Traumatic alterations in GABA signaling disrupt hippocampal network activity in the developing brain

Severe head trauma causes widespread neuronal shear injuries and acute seizures. Shearing of neural processes might contribute to seizures by disrupting the transmembrane ion gradients that subserve normal synaptic signaling. To test this possibility, we investigated changes in intracellular chloride concentration ([Cl(-)](i)) associated with the widespread neural shear injury induced during preparation of acute brain slices. In hippocampal slices and intact hippocampal preparations from immature CLM-1 mice, increases in [Cl(-)](i) correlated with disruption of neural processes and biomarkers of cell injury. Traumatized neurons with higher [Cl(-)](i) demonstrated excitatory GABA signaling, remained synaptically active, and facilitated network activity as assayed by the frequency of extracellular action potentials and spontaneous network-driven oscillations. These data support a more inhibitory role for GABA in the unperturbed immature brain, demonstrate the utility of the acute brain slice preparation for the study of the consequences of trauma, and provide potential mechanisms for both GABA-mediated excitatory network events in the slice preparation and early post-traumatic seizures.     

Enhancement of Y5−xPrxSb3−yMy (M = Sn,Pb) Electrodes for Lithium- and Sodium-Ion Batteries by Structure Disordering and CNTs Additives

The maximally disordered (MD) phases with the general formula Y_5−xPr_xSb_3−yM_y (M = Sn, Pb) are formed with partial substitution of Y by Pr and Sb by Sn or Pb in the binary Y₅Sb₃ compound. During the electrochemical lithiation and sodiation, the formation of Y_5-xPr_xSb_3-yM_yLi_z and Y_5−xPr_xSb_3−yM_yNa_z maximally disordered–high entropy intermetallic phases (MD-HEIP), as the result of insertion of Li/Na into octahedral voids, were observed. Carbon nanotubes (CNT) are an effective additive to improve the cycle stability of the Y_5−xPr_xSb_3−yM_y (M = Sn, Pb) anodes for lithium-ion (LIBs) and sodium-ion batteries (SIBs). Modification of Y_5−xPr_xSb_3−ySn_y alloys by carbon nanotubes allowed us to significantly increase the discharge capacity of both types of batteries, which reaches 280 mAh · g⁻¹ (for LIBs) and 160 mAh · g⁻¹ (for SIBs), respectively. For Y_5−xPrxSb_3−yPb_y alloys in which antimony is replaced by lead, these capacities are slightly smaller and are 270 mAh · g⁻¹ (for LIBs) and 155 mAh · g⁻¹ (for SIBs), respectively. Results show that structure disordering and CNT additives could increase the electrode capacities up to 30% for LIBs and up to 25% for SIBs.     

Internal Kinematics of the Tongue During Feeding in Pigs

Six ultrasonic crystals (Ø2 mm) were implanted into the tongue body to form a wedge‐shaped configuration in six 12‐week‐old Yucatan minipigs. These crystals allow recording of the distance changes in bilateral lengths (RL/LL) and base thicknesses (RT/LT), and anterior (AW) and posterior (dorsal and ventral, PDW and PVW) widths during natural feeding. Results indicated that changes in all measured dimensions were stereotypical with considerable regularity. The greatest dimensional changes during chewing were seen in the AW (33.3%), significantly larger than those in other dimensions (P < 0.05–0.001). During ingestion, change in all widths and thicknesses reduced significantly compared with those during chewing (P < 0.05), but changes in the lengths (RL/LL) were significantly larger than those during chewing (P < 0.01). During drinking, overall dimensional changes reduced and amplitudes were symmetrically distributed in all dimensions. The timing analysis indicated that, during chewing, the reversal of dimensional decrease to increase in the PVW occurred first, followed by those of PDW, AW, RT/LT, and RL/LL (P < 0.05). During ingestion, the AW started widening first. Time sequence of these reversals during drinking was similar to that during chewing, but RT/LT thickening was behind RL/LL lengthening. These results suggested that during natural feeding, regional tongue deformations are rhythmic and stereotypical similar to jaw movement. The reversals of expansion–contraction of various dimensions are not synchronous, but occur in a sequential manner in timing. Tongue internal deformations are task‐specific in both timing and amplitude. The dimensional expansions–contractions are dominant in the transverse and sagittal planes during chewing and ingestion, respectively, but are smaller and more symmetrically distributed across various dimensions during drinking. Anat Rec, 290:1288‐1299, 2007. © 2007 Wiley‐Liss, Inc.     

Race and sex differences and contribution of height: a study on bone size in healthy Caucasians and Chinese.

Osteoporosis is characterized by a loss of bone strength, of which bone size (BS) is an important determinant. However, studies on the factors determining BS are relatively few. The present study evaluated the independent effects of height, age, weight, sex, and race on areal BS at the hip and spine, measured by dual-energy X-ray absorptiometry, while focusing on the differential contributions of height to BS across sex, race, and skeletal site. The subjects were aged 40 years or older, including 763 Chinese (384 males and 379 females) from Shanghai, People's Republic of China, and 424 Caucasians (188 males and 236 females) from Omaha, Nebraska. Basically, Caucasians had significantly larger BS than Chinese. After adjusting for height, age, and weight, the Chinese had similar spine BS, but significantly larger intertrochanter BS in both sexes and larger total hip BS in females compared with Caucasians. Males had significantly larger BS than females before and after adjustment in both ethnic groups. The effects of age, weight, and race varied, depending on skeletal site. As expected, height had major effects on BS variation in both sexes and races. Height tended to account for larger BS variation at the spine than at the hip (except for Chinese females), and larger BS variation in Caucasians than in Chinese of the same sex (except for the trochanter in females). We conclude that height is a major predictor for BS, and its contributions vary across sex, race, and skeletal site.     

Genetic Dissection of Human Stature in a Large Sample of Multiplex Pedigrees

Recently, we reported a whole genome scan on a sample of 630 Caucasian subjects from 53 human pedigrees. Several genomic regions were suggested to be linked to height. In an attempt to confirm the identified genomic regions, as well as to identify new genomic regions linked to height, we conducted a whole genome linkage study on an extended sample of 1,816 subjects from 79 pedigrees, which includes the 53 pedigrees containing the original 630 subjects from our previous whole genome study and an additional 128 new subjects, and 26 further pedigrees containing 1,058 subjects. Several regions achieved suggestive linkage signals, such as 9q22.32 [MLS (multipoint LOD score) = 2.74], 9q34.3 [MLS = 2.66], Xq24 [two‐point LOD score = 2.64 at the marker DXS8067], and 7p14.2 [MLS = 2.05]. The importance of the above regions is supported either by other whole genome studies or by candidate genes within these regions relevant to linear growth or pathogenesis of short stature. In addition, this study has tentatively confirmed the Xq24 region's linkage to height, as this region was also detected in the previous whole genome study. To date, our study has achieved the largest sample size in the field of genetic linkage studies of human height. Together with the findings of other studies, the current study has further delineated the genetic basis of human stature.     

Cl− flux through a non-selective, stretch-sensitive conductance influences the outer hair cell motor of the guinea-pig

Outer hair cells underlie high frequency cochlear amplification in mammals. Fast somatic motility can be driven by voltage-dependent conformational changes in the motor protein, prestin, which resides exclusively within lateral plasma membrane of the cell. Yet, how a voltage-driven motor could contribute to high frequency amplification, despite the low-pass membrane filter of the cell, remains an enigma. The recent identification of prestin's Cl⁻ sensitivity revealed an alternative mechanism in which intracellular Cl⁻ fluctuations near prestin could influence the motor. We report the existence of a stretch-sensitive conductance within the lateral membrane that passes anions and cations and is gated at acoustic rates. The resultant intracellular Cl⁻ oscillations near prestin may drive motor protein transitions, as evidenced by pronounced shifts in prestin's state-probability function along the voltage axis. The sensitivity of prestin's state probability to intracellular Cl⁻ levels betokens a more complicated role for Cl⁻ than a simple extrinsic voltage sensor. Instead, we suggest an allosteric modulation of prestin by Cl⁻ and other anions. Finally, we hypothesize that prestin sensitivity to anion flux through the mechanically activated lateral membrane can provide a driving force that circumvents the membrane's low-pass filter, thus permitting amplification at high acoustic frequencies.     

The effect of potassium dichromate on free radical processes in goldfish: possible protective role of glutathione

The effects of 96 h exposure to Cr(6+) (added as potassium dichromate) on the status of antioxidant defenses and markers of oxidative damage were evaluated in three tissues of goldfish, Carassius auratus. Fish exposure to high dichromate concentrations, 10 and 50mg/l, increased protein carbonyl levels in brain and liver, but not in kidney. Chromium exposure also increased concentrations of lipid peroxides in brain (at 5mg/l) and liver (10mg/l), but not in kidney. The concentrations of reduced glutathione (GSH) were higher in the liver of goldfish treated with 5-50mg/l Cr(6+) than in controls, but in kidney only the 5mg/l-treated group showed increased GSH levels. Dichromate at 1mg/l increased the concentration of oxidized glutathione (GSSG) in liver and kidney by 80% and 60%, respectively, whereas at 10 and 50mg/l the levels of GSSG decreased by 50% in kidney. These results indicate that the dichromate concentrations used induced oxidation of lipids and proteins in goldfish tissues in a concentration- and tissue-specific manner. Also, the redox status of fish tissues was affected in a concentration- and tissue-specific manner. The activities of glutathione reductase increased in all three tissues in response to dichromate treatment, increasing by approximately 2-fold in brain and liver in goldfish treated with 50mg/l Cr(6+). Dichromate treatment did not change the activities of SOD, catalase or GST in brain, but reduced the activities of SOD in liver and kidney, and catalase in liver. The results suggest that the glutathione system may be responsible for protecting against the deleterious effects of dichromate in fish and indicate the possible development of an adaptive response during the 96 h treatment with the toxicant.     

Targeting the viral nucleocapsid protein in anti-HIV-1 therapy

The nucleocapsid protein (NC) plays seminal roles in HIV replication, thus representing a major drug target. NC functions rely on its two zinc-fingers and flanking basic residues. Zinc ejectors inhibit NC functions, but with limited specificity. New classes of molecules competing with NC or its viral nucleic acid and enzyme partners are reviewed here.     

SUR1‐TRPM4 and AQP4 form a heteromultimeric complex that amplifies ion/water osmotic coupling and drives astrocyte swelling

Astrocyte swelling occurs after central nervous system injury and contributes to brain swelling, which can increase mortality. Mechanisms proffered to explain astrocyte swelling emphasize the importance of either aquaporin‐4 (AQP4), an astrocyte water channel, or of Na⁺‐permeable channels, which mediate cellular osmolyte influx. However, the spatio‐temporal functional interactions between AQP4 and Na⁺‐permeable channels that drive swelling are poorly understood. We hypothesized that astrocyte swelling after injury is linked to an interaction between AQP4 and Na⁺‐permeable channels that are newly upregulated. Here, using co‐immunoprecipitation and Förster resonance energy transfer, we report that AQP4 physically co‐assembles with the sulfonylurea receptor 1—transient receptor potential melastatin 4 (SUR1‐TRPM4) monovalent cation channel to form a novel heteromultimeric water/ion channel complex. In vitro cell‐swelling studies using calcein fluorescence imaging of COS‐7 cells expressing various combinations of AQP4, SUR1, and TRPM4 showed that the full tripartite complex, comprised of SUR1‐TRPM4‐AQP4, was required for fast, high‐capacity transmembrane water transport that drives cell swelling, with these findings corroborated in cultured primary astrocytes. In a murine model of brain edema involving cold‐injury to the cerebellum, we found that astrocytes newly upregulate SUR1‐TRPM4, that AQP4 co‐associates with SUR1‐TRPM4, and that genetic inactivation of the solute pore of the SUR1‐TRPM4‐AQP4 complex blocked in vivo astrocyte swelling measured by diolistic labeling, thereby corroborating our in vitro functional studies. Together, these findings demonstrate a novel molecular mechanism involving the SUR1‐TRPM4‐AQP4 complex to account for bulk water influx during astrocyte swelling. These findings have broad implications for the understanding and treatment of AQP4‐mediated pathological conditions.