Evidence for the earliest structural use of wood at least 476,000 years ago.

Wood artefacts rarely survive from the Early Stone Age since they require exceptional conditions for preservation; consequently, we have limited information about when and how hominins used this basic raw material1. We report here on the earliest evidence for structural use of wood in the archaeological record. Waterlogged deposits at the archaeological site of Kalambo Falls, Zambia, dated by luminescence to at least 476 ± 23 kyr ago (ka), preserved two interlocking logs joined transversely by an intentionally cut notch. This construction has no known parallels in the African or Eurasian Palaeolithic. The earliest known wood artefact is a fragment of polished plank from the Acheulean site of Gesher Benot Ya'aqov, Israel, more than 780 ka (refs. 2,3). Wooden tools for foraging and hunting appear 400 ka in Europe4-8, China9 and possibly Africa10. At Kalambo we also recovered four wood tools from 390 ka to 324 ka, including a wedge, digging stick, cut log and notched branch. The finds show an unexpected early diversity of forms and the capacity to shape tree trunks into large combined structures. These new data not only extend the age range of woodworking in Africa but expand our understanding of the technical cognition of early hominins11, forcing re-examination of the use of trees in the history of technology12,13.

Magnetic Field Amplification by a Nonlinear Electron Streaming Instability.

Magnetic field amplification by relativistic streaming plasma instabilities is central to a wide variety of high-energy astrophysical environments as well as to laboratory scenarios associated with intense lasers and electron beams. We report on a new secondary nonlinear instability that arises for relativistic dilute electron beams after the saturation of the linear Weibel instability. This instability grows due to the transverse magnetic pressure associated with the beam current filaments, which cannot be quickly neutralized due to the inertia of background ions. We show that it can amplify the magnetic field strength and spatial scale by orders of magnitude, leading to large-scale plasma cavities with strong magnetic field and to very efficient conversion of the beam kinetic energy into magnetic energy. The instability growth rate, saturation level, and scale length are derived analytically and shown to be in good agreement with fully kinetic simulations.

Regulation of tamoxifen sensitivity by a PAK1-EBP1 signalling pathway in breast cancer.

BACKGROUND: EBP1, an ErbB3-binding protein, sensitises breast cancer cells to tamoxifen in part by decreasing ErbB2 protein levels. The p21-regulated serine/threonine kinase PAK1, implicated in tamoxifen resistance, phosphorylates EBP1 in vitro and in vivo at T261. Phosphorylation of EBP1 at this site induces tamoxifen resistance. We thus postulated that inhibition of PAK1 activity, by restoring EBP1 function, could ameliorate the hormone refractory phenotype of ErbB2-overexpressing breast cancer cells. METHODS: Effects of EBP1 on ErbB2 levels were measured by western blotting. Effects of EBP1 and IPA-3 on tamoxifen sensitivity were measured using a tetrazolium based cell viability assay. RESULTS: Transient transfection studies indicated that an EBP1 T261E mutant, which mimics EPB1 phosphorylated by PAK1, increased ErbB2 protein levels. An EBP1 T261A mutant, unable to be phosphorylated by PAK1, ameliorated PAK1-induced tamoxifen resistance, suggesting that phosphorylation of EBP1 by PAK1 contributes to tamoxifen resistance. We then tested if pharmacological inhibition of PAK1 activity might render hormone resistant cells, which endogenously overexpress PAK1, tamoxifen sensitive. IPA-3, a specific small MW PAK1 inhibitor, sensitised cells to tamoxifen only when EBP1 was ectopically expressed. IPA had no effect on tamoxifen resistance in T47D cells in which EBP1 protein had been ablated by shRNA. The IPA-induced increase in tamoxifen sensitivity was accompanied by a decrease in ErbB2 levels only in EBP1-overexpressing cells. CONCLUSION: These studies suggest that phosphorylation of EBP1 may be one mechanism of PAK1-induced hormone resistance and that PAK1 inhibitors may be useful in cells in which EBP1 is overexpressed.

Chemical inhibition through conformational stabilization of Rho GTPase effectors.

The Rho family of small GTP-binding proteins can activate a large number of downstream effectors and participate in a wide variety of biological processes, including cell motility, membrane trafficking, cell polarity, gene transcription, and mitosis. Specific small-molecule inhibitors of individual effector proteins downstream of Rho GTPases would be powerful tools to elucidate the contributions of particular effectors to these processes. In this chapter we describe the identification of a chemical inhibitor of a Rho effector and scaffolding protein neural-Wiskott-Aldrich syndrome protein (N-WASP), and the discovery of its novel mechanism of action, stabilization of N-WASP's native autoinhibited conformation. Inasmuch as several other Rho GTPase effectors are regulated by autoinhibition, we discuss how this regulatory mechanism could be exploited by small molecules to develop highly specific inhibitors of other Rho GTPase effectors. We illustrate this concept with the Rac/Cdc42 effector p21-activated kinase (Pak1) and the Rho effector mammalian diaphanous-related formin (mDia1).

Transient, lectin-like association of calreticulin with folding intermediates of cellular and viral glycoproteins.

The soluble, calcium-binding protein calreticulin shares high sequence homology with calnexin, a transmembrane chaperone of glycoprotein folding. Our experiments demonstrated that calreticulin, like calnexin, associated transiently with numerous newly synthesized proteins in the endoplasmic reticulum. The population of proteins that bound to calreticulin was partially overlapping with those that bound to calnexin. Hemagglutinin (HA) of influenza virus was shown to associate with both calreticulin and calnexin. Using HA as a model substrate, it was found that both calreticulin- and calnexin-bound HA corresponded primarily to incompletely disulfide-bonded folding intermediates and conformationally trapped forms. Binding of all substrates was oligosaccharide-dependent and required the trimming of glucose residues from asparagine-linked core glycans by glucosidases I and II. In vitro, alpha-mannosidase digestion of calreticulin-bound HA indicated that calreticulin was specific for monoglucosylated glycans. Thus, calreticulin appeared to be a lectin with similar oligosaccharide specificity as its membrane-bound homologue, calnexin. Both are therefore likely to play an important role in glycoprotein maturation and quality control in the endoplasmic reticulum.

Isolation of a mouse cDNA encoding Rab23, a small novel GTPase expressed predominantly in the brain.

The full-length cDNA encoding Rab23, a novel Ras-related small GTPase, was isolated using the sequence of a previously described [Chavrier et al., Gene 112 (1992) 261-264] short cDNA fragment and the rapid amplification of cDNA ends (RACE) PCR techniques. The deduced amino acid sequence was not very closely related to any previously described small GTPase, but was within the Rab subfamily. A Northern analysis revealed that the rab23 mRNA is predominantly expressed in the brain, which places the protein, together with Rab3a and Rab15, in the group of small GTPases characteristic of the nervous system.

Prolonged electrocardiographic monitoring in patients with syncope. Importance of frequent or repetitive ventricular ectopy.

The purposes of this study were to document the findings on prolonged electrocardiographic monitoring in patients with syncope, correlate these findings with symptoms during monitoring, and define the prognostic importance of these findings. A total of 235 patients with syncope in whom a cause was not assigned or suggested by the initial history, physical examination, and electrocardiography were studied. Although a variety of arrhythmias were documented during monitoring, the vast majority of arrhythmias were of short duration and did not produce symptoms. At two years, the patients with frequent or paired premature ventricular contractions (PVCs) when compared with patients with rare PVCs, had a higher incidence of sudden death (18.2 percent versus 4.0 percent; p less than 0.001) and higher overall mortality (28.3 percent versus 10.8 percent; p less than 0.003). Similarly, patients with ventricular tachycardia, when compared with patients with rare PVCs, had a higher incidence of sudden death (18.7 percent versus 4.0 percent; p less than 0.0001) and higher overall mortality (36.5 percent versus 10.8 percent; p less than 0.00001). Cox regression analyses revealed that frequent or repetitive PVCs and sinus pauses were independent electrocardiographic predictors of sudden death and mortality in patients presenting with syncope. Therefore, patients with syncope and frequent or repetitive ventricular ectopy or sinus pauses constitute a high-risk subgroup and may be candidates for more extensive diagnostic evaluation.

Copyrine alkaloids: synthesis, spectroscopic characterization, and antimycotic/antimycobacterial activity of A- and B-ring-functionalized sampangines.

Several A- and B-ring-substituted sampangines were synthesized and evaluated for antifungal and antimycobacterial activity against AIDS-related opportunistic infection pathogens. Electrophilic halogenation provided a channel for structural elaboration of the sampangine B-ring at position 4, while the synthesis of A-ring 3-substituted sampangines and benzo[4,5]sampangine (24) were achieved from the corresponding functionalized cleistopholines. Two-dimensional NMR spectroscopy was used to rigorously characterize the A- and B-ring substituent patterns. Structure-activity relationship studies revealed the activity of the sampangines was enhanced by the presence of a substituent at position 3 or by a 4,5-benzo group.

Consumer acceptance of prepaid and fee-for-service medical care: results from a randomized controlled trial.

Do consumers find the care provided by health maintenance organizations (HMOs) and that provided in the fee-for-service (FFS) system equally acceptable? To address this question, we randomly assigned 1,537 people ages 17 to 61 either to FFS insurance plans that allowed choice of physicians or to a well-established HMO. We also studied 486 people who had already selected the HMO (control group). Those who had chosen the HMO were as satisfied overall with medical care providers and services as their FFS counterparts. The typical person assigned to the HMO, however, was significantly less satisfied overall relative to FFS participants. Attitudes toward specific features of care favored both FFS and HMO, depending on the feature rated. Four differences (length of appointment waits, parking arrangements, availability of hospitals, and continuity of care) favored FFS; two (length of office waits, costs of care) favored the HMO. HMO versus FFS differences in ratings of access to care and availability of resources mirror differences in the organizational features of these two systems that are generally considered responsible for the significantly lower medical expenditures at HMOs. Regardless of their origin, less favorable attitudes toward interpersonal and technical quality of care in the HMO have marked consequences: dissatisfaction and disenrollment.

Antimicrobial properties of alkaloids from Xanthorhiza simplicissima.

The organic extract of the whole plant Xanthorhiza simplicissima was found to exhibit good activity against the AIDS-related opportunistic pathogens Candida albicans, Cryptococcus neoformans, and Mycobacterium intracellularae. Bioassay-directed fractionation of the extract led to the isolation of the known alkaloid berberine as the major active component. A second alkaloid of the isohomoprotoberberine family, puntarenine, was isolated from this plant family for the first time. Puntarenine also showed marginal activity against the dermatophytic fungus Trichophyton mentagrophytes and the yeast Saccharomyces cerevisiae.

Novel sample container for solution calorimetry.

A new design for calorimeter sample containers is described. The basic design is a hollow right cylinder with thin, glass membranes covering both ends. The membranes are intended to be broken out completely to release the sample contained within. The membranes are sealed to the container body with silicone rubber. The sample containers are easily fabricated, have highly reproducible volumes, and are surprisingly durable. Even though the membranes are fragile, the design permits considerable handling of the container with impunity.

Time-intensity trading in the late auditory evoked potential.

The present study investigated physiological correlates of the time-intensity trading relationship in late components (N1, P2) of the auditory evoked potential. Late-potential and behavioral thresholds were estimated in five normal-hearing, young adult participants for 1000- and 4000-Hz tone bursts having durations of 8, 16, 32, 64, and 128 ms. The results showed that late-potential thresholds decreased by an average of 24 dB for 1000-Hz conditions and 18 dB for 4000-Hz conditions. Behavioral thresholds also improved by about 22 dB and 18 dB for 1000-Hz and 4000-Hz conditions, respectively. The slope of improvement for both late-potential and behavioral thresholds was on the order of -4 to -6 dB per doubling of stimulus duration, depending on stimulus frequency. Stimulus duration also influenced latency and amplitude measures of the N1 and P2 components such that response latency decreased and amplitude increased as stimulus duration increased. The present results demonstrate a time-intensity trading relationship in components of the late potentials that is consistent with previous psychophysical and physiological data.

Intra-articular ganglion cyst arising from the anterior cruciate ligament: a case report.

Intra-articular ganglion cysts have been reported in the medical literature but are extremely rare. A MEDLINE search from 1966 to July 1995 revealed no reported cases in the Physical Medicine literature. This case report details the presentation, evaluation and treatment course of a patient with knee complaints who was subsequently diagnosed to have a ganglion cyst arising from the anterior cruciate ligament. The patient was a 38-year-old woman with a 6-month history of knee swelling and pain. She had difficulty walking. Non-steroidal anti-inflammatory agents had not alleviated her symptoms significantly. Physiatric evaluation revealed a supra-patellar effusion and a mass lateral to the patellar tendon. MRI evaluation revealed an intra-articular cyst. The patient underwent surgical removal of what was subsequently determined to be an intra-articular ganglion cyst arising from the anterior cruciate ligament. The patient has had progressive resolution of her knee symptoms post-operatively. Physiatrists need to be aware of this cause of mechanical knee symptoms.

Acupuncture in the 1990s. A review for the primary care physician.

The purpose of this article is to educate primary care providers regarding the theory and basic principles of acupuncture. Various indications for acupuncture are discussed. It is hoped that this article will allow the primary care practitioner to correctly identify patients in his or her practice who might benefit from acupuncture treatment.

Fever, bacteriuria, and pyuria in spinal cord injured patients with indwelling urethral catheters.

Little is known about the significance of pyuria in spinal cord injury patients with indwelling urethral catheters (IUCs). The hospital courses of 32 such patients admitted to a rehabilitation hospital from January 1986 to December 1987 were reviewed to determine the incidence of unexplained febrile episodes, ie, no obvious nonurinary source of infection. All patients had positive admission urine cultures (greater than 100,000 colony-forming units/mL). Patients were divided into two groups based on the level of pyuria in admission urinalyses. Group A (the low pyuria group) was composed of 22 patients with less than or equal to 50 white blood cells per high-power field (WBC/HPF). Group B (the high pyuria group) was composed of ten patients with less than 50 WBC/HPF. None were admitted to the rehabilitation program taking antibiotics; none were prophylactically treated for urinary tract infection. The difference in incidence of fever between febrile episodes. Group B had an incidence of 6/10 (60%) febrile episodes. The difference in incidence of fever between the groups was statistically significant (chi2 = 7.31, p less than .01). These results suggest that SCI patients with IUCs and gross pyuria may be at risk for increased morbidity secondary untreated urinary tract infection.

A signal-processing system for real-time ultrasonic measurement of urine flow parameters.

An application of a signal-processing system to the urethra is described which allows for real-time measurement of the average velocity of the urine at a particular location along the urethra during voiding through measurement of the average frequency in ultrasonic return from scatterers in the flowing urine. In addition, this comparatively simple system provides, without additional instrumentation, the relative urethral cross-sectional area at this location and the relative urine flow rate as functions of time throughout the voiding period. Tests indicate its potential as a valuable transcutaneous diagnostic aid in the detection, study, and treatment of various disorders and diseases of the lower urinary system. The key element of the system is a circuit having a voltage transfer function magnitude proportional to the square root frequency.

In vitro reconstitution of calreticulin-substrate interactions.

Calreticulin is a soluble, endoplasmic reticulum-resident protein and a molecular chaperone for glycoproteins. We have reconstituted the binding of recombinant calreticulin to two glycoprotein substrates, vesicular stomatitis virus G protein and influenza hemagglutinin, in vitro. The binding was found to be direct and to require monoglucosylated, asparagine-linked oligosaccharides on the substrate glycoprotein but no other cellular factors. The binding could be modulated in vitro by incubation of substrate with purified preparations of the glycan modifying enzymes glucosidase II and the UDP-glucose:glycoprotein glucosyltransferase, thus recapitulating the regulation of calreticulin-binding by glycan modification that occurs in vivo. Using the purified ER enzymes and the recombinant calreticulin, an assay was established for reconstituting a complex, multicomponent chaperone binding cycle in vitro. We demonstrated, moreover, that the acidic C-terminal 62 residues of calreticulin are dispensable for substrate binding whereas further deletions inhibit substrate binding.

Micturition syncope. A reappraisal.

We prospectively studied 33 patients with micturition syncope. Of these, eight were young (mean age, 25 years), healthy individuals whose diagnostic evaluation gave normal findings. The remaining 25 patients were older (mean age, 60 years), and 16 were women. This group had an average of 3.8 acute and chronic illnesses per patient, and was taking 3.5 medications per patient. Physical examination disclosed orthostatic hypotension in 22 of these 25 patients. Therapy was directed at improving orthostasis. Over a mean of 15.3 months, no recurrent micturition syncope or sudden death occurred in the entire group. We conclude that there are two groups of patients with micturition syncope. A group consisting of young healthy men has been well described previously. Our larger group, however, consisted of older patients, more often women with multiple illnesses and the majority having orthostatic hypotension.

Platelet activating factor antagonist design: structure of methyl trans-5-(3,4-dimethoxyphenyl)-2,3,4,5-tetrahydro-2-oxo-4- furancarboxylate.

C14H16O6, Mr = 280.28, monoclinic, P2(1)/c, a = 6.070 (2), b = 9.526 (5), c = 22.418 (5) A, beta = 94.32 (2) degrees, V = 1293 A3, Z = 4, Dx = 1.44 g cm-3, lambda(Mo K alpha) = 0.71073 A, mu = 0.71 cm-1, F(000) = 592, T = 293 K, final R = 0.043 for 1400 observed [F0 greater than or equal to 5 sigma(F0)] reflections. The observed structure confirms a trans stereorelationship for the two substituents and an envelope conformation for the lactone ring. There is no crystallographically imposed symmetry. An analysis of the closest contacts in the cell lattice reveals two types of intermolecular interactions for this compound.

Platelet activating factor antagonist design. 2. X-ray structure of dimethyl 2,3,4,5-tetrahydro-5 beta-(3,4-methylenedioxyphenyl)-2-oxo-3 beta-(3,4,5-trimethoxybenzoyl)-3 alpha,4 alpha-furandicarboxylate.

C25H24O12, Mr = 516.46, triclinic, P-1, a = 8.780 (3), b = 11.298 (4), c = 13.271 (6) A, alpha = 71.77 (4), beta = 70.31 (3), gamma = 72.66 (3) degrees, V = 1189 A3, Z = 2, Dx = 1.44 g cm-3, lambda (Mo K alpha) = 0.71073 A, mu = 0.74 cm-1, F(000) = 540, T = 293 K, final R = 0.046 for 2495 observed [Fo greater than or equal to 5 sigma (Fo)] reflections. The observed structure reveals a trans disposition for the methoxycarbonyl and aryl substituents at positions 4 and 5 of the heterocycle and a cis-3,4-bis(methoxycarbonyl) relationship. There is no crystallographically imposed symmetry. Several intermolecular van der Waals interactions occur in the cell lattice of this compound.