, the musculus circumradialis pelvici, are separated by connective tissue sheets that connect the skeletal elements to the skin. The simplicity of the protractor and retractor muscles at the base of the fin is surprising, given the complex rotational movement those muscles generate. In contrast, the series of many repeating segmental muscles along the length of the fin is consistent with the dexterity of bending of the distal limb. P. annectens can provide a window into softtissue anatomy and sarcopterygian fish fin function that complements the fossil data from related taxa. This work, combined with previous behavioral examination of P. annectens, illustrates that fin morphologies that do not appear to be capable of walking can accomplish that function, and may inform the interpretation of fossil anatomical evidence.

We examined attentional biases for social and non-social emotional stimuli in young adult men and compared the results to those of male rhesus monkeys (Macaca mulatta) previously tested in a similar dot-probe task (King et al. in Psychoneuroendocrinology 37(3):396-409, 2012). Recognition memory for these stimuli was also analyzed in each species, using a recognition memory task in humans and a delayed non-matching-to-sample task in monkeys. We found that both humans and monkeys displayed a similar pattern of attentional biases toward threatening facial expressions of conspecifics. The bias was significant in monkeys and of marginal significance in humans. In addition, humans, but not monkeys, exhibited an attentional bias away from negative non-social images. Attentional biases for social and non-social threat differed significantly, with both species showing a pattern of vigilance toward negative social images and avoidance of negative non-social images. Positive stimuli did not elicit significant attentional biases for either species. In humans, emotional content facilitated the recognition of non-social images, but no effect of emotion was found for the recognition of social images. Recognition accuracy was not affected by emotion in monkeys, but response times were faster for negative relative to positive images. Altogether, these results suggest shared mechanisms of social attention in humans and monkeys, with both species showing a pattern of selective attention toward threatening faces of conspecifics. These data are consistent with the view that selective vigilance to social threat is the result of evolutionary constraints. Yet, selective attention to threat was weaker in humans than in monkeys, suggesting that regulatory mechanisms enable non-anxious humans to reduce sensitivity to social threat in this paradigm, likely through enhanced prefrontal control and reduced amygdala activation. In addition, the findings emphasize important differences in attentional biases to social versus non-social threat in both species. Differences in the impact of emotional stimuli on recognition memory between monkeys and humans will require further study, as methodological differences in the recognition tasks may have affected the results.

Testosterone (T) has repeatedly been shown to have anxiolytic properties in rodents, but findings in primates are more mixed. To examine the effects of exogenous T on anxiety, we tested pharmacologically-castrated adult male rhesus monkeys in a modified version of the Human Intruder Paradigm, which measured defensive responses to an unfamiliar human staring directly at them for 2 min. Monkeys were tested at 2 week intervals during 4 experimental conditions lasting 4 weeks each: at baseline, during treatment with the gonadotropin releasing hormone (GnRH) agonist leuprolide acetate (200 μg/kg; Lupron phase), during treatment with Lupron+T enanthate (TE, 5 mg/kg; TE phase) and during treatment with Lupron+oil vehicle (oil phase). We found that the number of anxious behaviors was lower during periods of low T (Lupron only and Lupron+oil phases) than during the Lupron+TE phase. No change in pacing or watching behavior was observed. Thus, in contrast to rodent data, we found no evidence for anxiolytic properties of T in male rhesus monkeys. Rather, T supplementation restored baseline levels of anxiety in Lupron-treated monkeys. These discrepant findings may be best explained by the low levels of gonadotropins achieved by the GnRH agonist. We suggest that Lupron-induced luteinizing hormone (LH) suppression reduced anxiety and that this effect was abolished by T administration. This interpretation is consistent with the view that T increases emotional reactivity to a potential threat and facilitates adaptive arousal response in face of immediate social challenge., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Increasing evidence in humans and other animals suggests that testosterone (T) plays an important role in modulating emotion. We previously reported that T treatment in rhesus monkeys undergoing chemically induced hypogonadism results in increased watching time of videos depicting fights between unfamiliar conspecifics (Lacreuse et al., 2010). In the current study, we aimed to further investigate the effect of T manipulations on attention and memory for emotional stimuli in male rhesus monkeys. Six males (7 years old) were administered Depot Lupron to suppress endogenous T levels and treated with either testosterone enanthate (TE, 5 mg/kg) or oil, before crossing over to the alternate treatment. Animals were tested for 16 weeks on two computerized touchscreen tasks with both social and nonsocial emotional and neutral stimuli. The Dot-Probe task was used to measure attention, and the Delayed-Non-Matching-to-Sample task with a 1s delay (DNMS) was used to measure recognition memory for these stimuli. Performance on the two tasks was examined during each of four month-long phases: Baseline, Lupron alone, Lupron+TE and Lupron+oil. It was predicted that T administration would lead to increased attention to negative social stimuli (i.e., negative facial expressions of unfamiliar conspecifics) and would improve memory for such stimuli. We found no evidence to support these predictions. In the Dot-Probe task, an attentional bias towards negative social stimuli was observed at baseline, but T treatment did not enhance this bias. Instead, monkeys had faster response times when treated with T compared to oil, independently of the emotional valence or social relevance of stimuli, perhaps reflecting an enhancing effect of T on reward sensitivity or general arousal. In the DNMS, animals had better memory for nonsocial compared to social stimuli and showed the poorest performance in the recognition of positive facial expressions. However, T did not affect performance on the task. Thus, even though monkeys were sensitive to the social relevance and emotional valence of the stimuli in the two tasks, T manipulations had no effect on attention or memory for these stimuli. Because habituation to the stimuli may have mitigated the effect of treatment in the attentional task, we suggest that T may increase attentional biases to negative social stimuli only during early exposure to the stimuli with acute treatment or when stimuli are highly arousing (i.e., dynamically presented) with chronic treatment. In addition, the data suggest that T does not enhance working memory for emotional stimuli in young male macaques., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Tetrapods evolved from sarcopterygian fishes in the Devonian and were the first vertebrates to colonize land. The locomotor component of this transition can be divided into four major events: terrestriality, the origins of digited limbs, solid substrate-based locomotion, and alternating gaits that use pelvic appendages as major propulsors. As the sister group to tetrapods, lungfish are a morphologically and phylogenetically relevant sarcopterygian taxon for understanding the order in which these events occurred. We found that a species of African lungfish (Protopterus annectens) uses a range of pelvic fin-driven, tetrapod-like gaits, including walking and bounding, in an aquatic environment, despite having a derived limb endoskeleton and primitively small, muscularly supported pelvis. Surprisingly, given these morphological traits, P. annectens also lifts its body clear of the substrate using its pelvic fins, an ability thought to be a tetrapod innovation. Our findings suggest that some fundamental features of tetrapod locomotion, including pelvic limb gait patterns and substrate association, probably arose in sarcopterygians before the origin of digited limbs or terrestriality. It follows that the attribution of some of the nondigited Devonian fossil trackways to limbed tetrapods may need to be revisited.

We perform molecular dynamics simulations of 'floating bond' (FB) models of network-forming liquids and compare the structure and dynamics against the BKS model of silica (van Beest et al 1990 Phys. Rev. Lett. 64 1955), with the aim of gaining a better understanding of glassy silica in terms of the variety of non-ergodic states seen in colloids. At low densities, all the models form tetrahedral networks. At higher densities, tailoring the FB model to allow a higher number of bonds does not capture the structure seen in BKS. Upon rescaling the time and length in order to compare mean squared displacements between models, we find that there are significant differences in the temperature dependence of the diffusion coefficient at high density. Additionally, the FB models show a greater range in variability in the behavior of the non-ergodicity parameter and caging length, quantities used to distinguish colloidal gels and glasses. Hence, we find that the glassy behavior of BKS silica can be interpreted as a 'gel' at low densities, with only a marginal gel-to-glass crossover at higher densities.

Animal studies indicate that sex hormones have widespread effects on the brain, cognition and emotion, but findings in humans are inconsistent. Well-controlled studies in nonhuman primates are crucial to resolve these discrepancies. In this study, we examined the effects of testosterone (T) on emotion in male rhesus monkeys. Six young adult males were tested on two emotional tasks during three hormonal conditions in a crossover design: when intact at baseline and when pharmacologically hypogonadal with add-back of T or placebo. The emotional tasks were the Approach-Avoidance task, which tested behavioral responses to three categories of objects (familiar, novel, and negative) and a Social Playback task which tested behavioral responses to scenes of unfamiliar conspecifics engaged in three types of social activities (neutral, positive, or negative). Following a 4-week baseline period, monkeys were treated with Depot Lupron, 200μg/kg before being randomly assigned to one of two treatment groups: Depot Lupron+Testosterone Enanthate (TE, 20mg/kg) or Depot Lupron+oil vehicle. In each treatment group, monkeys received one injection of Lupron and one injection of TE or one injection of Lupron and one injection of oil at the onset of a 4-week testing period, before crossing over to the alternate treatment for an additional 4weeks of testing. TE treatment had no effect on behavioral measures in the Approach-Avoidance task. For the Social Playback task, however, TE significantly increased watching time of video clips which depicted fights between unfamiliar conspecifics. The enhancing effect of T on watching time for negative social scenes is consistent with human data suggesting that T decreases aversion or facilitates approach to threatening social stimuli. Further studies are needed to understand the mechanisms by which T may mediate responsiveness to social threat in male primates., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The convergent validity of the Trauma Symptom Checklist for Young Children (TSCYC) was examined with a sample of 172 sexually abused outpatient treatment-seeking children and their caregivers. The TSCYC evidenced good convergent validity with other parent ratings (e.g., the Child Behavior Checklist, Child Sexual Behavior Inventory, and the University of California at Los Angeles Post-Traumatic Stress Disorder Reaction Index [UCLA PTSD Index]). The convergent validity of the TSCYC and the Trauma Symptom Checklist for Children was weak, perhaps illustrating the lack of agreement often found between children and caregivers and illustrating the need for a multi-informant approach to screening and assessment of sexually abused children. The TSCYC seems to hold promise based on the emerging evidence for its convergent validity.

Content uniformity (CU) of pharmaceutical dosage units can be affected by active pharmaceutical ingredient (API) particle size and size distribution. Previous authors have estimated this impact but use of different particle size descriptors led to confusion and difficulty in applying the theoretical models developed. We show that when the same descriptors for particle size and distribution are used (i.e., median diameter on a weight basis (d(50)) and geometric standard deviation (sigma(g))), previously published models are consistent. The approach of Yalkowsky and Bolton4 [Pharm Res 7:962-966, 1990] is modified to use these descriptors and updated for current USP28/NF23 CU criteria. A nomograph is provided to allow easy estimation of an acceptable d(50) for a given dose and sigma(g). To test the model's validity, tablets were manufactured over a wide range of doses and assayed for CU. As predicted, %relative standard deviation (RSD) increased as dose decreased. However, for APIs that deviate significantly from the assumed log-normal distribution, sigma(g) is more appropriately described by the upper region of the API size distribution, presumably because large particles have greatest influence on CU. At very low doses, CU values deviate significantly from normality, consistent with the presence of single large API particles causing super-potent dosage units., ((c) 2006 Wiley-Liss, Inc. and the American Pharmacists Association)

TlpC is encoded in the second chemotaxis operon of Rhodobacter sphaeroides. This protein shows some homology to membrane-spanning chemoreceptors of many bacterial species but, unlike these, is essential for R. sphaeroides chemotaxis to all compounds tested. Genomic replacement of tlpC with a C-terminal gfp fusion demonstrated that TlpC localized to a discrete cluster within the cytoplasm. Immunogold electron microscopy also showed that TlpC localized to a cytoplasmic electron-dense region. Correct TlpC-GFP localization depended on the downstream signalling proteins, CheW3, CheW4 and CheA2, and was tightly linked to cell division. Newly divided cells contained a single cluster but, as the cell cycle progressed, a second cluster appeared close to the initial cluster. As elongation continued, these clusters moved apart so that, on septation, each daughter cell contained a single TlpC cluster. The data presented suggest that TlpC is either a cytoplasmic chemoreceptor responding to or integrating global signals of metabolic state or a novel and essential component of the chemotaxis signalling pathway. These data also suggest that clustering is essential for signalling and that a mechanism may exist for targeting and localizing proteins within the bacterial cytoplasm.

Little information is available regarding the safety and efficacy of lipid lowering therapy in the elderly. Records of 80 octogenarians, taken from the database of the LifeHelp Lipid Clinic of the Heart Institute of St. Petersburg, FL, were examined, representing 1863 patient months of treatment. Therapy was effective, lowering low density lipoprotein cholesterol (from 140Â+/-4 to 92Â+/-3 mg/dL), raising high density lipoprotein cholesterol (from 44Â+/-1 to 50Â+/-1 mg/dL), and lowering triglycerides (from 199Â+/-21 to 146Â+/-9 mg/dL). Six patients developed myalgias (without significant creatine phosphokinase rise) or gastrointestinal disturbances. Three of these patients restarted therapy without difficulty. No patient developed rhabdomyolysis (including the 11% of patients on combination therapy). One patient developed an elevation of liver (more than 3 times upper limits of normal), but later restarted therapy without sequelae. We conclude that lipid lowering therapy was effective at modifying hyperlipidemia in the elderly without significant adverse effects. (c) 2000 by CVRR, Inc.

Bioaccumulation studies of wastewater from a thermo-mechanical paper mill using the freshwater crayfish (Cherax destructor) consistently demonstrated elevated levels of manganese. Most of the Mn appeared to be associated with the carapace of the animals. It is suggested that the elevated Mn levels are the result of Mn-oxidising bacteria forming biofilms on the carapace of the crayfish followed by Mn oxide precipitation rather than active uptake of Mn by the crayfish.