D1 D5 Research Articles

Pathological response to preoperative concurrent chemo-radiotherapy for breast cancer: Results of a phase II study

This study evaluated, in terms of pathological complete response (pCR) and acute toxicity, preoperative concurrent (5-fluorouracil (5-FU)-vinorelbine) chemoradiotherapy for large breast cancers. A total of 60women were included in the study. Chemotherapy consisted of 4 cycles of 5-FU, 500mg/m2/d, continuous infusion (d1–d5) and vinorelbine, 25mg/m2 (d1; d6). Starting with the second cycle, radiotherapy delivered 50Gy to the breast and 46Gy to the internal mammary and supra/infra-clavicular lymph nodes. Breast surgery and axillary lymph node dissection were then performed. Four patients did not complete their chemotherapy. Breast conservation was possible in 69% of patients. The rate of pCR was 27%. Three factors were associated with pCR: histological grade 3, absence of hormonal receptors and high mitotic index. Grade 4 haematological toxicity occurred in 22% of patients. In conclusion, chemoradiotherapy demonstrated good efficacy, both in terms of pCR and in allowing breast conservation with acceptable tolerance.

NEUROMOTOR COORDINATION OF MULTISEGMENTAL MUSCLE DURING A CHANGE IN MOVEMENT DIRECTION

The aim of this investigation was to determine how the CNS controlled seven segments of the human deltoid muscle during a change in the direction of shoulder joint motion. Specifically, we wished to determine how the prime mover, synergist and antagonist muscle segments of this muscle were manipulated to assume new functional roles as the direction of shoulder motion was rapidly changed from shoulder abduction to shoulder adduction. Seven bipolar surface electrodes (7 mm inter-electrode distance) were placed over the seven segments (D1–D7) of the right deltoid, in seven young (19–24yrs) male subjects, to detect changes in muscle segment activation as the subjects transitioned from a rapid shoulder-abduction to a rapid-adduction force impulse (MT = 1000 ms). For each subject, fifteen trials were recorded at an inter-trial interval of 30 seconds. Comparisons of muscle segment timing and intensity of activation were made across 6 equal time intervals between just before the peak of the abduction force impulse and the subsequent peak of the adduction force impulse. The results of this study have shown that segments of the deltoid were activated during both the shoulder abduction and shoulder adduction motor task. In addition, the pattern of muscle segment activation (timing and intensity), during the transition from shoulder abduction to shoulder adduction, was dependent upon the muscle's moment arm and line of pull in relation to the axis of shoulder joint rotation. Three distinct patterns of neuromotor activation were noted within the segments of the deltoid muscle. During abduction the agonist prime mover and synergist segments (D1–D5) were totally deactivated (< 10% MVC) as they became antagonist segments during adduction. The antagonist segment (D7), during abduction, was deactivated and then reactivated as it became a synergist segment during adduction. Finally segment D6 was shown to have a nearly continuous period of activation. The study has shown that during a transition to a new movement direction, a muscle segment's line of pull and future function in the next phase of the movement appears to determine its period and intensity of activation.

Fuzzball geometries and higher derivative corrections for extremal holes

2-charge D1–D5 microstates are described by geometries which end in ‘caps’ near r = 0 ; these caps reflect infalling quanta back in finite time. We estimate the travel time for 3-charge geometries in 4D, and find agreement with the dual CFT. This agreement supports a picture of ‘caps’ for 3-charge geometries. We argue that higher derivative corrections to such geometries arise from string winding modes. We then observe that the ‘capped’ geometries have no non-contractible circles, so these corrections remain bounded everywhere and cannot create a horizon or singularity.

Impaired long-term habituation is dissociated from increased locomotor activity after sensorimotor cortex compression

Behavioural habituation to a novel environment is a simple form of learning in rodents. We studied the habituation and locomotor activity (LMA) of Wistar rats subjected to unilateral, transient (30 min) extradural compression (EC) of the right sensorimotor cortex. One group of rats was tested every 24 h during the first 5 days (D1–D5) post-EC. Two other groups were tested for the first time in the LMA boxes on D3 and D6 post-EC and their performance was compared with the group tested on D1 (activity in a novel environment). Total and center locomotion, vertical activity and time spent in the center of the LMA box were reduced on D1 post-EC and normalized by D2. The EC-induced motor paresis was undetectable on the rotarod by D2 and on the beam-walking by D3. Total locomotion, vertical activity and time spent in the center of EC-rats significantly increased from D1 to D3. EC caused neurodegeneration in the cortex, caudate putamen and thalamus as detected by Fluoro–Jade staining. The size of the cortical damage decreased from D2 to D5 in the medial and caudal regions of the compressed hemisphere, in accordance with recovery of motor function. LMA provided additional information in the follow-up of recovery from brain injury and habituation to the environment. Thus, long-term, inter-session habituation was impaired from D1 to D3 but dissociated from increased LMA intra-session on D3, when the motor deficits provoked by EC were already undetectable in the rotarod and beam-walking tests.

Massless black holes and black rings as effective geometries of the D1–D5 system

We compute correlation functions in the AdS3/CFT2 correspondence to study the emergence of effective spacetime geometries describing complex underlying microstates. The basic argument is that almost all microstates of fixed charges lie close to certain ‘typical’ configurations. These give a universal response to generic probes, which is captured by an emergent geometry. The details of the microstates can only be observed by atypical probes. We compute two-point functions in typical ground states of the Ramond sector of the D1–D5 CFT, and compare with bulk two-point functions computed in asymptotically AdS3 geometries. For large central charge (which leads to a good semiclassical limit), and sufficiently small time separation, a typical Ramond ground state of vanishing R-charge has the M = 0 BTZ black hole as its effective description. At large time separation this effective description breaks down. The CFT correlators we compute take over, and give a response whose details depend on the microstate. We also discuss typical states with nonzero R-charge, and argue that the effective geometry should be a singular black ring. Our results support the argument that a black hole geometry should be understood as an effective coarse-grained description that accurately describes the results of certain typical measurements, but breaks down in general.

Geometry of D1–D5–P bound states

Supersymmetric solutions of 6D supergravity (with two translation symmetries) can be written as a hyper-Kähler base times a 2D fiber. The subset of these solutions which correspond to true bound states of D1–D5–P charges give microstates of the 3-charge extremal black hole. To understand the characteristics shared by the bound states we decompose known bound state geometries into base–fiber form. The axial symmetry of the solutions make the base Gibbons–Hawking. We find the base to be actually ‘pseudo-hyper-Kähler’: The signature changes from ( 4 , 0 ) to ( 0 , 4 ) across a hypersurface. 2-charge D1–D5 geometries are characterized by a ‘central curve’ S 1 ; the analogue for 3-charge appears to be a hypersurface that for our metrics is an orbifold of S 1 × S 3 .

Microstates of the D1-D5–Kaluza-Klein monopole system

We find supergravity solutions corresponding to all $U(1)\ifmmode\times\else\texttimes\fi{}U(1)$ invariant chiral primaries of the D1-D5-KK system. These solutions are 1/8 BPS, carry angular momentum, and are asymptotically flat in the $3+1$ dimensional sense. They can be thought of as representing the ground states of the four-dimensional black hole constructed from the D1-D5-KK-P system. Demanding the absence of unphysical singularities in our solutions determines all free parameters, and gives precise agreement with the quantum numbers expected from the CFT point of view. The physical mechanism behind the smoothness of the solutions is that the D1 branes and D5 branes expand into a KK-monopole supertube in the transverse space of the original KK monopole.

Visualisation of the cortical dopamine D3 receptors in alcoholics and controls with human whole-hemisphere autoradiography

The dopaminergic system is critically involved in reward mechanisms mediating the reinforcing effects of ethanol (di Chiara and Imperato 1988). However, it has remained unclear if the alcohol-abuse-related dopaminergic deficit is specifically associated with a certain dopamine (DA) receptor subtype. One of these DA D1–D5 receptors (Hartman and Lanau 1997), the DA D3 receptor, is expressed primarily in the regions of the brain that are thought to influence cognitive, emotional and behavioural function (Sokoloff and Schwartz 1995). However, the role of the DA D3 receptor in alcoholics has been difficult to study because of its low abundance and the lack of selective ligands, and to our knowledge, there is only one published study on the issue (Tupala et al. 2003a). The aim of this study was to compare DA D3 receptors in the anterior cingulate and frontal and temporal cortices of nine type 1 alcoholics, eight type 2 alcoholics and ten healthy controls by using [H]PD 128907 as a radioligand in postmortem human whole-hemisphere autoradiography. The procedure has been previously described in detail (Tupala et al. 2003a). Type 1 alcoholics are characterised by late onset, social dependency and alternating binges and abstinence, whereas type 2 alcoholics are characterised by early onset with impulsive and antisocial behaviour (Cloninger 1995). [H]PD 128 907 [(+)-(4aR,10bR)-3,4,4a, 10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano-(4,3b)-1, 4-oxazin-9-ol] binds specifically with a high affinity to DA D3 receptors, with 18to 40-fold selectivity for DA D3 over D2 receptors (Pugsley et al. 1995), whereas the more commonly used older ligand [H]7-OH-DPAT has only 7to 24fold selectivity using different assay conditions (Gonzalez and Sibley 1995; Pugsley et al. 1995). In addition, because we have previously shown striatal DA transporter (DAT) binding to correlate between the mesolimbic nucleus accumbens (NAC) and dorsal striatum (caudate and putamen) and a similar phenomenon has been shown in one singlephoton emission tomography (SPET) study in type 1 alcoholics, but not in controls (Repo et al. 1999; Tupala et al. 2001), we also evaluated the correlations of [H]PD 128707 binding between the cortical and subcortical areas by comparing the present results with our earlier studies on the NAC and substantia nigra (SN) to test whether the relative individual levels of these receptors are maintained in different brain areas in these three groups. In addition, we compared the present results with our earlier findings on cortical DA D2 receptors with [ I]epidepride in these same subjects (Tupala et al. 2004). Our results show that, in spite of the very low densities, it is possible to visualise DA D3 receptors in cortical areas of human whole-hemisphere cryosections. The DA D3 receptors were at the same level in all groups (1.75–2.33± 0.42–0.81 fmol/mg, mean±SD) and no statistically significant differences were found. In addition, the calculated effect sizes (Cohen 1988) were also quite low, thus supporting the results. There was some tendency towards posE. Tupala (*) Department of Forensic Psychiatry, Niuvanniemi Hospital, University of Kuopio, 70240 Kuopio, Finland e-mail: erkki.tupala@niuva.fi Tel.: +358-44-5597317 Fax: +358-17-203494

Animators and animals: john halas, joy batchelor, and george orwell's Animal Farm

The brouhaha over the CIA's funding of a cultural Cold War against the Soviet Union has obscured various projects that benefited from the infusion of those dollars. Whatever the political rationale...

Dual Function for a Unique Site within the β2I Domain of Integrin αMβ2

Integrin activation has been postulated to occur in part via conformational changes in the I domain of the beta subunit (the betaI domain), especially near the F-alpha(7) loop, in response to "inside-out" signaling. However, direct evidence for a role of the F-alpha(7) loop in ligand binding and activity modulation is still lacking. Here, we report our finding that the F-alpha(7) loop (residues 344-358) within the beta(2)I domain has dual functions in ligand binding by alpha(M)beta(2). On the one hand, it supports intercellular adhesion molecule 1 (ICAM-1) binding to alpha(M)beta(2) directly as part of a recognition interface formed by five noncontiguous segments (Pro(192)-Glu(197), Asn(213)-Glu(220), Leu(225)-Leu(230), Ser(324)-Thr(329), and Glu(344)-Asp(348)) on the apex of the beta(2)I domain. On the other hand, it controls the open and closed conformation of the alpha(M)beta(2) receptor, thereby indirectly affecting alpha(M)beta(2) binding to other ligands. Switching the five constituent sequences of the ICAM-1-binding site within the beta(2)I domain to their beta(1) counterparts destroyed ICAM-1 binding but had no effect on the gross conformations of the receptor. Of the five ICAM-1 binding-defective mutants, four had normal or even stronger interaction with Fg and C3bi, as reported in our previous study. Synthetic peptides derived from the identified site inhibited alpha(M)beta(2)-ICAM-1 interaction and supported direct binding to ICAM-1. Most importantly, perturbation of the F-alpha(7) loop caused conformational changes within the beta(2)I domain, which was further propagated to other regions of alpha(M)beta(2). Altogether, our data demonstrate that inside-out signaling could modulate ligand binding directly by changing the ligand-binding pocket per se and/or indirectly by inducing multiple conformational changes within the receptor.

3-charge geometries and their CFT duals

We consider two families of D1–D5–P states and find their gravity duals. In each case the geometries are found to ‘cap off’ smoothly near r = 0 ; thus there are no horizons or closed timelike curves. These constructions support the general conjecture that the interior of black holes is nontrivial all the way up to the horizon.

Dual geometries for a set of 3-charge microstates

We construct a set of extremal D1–D5–P solutions, by taking appropriate limits in a known family of nonextremal 3-charge solutions. The extremal geometries turn out to be completely smooth, with no horizon and no singularity. The solutions have the right charges to be the duals of a family of CFT microstates which are obtained by spectral flow from the NS vacuum.

Gravitational waves in string theory in anti-de Sitter background

Inspired by the studies of gravitational waves in anti-de Sitter universe, in general relativity, in this Letter we investigate the possibility of similar solutions in IIB string theory on AdS3×S3×R4. We give a general form for such solutions in this background and present several explicit examples, by directly solving the field equations, as well as the ones obtained by taking a scaling limit on D1–D5 brane systems in a pp-wave background. The form of the metric in our solutions corresponds to a gravitational wave in AdS3. We show the supersymmetric nature of these solutions and discuss the possibility of their generalizations to other anti-de Sitter backgrounds, including the ones in four dimensions.

Memory Impairment Means Less Pain for Mice

Background: Clinical observations have reported that individuals with memory deterioration, like in Alzheimer’s disease, display a lesser pain sensibility than patients with no cognitive impairment. Objective: To clarify the link between pain and loss of memory, we studied how memory-impaired mice behave when submitted to hotplate nociceptive tests. Methods: For 5 days (D1–D5), male CD1 mice were injected daily intraperitonealy with saline or scopolamine (s, an anticholinergic drug, 0.2 mg/kg) or ketamine (k, an N-methyl-D-aspartate receptor antagonist (NMDAr), 2.5 mg/kg), at doses leading to memory impairment with no analgesic effect. From D6 to D9, all received saline only. They were placed on the hotplate and removed at the first sign of discomfort, response time being recorded. Results: From D1 to D5, reaction time decreased significantly in controls only and did not change in mice with scopolamine or ketamine. From D6 to D9, response times decreased (p < 0.05 (s) and p < 0.0001 (k)) to reach the steady state of control animals. At D5, response time was significantly prolonged for scopolamine (p < 0.01) and ketamine (p < 0.05), compared to controls. Conclusion: These results show that pain sensibility needs the integrity of the central cholinergic and of the NMDA systems, and that mice with memory impairment display a lesser pain sensibility than normal mice. Further research on the complex interactions of receptors and neurotransmitters involved in pain and cognition could assist in gaining a better understanding of pain and analgesia in patients with memory impairment and in demented individuals.

Constructing ‘hair’ for the three charge hole

It has been found that the states of the 2-charge extremal D1–D5 system are given by smooth geometries that have no singularity and no horizon individually, but a ‘horizon’ does arise after ‘coarse-graining’. To see how this concept extends to the 3-charge extremal system, we construct a perturbation on the D1–D5 geometry that carries one unit of momentum charge P. The perturbation is found to be regular everywhere and normalizable, so we conclude that at least this state of the 3-charge system behaves like the 2-charge states. The solution is constructed by matching (to several orders) solutions in the inner and outer regions of the geometry. We conjecture the general form of ‘hair’ expected for the 3-charge system, and the nature of the interior of black holes in general.

Distinct in vitro interaction pattern of dopamine receptor subtypes with adaptor proteins involved in post-endocytotic receptor targeting

The mechanisms underlying targeted sorting of endocytosed receptors for recycling to the plasma membrane or degradation in lysosomes are poorly understood. In this report, the C-terminal tails of the five dopamine receptors (D1–D5) were expressed as glutathione S-transferase (GST) fusion proteins and studied for their interaction with ezrin–radixin–moesin-binding phosphoprotein 50 (EBP50) and N-ethylmaleimide-sensitive factor (NSF), which are known to be involved in post-endocytic recycling of receptors back to the plasma membrane, and with sorting nexin 1 (SNX1), known to be involved in targeting receptors to lysosomal degradation. EBP50 did not bind any of the dopamine receptor tails. NSF bound strongly to D1 and D5 and only weakly to D2, D3 and D4. However, SNX1 clearly distinguished between D1 and D5, as only D5 bound strongly to this protein. This report shows that there are distinct interaction patterns for NSF and SNX1 to the various dopamine receptor subtypes.

Tachyon condensation and ‘bounce’ in the D1–D5 system

We construct supergravity solutions dual to microstates of the D1–D3–D5 system with nonzero B field moduli. Just like the D1–D5 solutions in [ hep-th/0109154] these solutions are generically nonsingular everywhere, with the ‘throat’ closing smoothly near r=0. We write expressions relating the asymptotic supergravity fields to the integral brane charges. We study the infall of a D1 brane down the throat of the geometries. This test brane ‘bounces’ off the smooth end for generic initial conditions. The details of the bounce depend on both the choice of D1–D3–D5 microstate and the direction of approach of the infalling D1 brane. In the dual field theory description we see that the tachyon mode starts to condense, but the tachyon bounces back up the potential hill without reaching the deepest point of the potential.

Reply to Discussion on ?Dissolution channels in quartz and the role of pressure changes in gold and sulfide deposition in the Archean, greenstone-hosted, Hutti gold deposit, Karnataka, India? by Kolb J, Rogers A and Meyer FM

The discussion on our paper (Pandalai et al. 2003) by Kolb et al. (2003, DOI 10.1007/s00126-002-0345-9) raises important issues related to the genesis of the Hutti gold deposit. The main points raised by Kolb et al. (2003) relate to the estimation of P and T of ore formation and the chronological (and genetic) order of vein formation in the shear zones at Hutti as identified by them. Rogers et al. (2002) and Kolb et al. (2003) recognize five stages of deformation (D1–D5), one prograde (M1) and two retrograde (M2, M3) stages of metamorphism, and four stages of quartz vein formation with attendant alteration. Rogers et al. (2002) and Kolb et al. (2001, 2003) do not refer to previously published literature on structural studies of the Hutti–Maski schist belt. Nevertheless, the deformational stages identified by Kolb et al. (2003) need to be placed in the framework of the regional tectonic history of the Hutti–Maski belt. Structural studies on this belt are reported in Roy (1979, 1991) and Biswas (1990). These studies identify three phases of deformation and metamorphism that are codified here as D1 , D2 , D3 * and M1 , M2 * , M3 * respectively to distinguish them from those of Kolb et al. (2003). A brief summary of the structural framework is given below before discussing the points raised in Kolb et al. (2003). The first deformational stage (D1 ) led to the development of tight isoclinal (F1 ) folds, penetrative schistosity (S1 ), synchronous prograde metamorphism (M1 ) and syntectonic emplacement of tonalite and tronjhemite around the Hutti–Maski belt. Additionally, mylonite and mylonitic foliation (Sm ) developed in narrow shear zones. On account of the parallelism of Sm * with S1 * it is inferred that they developed during the phase of D1 * deformation. The prograde M1 * phase of metamorphism is low grade (greenschist facies), but rises to medium grade (amphibolite facies) with development of garnet and cordierite in the north-eastern peripheral zone of the greenstone belt. The D2 * deformation stage gave rise to small and large-scale (F2 ) folds with subvertical axial planes (S2 ) and axes that plunge 50 to 60 NW. F2 folds bring F1 isoclinal folds into parallelism with F2 * limbs and are responsible for the map pattern of the exposed rocks. S2 *

Differential deletions in 3p are associated with the development of head and neck squamous cell carcinoma in Indian patients

In this study we performed detailed deletion mapping of two broad regions in the short arm (p) of chromosome 3 (i.e., 3p21.2∼p22 and 3p12∼p13), which were shown to have a high rate of deletions in head and neck lesions in our previous study. Using 18 highly polymorphic microsatellite markers, the deletion mapping was done in 35 dysplastic lesions and 46 primary head and neck squamous cell carcinoma (HNSCC) samples from Indian patients. Within the 21.6-megabase (Mb) region of 3p21.1∼p21.33, we have identified four areas (D1, 3p21.33; D2, 3p21.32; D3, 3p21.31; D4, 3p21.1) that showed a high frequency (46%–69%) of deletions in our samples. In the 3p12∼p13 region, we narrowed down the deletion within the 0.7-Mb region (D5, 3p12.1). Among these five regions (D1–D5), deletion in D3 is suggested to be necessary for the development of early dysplastic lesions, whereas the deletion in D2 may be necessary for dysplastic lesions and tumor progression. On the other hand, the deletion in D5 is significantly associated with progression of the lesions from mild/moderate to severe dysplasia. The deletions in D1 and D4, however, are required for tumor progression. As in our previous study, microsatellite size alterations (MA) were observed to be high in and around the highly deleted regions and gradually increased during the progression of the tumor. Loss of normal copy/interstitial alterations of chromosome 3 in the late stages of the tumor as well as rare biallelic alterations around the highly deleted regions also were seen in our samples. Human papilloma virus infection has been found to be associated with the deletion in the D5 region and MA in the D1 region, whereas nodal involvement of the tumor correlated only with the MA in D1 and D5. Thus, this study indicates that multiple tumor suppressor genes whose differential deletions are associated with the development of HNSCC may be present in 3p.

Spinning deformations of the D1–D5 system and a geometric resolution of closed timelike curves

The SO(4) isometry of the extreme Reissner–Nordstrom black hole of N=1 , D=5 supergravity can be partly broken, without breaking any supersymmetry, in two different ways. The “right” solution is a rotating black hole (BMPV); the “left” is interpreted as a black hole in a Gödel universe (GBH). In ten dimensions, both spacetimes are described by deformations of the D1–D5-pp-wave system with the property that the non-trivial closed timelike curves (CTC's) of the five-dimensional manifold are absent in the universal covering space of the ten-dimensional manifold. In the decoupling limit, the BMPV deformation is normalizable. It corresponds to the vev of an IR relevant operator of dimension Δ=1. The Gödel deformation is sub-leading in α′ unless we take an infinite vorticity limit; in such case it is a non-normalizable perturbation. It corresponds to the insertion of a vector operator of dimension Δ=5. Thus we conclude that from the dual (1+1)-CFT viewpoint the SO(4) R-symmetry is broken ‘spontaneously’ in the BMPV case and explicitly in the Gödel case.