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Pedro Leesander Rodríguez (Puerto Rico, 22 de enero de 1976), conocido como Sandy NLB (se lee "en el Bi")  fue un productor musical que se especializó en el ámbito de la música cristiana, trabajando mayormente para Manny Montes, Goyo, Bengie y otros artistas desde su sello Aldy's Studio, que tenía un lema "todo lo que sale de aquí, sale bueno" y se hizo muy popular al final de la década del 2000. A inicios de 2012, se complicó su salud, y el día 27 de enero se anunció su partida física por las redes sociales.

Historia
Sandy NLB comenzó su carrera como productor junto a Manny Montes en el año 2003 para el álbum United Kingdom. Produjo musicalmente para Funky, Manny Montes, Redimi2, Alex Zurdo, Bengie, Goyo, Luis Joel, Erick Daulet, entre otros.

Apareció en producciones importantes distribuidas por Machete Music, como Linaje Escogido de All Star Records y La iglesia de la calle de Gerardo Mejía, asimismo, produjo para Manny Montes en su participación en el álbum Chosen Few II de Boy Wonder.

Sandy apareció por primera vez como intérprete en un tema en el álbum De vuelta el Tonkka del Goyo en 2008 para la canción «Yo le creo a Él», sin embargo, acostumbraba a comentar algunas canciones o introducciones de los álbumes en que trabajaba, como Los Violentos, Letra con sentido de Soly y la saga «Calidad ambiental» de Goyo hasta la tercera entrega.

El 27 de enero de 2012, falleció a sus 36 años por problemas respiratorios, consecuencia de la condición de distrofia muscular con la cual luchó desde su infancia. Ese año, recibió un reconocimiento póstumo por parte de la Academia de la Música Cristiana desde la perspectiva Latina como Productor del año, compartiendo nominación con DJ Blaster, Lutek, entre otros, y nominado a los Premios Arpa en varias ocasiones por su trabajo como productor para Manny Montes en Los Inmortales y Nuevo comienzo.

En 2013, los raperos Bengie, Alex Zurdo, Ivan 2Filoz, Michael Pratts, Jun G, Micky Medina y Erick Daulet se unieron para un tema en conmemoración del productor llamada "No es adiós". Asimismo, Harold El Guerrero y el sello Da Worship lanzaron un proyecto que Sandy había comenzado en 2006 y no había sido publicado, llamado Los Guerreros.

Créditos de producción
Sandy llegó a producir en muchos álbumes donde participaban los artistas de Aldy's Studios, su sello discográfico.

Discografía

 2007: Manny Montes & Sandy NLB presentan Los Violentos
 2008: Sandy NLB presenta: Goyo - De Vuelta el Tonkka
 2008: JJ Musik & Sandy NLB presentan: Man Of Fire - Las Dos Caras
 2009: Manny Montes & Sandy NLB presentan: Los Violentos 2
 2013: Harold El Guerrero & Sandy NLB presentan: Los Guerreros (p.m.a)

Referencias

Arreglistas de Puerto Rico
Productores discográficos de Puerto Rico
Productores de reguetón

redpajama_set_name: RedPajamaWikipedia


TALLAHASSEE, Fla. (WCTV) -- When the college football season began, no one expected Florida A&M to compete for a MEAC title, yet alone turn in a winning record.
The expectation was the Rattlers found the right man for the job in Willie Simmons and it would take him a year or two to find success.
Surprise! That success is already on the Rattlers' doorstep.
FAMU sits in first place with a 4-0 conference record, needing just two more wins to clinch a MEAC title.
But, Simmons isn't taking the home-stretch lightly, saying the final four games are a playoff to the real postseason.
"Each game is important. We're in a playoff mindset that, if we want to achieve our goal of winning the conference championship, this is basically game one of a four-game playoff series," Simmons said. "We have to make sure we take car of business this week.
"We can't look down the road at who may be coming because, again, this team has shown that they're a very dangerous football team," Simmons continued.
The Rattlers close their 2018 season with matchups against Morgan State (10/27) and South Carolina State (11/10) and traveling to Howard (11/3) before the Florida Classic with Bethune-Cookman on 11/17.


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NXP Semiconductors Announces Assisted-GPS Chip
By Glen Gibbons
NXP Semiconductors launched its first assisted-GPS (A-GPS) chip, the GNS7560, targeting mobile phones and standalone personal navigation devices (PNDs) with the product's package size of less than nine square millimeters.
The February 4 announcement follows shortly after the January 23 closing of NXP's acquisition of GPS technology provider GloNav, Inc., by the Einhoven, The Netherlands–based company. The NXP GNS7560 is implemented on a 90-nanometer architecture and features a CMOS RF front end plus correlator engine with power management modes that reduce power consumption to less than 13mW for one-second updates, according to the company.
Reportedly, the OEM receiver is designed to automatically alter its sensitivity and tracking based on signal strength, multipath, and velocity. Host software for the product is structured to facilitate OS integration with Microsoft Windows CE, Windows Mobile, and Linux standard drivers, as well as a variety of real-time kernels in support of "smartphone" designs.
The single-chip GNS7560 is integrated with NXP's Nexperia UMTS/EDGE Cellular System Solution 7210, which supports multimedia applications and connectivity options for 2G and 3G mobile handsets. The Nexperia Cellular System Solution will be shown in NXP's booth (Hall 8, B110) at Mobile World Congress in Barcelona, Spain from February 11-14.
NXP says the standalone GNS7560 A-GPS chip is sampling now.
NXP/STMicroelectronics JV Launches
Atheros Launches GPS Receiver on a Chip
Navman Jupiter 32 GPS Chip
ESA Awards Contract for Network-Assisted PNT Assurance,…

redpajama_set_name: RedPajamaCommonCrawl


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Frontiers in Physiology
Cardiac Pacemaking in Health and Disease: From Genes to Function View all 9 Articles
Pietro Mesirca
INSERM U1191 Institut de Génomique Fonctionnelle (IGF), France
Elisabetta Cerbai
University of Florence, Italy
Wayne R. Giles
University of Calgary, Canada
Original Research ARTICLE
Front. Physiol., 09 November 2020 | https://doi.org/10.3389/fphys.2020.587040
Regulation of HCN2 Current by PI3K/Akt Signaling
Zhongju Lu1,2, Hong Zhan Wang1, Chris R. Gordon1,3, Lisa M. Ballou1, Richard Z. Lin1,4 and Ira S. Cohen1*
1Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY, United States
2Department of Medicine, Stony Brook University, Stony Brook, NY, United States
3Department of Nephrology, Stony Brook University, Stony Brook, NY, United States
4Medical Service, Northport VA Medical Center, Northport, NY, United States
It has long been known that heart rate is regulated by the autonomic nervous system. Recently, we demonstrated that the pacemaker current, If, is regulated by phosphoinositide 3-kinase (PI3K) signaling independently of the autonomic nervous system. Inhibition of PI3K in sinus node (SN) myocytes shifts the activation of If by almost 16 mV in the negative direction. If in the SN is predominantly mediated by two members of the HCN gene family, HCN4 and HCN1. Purkinje fibers also possess If and are an important secondary pacemaker in the heart. In contrast to the SN, they express HCN2 and HCN4, while ventricular myocytes, which do not normally pace, express HCN2 alone. In the current work, we investigated PI3K regulation of HCN2 expressed in HEK293 cells. Treatment with the PI3K inhibitor PI-103 caused a negative shift in the activation voltage and a dramatic reduction in the magnitude of the HCN2 current. Similar changes were also seen in cells treated with an inhibitor of the protein kinase Akt, a downstream effector of PI3K. The effects of PI-103 were reversed by perfusion of cells with phosphatidylinositol 3,4,5-trisphosphate (the second messenger produced by PI3K) or active Akt protein. We identified serine 861 in mouse HCN2 as a putative Akt phosphorylation site. Mutation of S861 to alanine mimicked the effects of Akt inhibition on voltage dependence and current magnitude. In addition, the Akt inhibitor had no effect on the mutant channel. These results suggest that Akt phosphorylation of mHCN2 S861 accounts for virtually all of the observed actions of PI3K signaling on the HCN2 current. Unexpectedly, Akt inhibition had no effect on If in SN myocytes. This result raises the possibility that diverse PI3K signaling pathways differentially regulate HCN-induced currents in different tissues, depending on the isoforms expressed.
The sinoatrial node (SN) initiates electrical activity in the heart that triggers the cardiac contractions responsible for circulation of the blood. This electrical activity includes action potentials associated with contraction and a period between action potentials called diastolic depolarization. The SN rate is dependent on both voltage-dependent ion channels (called the membrane voltage clock) and triggered release of intracellular Ca2+ (called the Ca2+ clock) (DiFrancesco, 1993; Lakatta et al., 2010). All of the elements necessary for this electrical event are intrinsic to the SN myocytes.
The membrane voltage clock includes a number of ion channels which generate net inward current during the diastolic interval, driving the SN toward the action potential threshold. One of these diastolic membrane currents is the pacemaker current, If. If is selective to Na+ and K+ and activates slowly on hyperpolarization (DiFrancesco, 1993). The cardiac pacemaker channels are comprised of heteromultimers of three members of the HCN gene family. HCN4 is the dominant isoform in rabbit SN myocytes (81% of the total HCN mRNA), while HCN1 (18%) and HCN2 (0.6%) are present at lower levels (Shi et al., 1999). By contrast, HCN2 is the predominant isoform in ventricular myocytes, and If in Purkinje fibers is mediated by HCN2 and HCN4 (Shi et al., 1999; Han et al., 2002).
An increase in If increases the SN pacing rate. The sympathetic nervous system increases heart rate in part by shifting the activation of If to more positive potentials, allowing greater activation during diastolic depolarization. The parasympathetic nervous system has the opposite effect on both heart rate and the voltage dependence of If (DiFrancesco, 1993). Although the details of this rapid sympathetic and parasympathetic regulation of heart rate and If have been studied in detail, little is known about other regulatory mechanisms that control intrinsic heart rate over longer time periods of time. One recent study pointed to a potential role for AMPK in this process (Yavari et al., 2017). Our own studies indicated that phosphoinositide 3-kinase (PI3K) regulates both SN rate and If independently of the autonomic nervous system (Lin et al., 2019).
Class I PI3Ks produce the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3]. The enzymes are heterodimers containing one of four distinct catalytic subunits bound to one of several regulatory subunits. PI3Ks in the Class IA subgroup can be activated by tyrosine kinases (TKs) via binding of the regulatory subunits to tyrosine-phosphorylated proteins. There are multiple downstream effectors of PI3K, including the protein kinase Akt (Ballou et al., 2015). We recently demonstrated that inhibition of PI3K by the pan PI3K isoform inhibitor PI-103 induced a slowing of sinus rate in situ and in vitro and a negative shift in activation of If in SN myocytes. There was no change in the whole cell conductance of If (Lin et al., 2019). This work built on a previous study which demonstrated that some TK inhibitors (TKIs) act through inhibition of PI3K signaling to induce an acquired long QT syndrome (Lu et al., 2012). PI3K inhibition caused alterations in a number of cardiac membrane currents, including a reduction in amplitude of INa, IKr, and IKs together with a reduction in ICaL and a positive shift in its activation. An increase in the persistent sodium current INaP was also observed (Lu et al., 2012). Earlier work showed that TKIs also caused a simple reduction in amplitude of If in SN myocytes (Wu and Cohen, 1997). However, the consequences of TK inhibition on heterologously expressed HCN isoforms varied widely, with no effect on HCN1, reduced amplitude and slowed activation kinetics of both HCN2 and HCN4, and a shift in the activation of HCN2 to more negative potentials (Yu et al., 2004). These differences in the effects of TK inhibition on different HCN isoforms, plus the fact that one of the downstream actions of TK inhibition can be a reduction in PI3K activity, induced us to study PI3K regulation of heterologously expressed HCN2, the dominant ventricular isoform (Shi et al., 1999).
Patch Clamp Recording of HCN2 Current Expressed in HEK293 Cells
We used a traditional whole-cell patch clamp (voltage-clamp) recording technique to examine HCN2 currents expressed in HEK293 cells. Experiments in Figures 1–3 employed a stable cell line expressing mouse HCN2 and GFP. The experiments in Figure 4 used HEK293 cells transiently transfected with GFP-mHCN2 constructs (see Section 2.2). Whole-cell patch clamp recording was performed using the Axopatch-1D amplifier coupled to the pCLAMP data acquisition and analysis software package (version 10, Axon Instruments, Inc). Patch electrode resistance was 4-6 MΩ and room temperature was 20 ± 1°C. The bath solution was (in mM): NaCl 140, KCl 5.4, MgCl2 1, CaCl2 1.8, HEPES 10, and glucose 10 (pH 7.4 with NaOH). The pipette solution contained: aspartate 130, KOH 146, NaCl 10, EGTA-KOH 5, CaCl2 2, Mg-ATP 2, and HEPES-KOH 10 (pH 7.2 with KOH) (Potapova et al., 2004). The voltage protocol to measure the HCN2 activation curve was to hold the cell at -30 mV and hyperpolarize for 1.5 s to voltages between −30 and −130 mV in 10-mV increments, followed by a 1-s voltage step to + 50 mV to record the tail currents, followed by a step back to −30 mV. The normalized plot of tail current versus test voltage was fit with a Boltzmann function, and then, the voltage at half maximum activation (V1/2) and slope factor (K) were calculated from the fit. Current densities are expressed as the value of the time-dependent component of current amplitude measured at the end of the test potential (-120 mV, 1.5-s duration) from a holding potential of -30 mV and normalized to cell membrane capacitance.
Figure 1. Effects of PI-103 and PI(3,4,5)P3 on If in HEK293 cells stably expressing mHCN2. (A) Traces of If activation in control cells or cells incubated for 2 h with 1 μM PI-103 or treated with PI-103 plus infusion of 1 μM PI(3,4,5)P3 in the patch pipette. Inset: Voltage clamp protocol for activating If (see text for details). (B) Boltzmann fit of 1-s isochronal activation curves for If shows that PI-103 negatively shifted the voltage at half-maximal activation and infusion of PI(3,4,5)P3 reversed the shifted midpoint to near the control level. (C) The mean time constants (tau) from a single exponential fit of If measured at –120 mV. (D) Summary data show a reduction of If amplitude by PI-103 which was reversed by PI(3,4,5)P3. If was measured at –120 mV from a holding potential of –30 mV. Numbers above the bars show the number of cells examined. **, P < 0.05.
Figure 2. Control phosphoinositides do not reverse PI-103 inhibition of mHCN2 current in HEK293 cells. (A) Original traces of PI-103-induced inhibition of mHCN2 current activation. Cells were incubated for 2 h at 37°C with 1 μM PI-103, with or without additional infusion of control phospholipid (1 μM) in the patch pipette solution. The voltage protocol for current activation is described in the text. (B) Activation curves from summarized data (left panel). The red curve is the fit to the PI-103 + PI(3,5)P2 data. Summarized data show If density in the presence of PI-103 was not increased by control phospholipids (right panel). Numbers above the bars indicate the number of cells examined.
Figure 3. Akt rescues the PI-103-induced inhibition of mHCN2 current in HEK293 cells. (A,B) Activation of mHCN2 currents. Cells were incubated for 2 h at 37°C with 10 μM Akt inhibitor (Akti) or 1 μM PI-103, or treated with PI-103 plus infusion of 20 nM active Akt1. The voltage protocol for current activation is described in the text. (C,D) Activation curves from summarized data. (E) Summarized data show a reduction of If density by the Akt inhibitor and rescue of the PI-103-induced reduction of mHCN2 current by Akt1. Numbers above the bars indicate the number of cells examined.
Figure 4. Effect of a putative Akt phosphorylation site on mHCN2-induced current. (A) Potential Akt phosphorylation sites in HCN proteins. Shown are two of the four subunits that form HCN channels and the position of serines in HCN1 (red), HCN2 (blue), and HCN4 (green) located within consensus sequences for Akt phosphorylation. The pore and S6 transmembrane segments are red and the cyclic nucleotide-binding domain (CNBD) is blue. (B,C) Mutation of serine 861 to alanine (S861A) in mHCN2 causes an inhibition of expressed current in HEK293 cells. (B) Upper panels, sample traces of activation of transiently expressed WT and mutant mHCN2. Note a more negative activation threshold (–80 mV in S861A vs. –60 mV for WT) and a reduced current density at voltages (–130 mV) with maximal current activation. Lower panel, activation curves for WT and S861A mHCN2 fit with the Boltzmann equation. The V1/2 values were -74.2 ± 0.4 mV (n = 10 cells, WT) and –88.6 ± 0.1 mV (n = 7 cells, S861A). The corresponding slope factors were 8.6 ± 0.4 mV and 9.2 ± 0.1 mV, respectively. The voltage protocol is described in the text. (C) Upper panels, sample traces of activation of transiently expressed WT and mutant mHCN2 in the presence of Akti (10 μM). Lower panel, activation curves for WT and S861A mHCN2 fit with the Boltzmann equation. Cells were incubated for 2 h at 37°C with Akti. The V1/2 values were -89.1 ± 0.3 mV (n = 7 cells, WT with Akti) and –86.5 ± 0.7 mV (n = 7 cells, S861A with Akti). The corresponding slope factors were 7.4 ± 0.3 mV and 10.0 ± 0.7 mV, respectively. Note that Akti caused an inhibition of expressed WT mHCN2 and a negative shift in voltage dependence but no further inhibition of the expressed mutant current.
Whole-Cell Patch Clamp Recording of If in Single SN Myocytes
Single SN myocytes were isolated from rabbit hearts as previously described (Lin et al., 2019). All animal-related procedures were approved by the Stony Brook University Institutional Animal Care and Use Committee. Electrophysiological measurements of If were performed at room temperature (20 ± 1°C). The external solution contained (in mM): NaCl 140, KCl 8, CaCl2 1.8, MgCl2 1.0, HEPES 5, glucose 10, MnCl2 2, CdCl2 0.2, and BaCl2 8 (pH adjusted to 7.4 with NaOH). The internal solution contained KCl 50, K-aspartate 80, MgCl2 1, EGTA 10, Mg-ATP 3, and HEPES 10 (pH 7.2). Mn2+ and Cd2+ were used to reduce Ca2+ currents, which can overlap with and obscure If tail currents. Ba2+ was used to block the background K+ current (IK1), which activates and inactivates in the same voltage range as If. The liquid junction potential (10 mV) between the electrode tip and cell interior was not corrected. The voltage-clamp protocol for If activation was to apply 1-s hyperpolarizing voltage steps ranging from -30 mV to -110 mV in -10-mV increments from a holding potential of -30 mV and then to apply a depolarizing step to + 50 mV for 0.5 s to record the tail currents, after which the preparation was stepped back to the holding potential. To generate the If activation curve, the normalized plot of tail current versus test voltage was fit with a Boltzmann function, and V1/2 and K were calculated from the fit.
Cell Treatments
PI(3,4,5)P3 or control phosphoinositides were diluted in internal solution to a final concentration of 1 μM and infused through the patch pipette. Where indicated, cells were pretreated with PI-103 (1 μM) or Akti (10 μM) for 2 h before patch clamping. HEK293 cells were treated with PI-103 or Akti at 37°C, and isolated SN cells were treated with Akti at room temperature.
When comparing different sets of data, statistical analysis was performed with either Student's t tests or ANOVA; significance was set to P ≤ 0.05. Results are given as mean ± SEM.
DNA Constructs
Mouse Hcn2 cDNA was subcloned into pEGFP-C1, and the putative mHCN2 Akt phosphorylation site mutant, S861A, was made by PCR. The 50 μl PCR reaction contained 1x Ultra AD buffer (Stratagene), 200 μM of each dNTP, 30 ng DNA template, 0.25 μM of each primer, 1.5 μl PfuUltra AD DNA polymerase (Stratagene), and 3% dimethylsulfoxide. The PCR program was: (1) 95°C for 1 min; (2) 95°C for 1 min; (3) 68°C for 1 min; (4) 72°C for 9 min; (5) 13x to step 2; (6) 72°C for 10 min; (7) hold at 4°C. The mutation was confirmed by sequencing both DNA strands. The primers (Eurofins Genomics) used for mutagenesis were 5′-CTCGCGCCTCTCTGCCAACTTGTGACC (forward) and 5′-GGTCACAAGTTGGCAGAGAGGCGCGAG (reverse). The constitutively active myristoylated Akt construct (Ballou et al., 2001) was subcloned into pcDNA3.1(−).
Western Blotting and Immunoprecipitation
HEK293 cells were transiently transfected with the appropriate constructs using TransIT-239 transfection reagent (Mirus Bio) and analyzed 2-3 days later. For western blotting, the cell layers were rinsed twice with PBS on ice and then scraped into a lysis buffer containing 50 mM HEPES, pH 7.5, 10 mM sodium pyrophosphate, 50 mM NaCl, 50 mM NaF, 5 mM EDTA, 0.1 mM sodium orthovanadate, 0.25% sodium deoxycholate, 1% IGEPAL CA-630, 200 μM phenylmethylsulfonyl fluoride, 1.7 μg/ml aprotinin and 2 μg/ml leupeptin. After strong vortexing, the lysates were centrifuged for 10 min at 4°C at 18,000 × g. Protein assays (Bio-Rad) were done on the supernatants, and equal amounts of protein were either directly subjected to SDS-PAGE or subjected to immunoprecipitation using GFP antibody. For immunoprecipitation, lysate supernatant was mixed with antibody and left on ice overnight, then protein G-agarose beads (Roche) were added. After rotating at 4°C for 2 h, the beads were washed 4 times with lysis buffer, boiled with SDS sample buffer, and subjected to SDS-PAGE. The proteins were transferred onto PVDF by semi-dry blotting, and signals were detected on film using horseradish peroxidase-linked secondary antibodies (GE Healthcare) and Western Lightning Plus ECL reagent (PerkinElmer). After signal detection, the blot was stripped at 50°C for 30 min in 62.5 mM Tris, 2% SDS, and 100 mM 2-mercaptoethanol, pH 6.7, reblocked in 5% non-fat dry milk in 20 mM Tris, 137 mM NaCl, and 0.1% Tween 20, pH 7.6, and probed with another antibody.
Reagents and Antibodies
Chemical agents employed in the studies include the pan-PI3K inhibitor PI-103 (Cayman Chemical), Akt inhibitor VIII (Akti; Millipore), and the diC8 phosphoinositides PI(3,4,5)P3, phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) and phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) from Echelon Biosciences. The antibodies used targeted GFP (Santa Cruz sc-9996), phospho-Ser/Thr Akt substrate sites (Cell Signaling 9614), Akt phospho-Thr308 (Cell Signaling 9275), or HCN2 (Abcam ab19346). Active recombinant Akt1 protein was from Millipore.
We began by investigating the effects of PI-103, which inhibits all four isoforms of class I PI3K, on mHCN2-induced currents. As indicated in Figure 1, exposure of cells expressing mHCN2 to PI-103 reduced the amplitude of the mHCN2-induced current (panel A) and shifted the voltage dependence of activation in the negative direction (panel B). The voltage at half-maximal activation (V1/2) was −78.9 ± 0.2 mV (control) versus −94.8 ± 0.4 mV (PI-103), a difference of 15.9 mV. These actions were prevented when PI(3,4,5)P3, the second messenger produced by PI3K, was present in the pipette solution (Figure 1). To confirm that this was a specific effect of the PI3K second messenger, we performed additional experiments with control phosphoinositides PI(3,5)P2 or PI(4,5)P2 in the pipette solution. The results are provided in Figure 2. Panel A shows the raw data. Neither PI(3,5)P2 nor PI(4,5)P2 prevented the actions of PI-103. Panel B shows an absence of effect of either control phospholipid on the voltage dependence of activation, as well as an absence of effect on the current amplitude at −120 mV, where activation is nearly complete and the current activates rapidly enough to reach steady state during the test pulse.
Next we examined which downstream elements in the PI3K signaling pathway might mediate the decrease in mHCN2-induced conductance and the shift in the voltage dependence of activation to more negative potentials. We began by examining the actions of an Akt inhibitor (Akti) on mHCN2-induced current. The results are provided in Figure 3. Panel A provides raw data which indicate that Akti produced virtually identical effects on the mHCN2-induced currents as PI-103. This result suggested that Akt acts downstream of PI3K to regulate mHCN2 channels. In support of this hypothesis, pipette perfusion of active Akt protein in cells pretreated with PI-103 completely reversed the inhibitory effects of PI-103 (panel B). Panel C illustrates that Akti caused a 15 mV negative shift in V1/2 as compared to the control, while panel D demonstrates that active Akt reversed the shift caused by PI-103. Finally, the effects of Akti alone or active Akt in the presence of PI-103 on mHCN2-induced current amplitude is provided in panel E. These results confirm that Akt functions downstream of PI3K to regulate the mHCN2-induced current.
It was possible that the actions of Akt were exerted through direct phosphorylation of the mHCN2 channel. We identified a number of potential Akt phosphorylation sites in HCN proteins, as illustrated in panel A of Figure 4. Interestingly, the sequence surrounding S861 at the C terminus of mHCN2 (RSRLSS861NL) is identical in human, dog and zebrafish, and similar highly conserved sequences are found at the C termini of HCN1 (KPRFAS908NL in mHCN1) and HCN4 (RSKLPS1199NL in mHCN4). To determine if Akt regulates mHCN2 by acting on S861, we made a non-phosphorylateable alanine mutation at this site. The S861A mHCN2 mutant recapitulated both the reduction in amplitude and negative shift in activation voltage dependence of the mHCN2-induced current caused by treatment of the wild-type channel with PI-103 or Akti (panel B). This result suggested that the mutation prevents Akt-mediated phosphorylation and regulation of the channel. Indeed, Akti had no effect on the S861A mHCN2 current (panel C). As indicated in panel A, S861 is located at the C terminus, close to the cAMP binding site.
We next attempted to confirm the importance of this phosphorylation site by western blotting. We immunoprecipitated GFP-mHCN2 from cell lysates and then probed western blots of the immunoprecipitated proteins with an antibody that recognizes phosphorylated Akt consensus sites (RXXS-P/T-P). Panel A of Figure 5 (upper blot) shows that expression of a constitutively active form of Akt (m-Akt) in cells stably expressing GFP-mHCN2 slightly increased the phosphorylation of the channel protein at these sites, whereas treatment with Akti abolished the signal. The middle blot demonstrates that similar amounts of GFP-mHCN2 protein were loaded in each lane, while the bottom blot demonstrates that phosphorylation (i.e., activation) of Akt and m-Akt was high in cells under control conditions, but nearly undetectable in cells treated with Akti. Panel B compares the response to Akti treatment of transiently transfected WT vs. S861A GFP-mHCN2. The upper blot shows that immunoprecipitates of cells transfected with empty vector contained a minimal level of protein containing phosphorylated Akt substrate sites, as expected. The strong signal for WT GFP-mHCN2 under control conditions was greatly reduced by Akti treatment, whereas S861A GFP-HCN2 did not appear to contain phosphorylated Akt substrate sites under either condition. The middle blot shows that the amount of channel protein was equivalent in the WT and S861A lanes, and the bottom blot shows that Akt was equally active in the WT and S861A cells and that Akti eliminated the activity of Akt. These results suggest that S861 may be the major Akt phosphorylation site in mHCN2. An alternative explanation is that mutation of S861 negatively affects Akt phosphorylation of another site.
Figure 5. Akt-mediated phosphorylation of GFP-mHCN2 protein. (A) HEK293 cells stably expressing GFP-HCN2 were transfected with vector (Con) or myristoylated Akt (m-Akt) and analyzed 2 days later or treated with 10 μM Akt inhibitor for 30 min. Cell lysates were subjected to immunoprecipitation with GFP antibody and the immunoprecipitated proteins were blotted for phospho-Ser/Thr Akt substrate sites (top) and HCN2 (middle). Cell lysates were analyzed with a phospho-Thr308 Akt antibody to assess the activation state of the enzyme (bottom). m-Akt migrates just above endogenous Akt. (B) Akt-mediated phosphorylation of GFP-HCN2 is abolished in the S861A mutant. HEK293 cells were transiently transfected with empty GFP vector (Vec), WT GFP-HCN2 or S861A GFP-HCN2. Two days later, the cells were treated with vehicle or 10 μM Akti for 1 h. Cell lysates were subjected to immunoprecipitation with GFP antibody, and the immunoprecipitated proteins were blotted for phospho-Ser/Thr Akt substrate sites (top) and GFP-HCN2 using HCN2 antibody (middle). The P-GFP-HCN2 signal comigrated with the upper band on the GFP-HCN2 blot. Cell lysates were analyzed with phospho-Thr308 Akt antibody to assess the activation state of the enzyme (bottom).
Given the dominant effect of PI3K/Akt signaling on the mHCN2 isoform, we next decided to investigate whether Akti exerts similar effects on If in rabbit SN myocytes. The results are provided in Figure 6. The raw currents in panel A indicate little or no effect of the inhibitor on If. This observation was confirmed by the absence of a shift in the voltage dependence of activation (panel B) or in the amplitude of the expressed current at −110 mV (panel C).
Figure 6. Effect of Akti on If in SN cells isolated from rabbit heart. (A) Traces of If activation in control cells (left panel) or cells incubated for 2 h with 10 μM Akti at room temperature (right panel). (B) Boltzmann fit of 1-s isochronal activation curves for If shows that Akti did not shift the voltage at half-maximal activation. The V1/2 values were -80.7 ± 0.7 mV (n = 10 cells, control) and –81.2 ± 1.1 mV (n = 7 cells, Akti). The corresponding slope factors were 10.7 ± 0.7 mV and 11.5 ± 0.9 mV, respectively. (C) Summary data show Akti did not affect If amplitude. If was measured at –110 mV from a holding potential of –30 mV.
Although there is a clear understanding of the mechanism by which SN rate responds to changes in demand via the autonomic nervous system, much less is known about the determinants of basal heart rate. Basal heart rate is important, as it decreases with age, and this decrease can result in simple bradycardia as well as sick sinus syndrome (Adán and Crown, 2003). Recently, it was reported that the protein kinase AMPK may play a role in regulating basal heart rate by affecting If and Ca2+ release in the SN (Yavari et al., 2017). We reported that PI3K signaling also affects basal heart rate (Lin et al., 2019). PI3K inhibition slowed the SN rate both in situ and in vitro and shifted the activation of If to more negative potentials. By contrast, artificially increasing PI3K signaling by addition of PI(3,4,5)P3 induced a positive shift in If. These shifts in voltage dependence were independent of and larger than those caused by autonomic agonists (Lin et al., 2019). A negative shift in the voltage dependence of If as well as a reduction in If magnitude have also been seen in mice with aging (Larson et al., 2013).
Proteins in the HCN family assemble as homotetramers or heterotetramers to form functional channels. We showed that heterologously expressed homotetramers of HCN1, HCN2 or HCN4 are differentially regulated by TKIs. The TKI genistein had no effect on HCN1, reduced the current magnitude of HCN4, and reduced the magnitude and caused a negative shift in the activation of HCN2 (Yu et al., 2004). Because TKs can activate PI3K signaling, we decided to investigate the effects of a PI3K inhibitor on HCN2 channels. Unlike HCN4 and HCN1, which are prominent in the SN, HCN2 plays a dominant role in ventricular myocytes. Similar to the results with genistein, we found that PI-103 reduced the amplitude and negatively shifted the activation of mHCN2 current. These effects were reversed by infusing PI(3,4,5)P3 in the pipette, but not PI(3,5)P2 or PI(4,5)2. Selective reversal by PI(3,4,5)P3 strongly suggests that the action of PI-103 is due to inhibition of PI3K. The positive effect of PI(4,5)P2 on HCN2 currents seen under some conditions (Pian et al., 2006) thus apparently cannot compensate for the loss of Akt-induced phosphorylation of HCN2 that we believe underlies the effect of PI-103.
Several pieces of evidence indicate that Akt acts downstream of PI3K to regulate HCN2. First, Akti and PI-103 had nearly identical effects on HCN2, reducing current magnitude and shifting its activation to more negative potentials. Second, an active form of Akt reversed the actions of PI-103. Third, mutation of a putative Akt phosphorylation site in mHCN2 to alanine mimicked the effects of PI-103 or Akti on current amplitude and voltage dependence. The mHCN2 S861A current was also insensitive to Akti. Finally, WT mHCN2 expressed in cells exhibited increased phosphorylation of Akt sites when coexpressed with an activated form of the enzyme and decreased phosphorylation in the presence of Akti. By contrast, mHCN2 S861A did not seem to contain phosphorylated Akt sites.
Given the similar effects of PI-103 on mHCN2 and If in SN myocytes (Lin et al., 2019), we decided to investigate whether Akt also regulates If. We were surprised to discover that there was no observable effect of Akti on rabbit SN If. One possible explanation for this result is that even though HCN4 and HCN1 in the SN contain possible Akt phosphorylation sites at their C termini as discussed above, these sites do not contribute to channel regulation by PI3K. Alternatively, a kinase distinct from Akt might be responsible for phosphorylating these sites in the SN. SGK1 is one likely candidate, as it is activated downstream of PI3K, phosphorylates the same optimal peptide sequence as Akt, and is insensitive to Akti (Logie et al., 2007; Di Cristofano, 2017). Further studies using heterologous expression systems and SN myocytes are needed to elucidate how PI3K regulates HCN4, HCN1 and If.
In conclusion, our experiments suggest that PI3K regulates homotetrameric mHCN2 channels through Akt-dependent phosphorylation of S861. A reduction in PI3K/Akt activity causes a negative shift in the voltage dependence of activation and a decrease in current magnitude. By contrast, PI3K regulation the HCN4/HCN1 heterotetrameric channels that mediate If in the SN seems to be mediated by an alternative signaling pathway that does not involve Akt. Thus, consistent with previous results reporting differential effects of TKIs on HCN isoforms (Yu et al., 2004), our results suggest that regulation of HCN channels by PI3K/Akt signaling is also isoform specific.
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Requests to access the datasets should be directed to IC.
The animal study was reviewed and approved by the IACUC Stony Brook University.
ZL and HW designed, performed, and analyzed the patch clamp experiments. CG designed, performed, and analyzed the biochemical experiments. LB made constructs, designed, performed, and analyzed the biochemical experiments, and co-wrote the manuscript. RL conceived of the project, analyzed the data, and co-wrote the manuscript. IC conceived the project, analyzed the data, oversaw the execution of the patch clamp experiments, and co-wrote the manuscript. All authors contributed to the article and approved the submitted version.
This project was funded by the National Institutes of Health (DK108989 to RL and HL126774 to IC). It was also funded by a Leducq Foundation award entitled "Fighting Against Sinus Node Dysfunction and Associated Arrthymias" to IC.
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.
Adán, V., and Crown, L. A. (2003). Diagnosis and treatment of sick sinus syndrome. Am. Fam. Physician 67, 1725–1732.
Ballou, L. M., Lin, R. Z., and Cohen, I. S. (2015). Control of cardiac repolarization by phosphoinositide 3-kinase signaling to ion channels. Circ. Res. 116, 127–137. doi: 10.1161/CIRCRESAHA.116.303975
Ballou, L. M., Tian, P. Y., Lin, H. Y., Jiang, Y. P., and Lin, R. Z. (2001). Dual regulation of glycogen synthase kinase-3beta by the alpha1A-adrenergic receptor. J. Biol. Chem. 276, 40910–40916. doi: 10.1074/jbc.M103480200
Di Cristofano, A. (2017). SGK1: the dark side of PI3K signaling. Curr. Top. Dev. Biol. 123, 49–71. doi: 10.1016/bs.ctdb.2016.11.006
DiFrancesco, D. (1993). Pacemaker mechanisms in cardiac tissue. Annu. Rev. Physiol. 55, 455–472. doi: 10.1146/annurev.ph.55.030193.002323
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Lin, R. Z., Lu, Z., Anyukhovsky, E. P., Jiang, Y. P., Wang, H. Z., Gao, J., et al. (2019). Regulation of heart rate and the pacemaker current by phosphoinositide 3-kinase signaling. J. Gen. Physiol. 151, 1051–1058. doi: 10.1085/jgp.201812293
Logie, L., Ruiz-Alcaraz, A. J., Keane, M., Woods, Y. L., Bain, J., Marquez, R., et al. (2007). Characterization of a protein kinase B inhibitor in vitro and in insulin-treated liver cells. Diabetes 56, 2218–2227. doi: 10.2337/db07-0343
Lu, Z., Wu, C. Y., Jiang, Y. P., Ballou, L. M., Clausen, C., Cohen, I. S., et al. (2012). Suppression of phosphoinositide 3-kinase signaling and alteration of multiple ion currents in drug-induced long QT syndrome. Sci. Transl. Med. 4:131ra50. doi: 10.1126/scitranslmed.3003623
Pian, P., Bucchi, A., Robinson, R. B., and Siegelbaum, S. A. (2006). Regulation of gating and rundown of HCN hyperpolarization-activated channels by exogenous and endogenous PIP2. J. Gen. Physiol. 128, 593–604. doi: 10.1085/jgp.200609648
Potapova, I., Plotnikov, A., Lu, Z., Danilo, P. Jr., Valiunas, V., Qu, J., et al. (2004). Human mesenchymal stem cells as a gene delivery system to create cardiac pacemakers. Circ. Res. 94, 952–959. doi: 10.1161/01.RES.0000123827.60210.72
Shi, W., Wymore, R., Yu, H., Wu, J., Wymore, R. T., Pan, Z., et al. (1999). Distribution and prevalence of hyperpolarization-activated cation channel (HCN) mRNA expression in cardiac tissues. Circ. Res. 85, e1–e6. doi: 10.1161/01.res.85.1.e1
Wu, J. Y., and Cohen, I. S. (1997). Tyrosine kinase inhibition reduces i(f) in rabbit sinoatrial node myocytes. Pflugers Arch. 434, 509–514. doi: 10.1007/s004240050430
Yavari, A., Bellahcene, M., Bucchi, A., Sirenko, S., Pinter, K., Herring, N., et al. (2017). Mammalian γ2 AMPK regulates intrinsic heart rate. Nat. Commun. 8:1258. doi: 10.1038/s41467-017-01342-5
Yu, H. G., Lu, Z., Pan, Z., and Cohen, I. S. (2004). Tyrosine kinase inhibition differentially regulates heterologously expressed HCN channels. Pflugers Arch. 447, 392–400. doi: 10.1007/s00424-003-1204-y
Keywords: HCN2, pacemaker current, PI3K, Akt, sinus node
Citation: Lu Z, Wang HZ, Gordon CR, Ballou LM, Lin RZ and Cohen IS (2020) Regulation of HCN2 Current by PI3K/Akt Signaling. Front. Physiol. 11:587040. doi: 10.3389/fphys.2020.587040
Published: 09 November 2020.
Pietro Mesirca, INSERM U1191 Institut de Génomique Fonctionnelle (IGF), France
Wayne Rodney Giles, University of Calgary, Canada
Elisabetta Cerbai, University of Florence, Italy
Copyright © 2020 Lu, Wang, Gordon, Ballou, Lin and Cohen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ira S. Cohen, ira.cohen@stonybrook.edu


Beyond the pledges, slogans and the 'dividends of democracy' rhetoric that have not dovetailed into reality, one striking issue is the apathy of voters during the elections. In practical terms, that the voter turnout was less than 36% of the 84,004,084 registered voters in the largely peaceful exercise did not detract from governance issues. That Nigerians of voting age were reluctant to vote was a clear attestation to the deep animosity and a growing sense of frightful disconnect between the political class and the masses. It showed how eerily cadaverous the electorate's morale and expectations have become. Apart from areas where the Independent National Electoral Commission (INEC) recorded over-voting, which was outright fraud, most of the polling areas recorded very low turnout of voters, even as quite a sizeable number of eligible voters opted to stay indoors for lack of better things to do.
Voter apathy is a product of many factors. For instance, a dose of rigging perception does more inestimable harm to the electorate's psyche than millions of campaign jingles or slogans. When the people hold the notion that whatever they do, rigging will still take place; or that some powers-that-be, somewhere, will still influence or manipulate the outcome of their franchise, the implications cannot but be grievous. The situation even becomes complicated if a government is perceived to be fraudulent or fraudulently installed. The possibility of being disobedient to such a flawed system cannot be ruled out.
Another area of our politics that must be critically looked into is alienation. It is a fact of life that, if the people are alienated from the programmes and policies of the government, it simply means that such a government is only planning for the people, not with the people. This, of course, negates the principle of democracy and development. Chances are therefore that such electorate will feel reluctant to vote.
not actually backed-up with the power of the people, it becomes a government that is not people-representational, even, if it goes on for 50 years. A cut-off government is empty and can falter anytime, which, in itself, is dangerous. Beyond the ceaseless elegance and captivating hymns of partisan concerns, Nigerians are hungry; and are angry; and may as such, become violent whenever 'opportunity' for it presents itself! The systemic decay is apparent, and the concomitant erosion of political capital of the country and socially-ascribed legitimacy, which for decades, has been taken for granted, or assumed as given, is gradually receding. It will therefore amount to political suicide on the part of our political leaders to task the people's tolerance by feigning ignorance of this ominous phenomenon!
Let us come back to Osun, a state not immune from the cancer called voter apathy. While I intend to dwell more on this sad side of our democracy in the coming days, to say that all is well with party politics in dear state is to fool oneself that voter apathy has something to do with specific instructions from different political parties. Well, one funny attribute of social action is that it has a life of its own; and once it is activated, it is difficult to be controlled. Yes! The outcome of the presidential election might have dampened the enthusiasm of the opposition who lost the election while the absence of gubernatorial contest in Osun might also have made the election less competitive, stress-, even, tension-free. Nevertheless, findings revealed a blatant expression of the people's reaction to the perception of the non-responsiveness of their political leaders – in and out of government – to their immediate and long-term plight.
Procrastination! Empty boast! Spirit of error! Attitude of the elite! Perfect plans without perfect actions! Cruel pragmatism! And a plethora of excuses! While Nigeria's political leadership needs self-appraisal, self-cleansing and a lot of refocusing, it is time the electorate's expectations were matched by government's delivery mechanisms. Politics must be inclusive, not divisive, or, non-exclusive! In a profound sense, there is always a threshold,or red line, which the modern state must never cross. In my considered view, it is not enough to call for Economic Summits. It is equally important that Political Summits are called, either by political parties or interested Civil Society Organizations (CSOs), to arrest this ugly trend before things become uglier! For a man to leave his home, hale and hearty, only to end up jumping into the lagoon is a lesson in season on how good it is to fight anti-corruption war and how equally important it is to take care of the human elements.
Please note, the opinion expressed in this article is of the writer and not necessarily of the Publisher!
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And because I'm now part of the wedding, I'm attending tonight's dress rehearsal.
I'm anxious. And not the antsy I-can't-wait type of excitement. It's more the I'm-actually-attending-this-alone kind of dread. For it's one thing to be comfortable with solitude and a whole 'nother to be comfortable being alone in a celebration of union. That's a level of strength and security I've yet to touch without feeling some tiny pang in my heart.
The reading another girl and I will do at tomorrow's ceremony will be the lyrics to Michael Bublé's "Everything." At first I thought I'd gag through it. But sitting here, listening to the song once again, I think it's going to take a lot to look out into the crowd, turn to the happy couple and not burst into tears.
I'm sure you will have a great time. And, as everyone knows, being somewhere without a date is a great opportunity to meet someone interesting...!
woohoo good luck ratona and have fun!
I mostly wanted to say that it's great that you're putting aside any feelings about going alone and are supporting your friend. I had a single friend that told me outright that she couldn't bring herself to celebrate with me because she didn't want to go alone. Our friendship was never the same after that.
I'm sure you'll have a better time than you think, but it's wonderful that you're being a good friend no matter how it goes.
Good luck, I am quite sure you'll do fabulously!
Good luck with it all! I hope it will be a great day!
For some reason I was hoping for a VLog of you doing that reading (and maybe some of you dancing afterwards)...but I guess that might of been a little... to much to ask for huh.


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PRTG: Helping a leading independent security analyst detect and prevent cryptojacking
Download as PDF File
Many believe that cryptocurrencies will serve as the financial underpinning of an increasingly global economy. Bitcoin is the most widely known, but there are hundreds of similar digital currencies or altcoins as they are sometimes called.
Monero, an open source cryptocurrency that was launched in 2014 is one. Anonymous and untraceable, it works much like small bills in a traditional open market. Other popular cryptocurrencies, or tokens, include Dash, Ethereum, Litecoin and Ripple - all of which provide a global standard that avoids the need for a centralized bank.
While numerous regulatory hurdles remain, the use of cryptocurrencies is increasing, spurred on in part by the fact that they enable faster transactions than more traditional means of finance. But the move to digital currency is not without challenges.
Blockchain, Cryptomining and the Crime of Cryptojacking
The underlying technology on which cryptocurrency is based is blockchain. With cryptography to ensure that privacy is maintained, blockchain acts as a public ledger - a public database spread across multiple computers. Every time a transaction or asset is sent to another member, a block of data is created. And because the block is shared with every member, but remains encrypted, the integrity of the transaction or the movement of the asset can't be tampered with. In other words, there's no way to "cook the books" because every member receives every block and in that way possesses the entire ledger.
Of course, the underlying cryptography and complex mathematical algorithms required to make this happen require massive computing power, such as when adding transactions to the blockchain or verifying them. Miners are the computers that complete these complex computations, and in payment for solving them first they receive newly created cryptocurrency. This cryptomining is the digital equivalent of the minting process.
Not surprisingly, cyber criminals are drawn to the money-making potential associated with mining – something Troy Mursch, an independent security researcher and creator of the Bad Packets Report, a website devoted to research on cryptojacking, botnets and other security topics, knows all too well. Mursch is not only the leading researcher on cryptojacking malware, but is also one of the most experienced professionals when it comes to helping companies, including numerous small and medium-sized businesses, detect and combat cyber threats like cryptojacking. Few people know more about the impact it can have on infected computers and mobile devices.
"Cryptojacking typically happens after a website is compromised to inject cryptojacking malware. In most cases this malware is merely a few lines of JavaScript," says Mursch. "Once it's placed on the website, visitors to the site immediately begin mining cryptocurrency on behalf of the cybercriminal who placed it there. It can also be delivered in the form of an executable that targets servers rather than clients, but in both cases the outcome is the same: computing resources are hijacked by the malware, which directs CPU capacity to the mining process. And of course, all newly minted cryptocurrency – typically in the form of Monero that can't be tracked – is then sent to the cybercriminal's account."
TROY MURSCH'S NETWORK MONITORING TIPS:
Remember that without monitoring you are flying blind.
Always be on the lookout for malware, whether it's cryptojacking-oriented JavaScript or an executable that impacts your servers.
Use remote probes. It's important to look at your network from outside and inside.
Use the non-security oriented data you get from your monitoring efforts to improve your network infrastructure and provide your users with greater service.
Monitor, monitor, monitor...today's increasingly complex networks require constant vigilance. You always want to be the first to know when a problem arises.
Using PRTG to Detect Cryptojacking Malware
Last year Mursch was the first security researcher to discover cryptojacking malware on two very popular websites – CBS's Showtime, and Politifact, a Pulitzer Prize-winning site that verifies the accuracy of politicians' claims. Both were infected with Coinhive, which immediately commandeered 60 percent or more of visitors' CPU capacity to mine Monero.
He also discovered a similar scheme that infected around 1,500 websites with a copy of the Coinhive cryptocurrency miner that was hidden in the JavaScript files used by LifeHelpNow, a live chat and customer support widget. Most of the sites infected were online shops or the homepages for private businesses.
In each case, Mursch used Paessler's PRTG Network Monitor to find the offending malware. With an on-premises deployment and PRTG in the Cloud, and using an HTTP Advanced sensor and remote probes, he was able not only to find the offending code but also to confirm when it was successfully removed.
"I've used PRTG to find and combat many high-profile cryptojacking incidents and a simple HTTP Advanced sensor is really all you need to monitor affected websites," notes Troy. "It confirms the malware is there, tells you when an affected site is cleaned up, and confirms how long it was infected for. And perhaps most importantly, you can do all of this without going through the trouble of visiting a website that's infected with malware."
"As with all things in IT, visibility is key. If you see a server running at peak capacity for no reason, you immediately know there's a problem. You can't account for, let alone combat, threats you can't see or don't know of. PRTG isn't a security tool, but it's my favorite compliment to them. Besides monitoring malware and botnets, I also use it to monitor phishing sites, which I find and report to the hosting provider."
Troy Mursch
A System Administrator's Nightmare
Mursch cautions that cryptojacking is a serious issue that all system administrators, particularly those that serve small and medium-sized businesses, should take very seriously. He recently used PublicWWW, a search engine that indexes the entire source code of websites, to gauge the seriousness of the problem.
What he discovered was disturbing. Mursch found more than 48,953 sites infected with cryptojacking malware, 7,368 of which were WordPress sites used primarily by small businesses.
"In addition to impacting consumers' trust, or in the case of executables impacting businesses' servers, the impact is always the same. Cryptojacking takes existing CPU resources and funnels it to the mining process. Given that some of these mining operations take place over months, affected businesses and consumers will see higher electric bills, far more wear and tear on hardware, lost productivity due to slow-performing networks and in some cases serious physical damage to devices," he says. "Mobile phones and tablets are particularly susceptible because they aren't designed to run at peak CPU capacity for extended periods of time. When infected with cryptojacking malware, they can literally burn themselves up if left on a charger."
Of course, all of this is further complicated by the fact that some websites are increasingly inserting Coinhive into browsers, and openly asking for visitors' consent as a legitimate way to generate revenue in exchange for content, gaming or other services – something Information Technology (IT) departments will increasingly need to address with policies that safeguard their IT infrastructure.
"As with all things in IT, visibility is key. If you see a server running at peak capacity for no reason, you immediately know there's a problem. You can't account for, let alone combat, threats you can't see or don't know of. PRTG isn't a security tool, but it's my favorite compliment to them. Besides monitoring malware and botnets, I also use it to monitor phishing sites, which I find and report to the hosting provider."
Liability is another issue. With more cybercriminals launching cryptojacking campaigns that target hundreds and even thousands of websites simultaneously, Mursch feels it's only a matter of time before the liability for cryptojacking becomes a serious issue.
"If your customer's mobile device fails because it overheated while cryptomining without their consent because they visited your e-commerce site, it wouldn't be inconceivable for them to look for compensation," adds Mursch. "Most importantly, they might not want to visit your site again."
For more information on cryptojacking, botnets, network abuse and other security topics, visit Bad Packets Report at www.badpackets.net. Mursch has also coauthored a peer-reviewed research paper, "A first look at browser-based cryptojacking" which further explains the topic in detail.
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Board of Trustees Chair Corbin out
February 21, 2005 12:00 am by Russell Nichols
First, former FAMU President Fred Gainous got the boot. Then, Love Collins III was released by Interim President Castell V. Bryant. Now, the curtain has closed on the Board of Trustees chairman.
James Corbin, appointed to the Board of Trustees in January 2002, was not reappointed by Gov. Jeb Bush Thursday, amending the FAMU administration for the third time in four months and proving that absolutely no position is secure.
It was nothing personal, according to the government officials.
"The governor wanted to give other people a chance," said Jacob DiPietre, a Bush spokesman. "This was the opportunity to get someone else who wanted to serve."
DiPietre said the decision had nothing to do with FAMU's current financial crisis or last year's Division 1-A fiasco. It was simply about getting a new face in the chairman's position.
After repeated attempts, Corbin could not be reached for comment.
The BOT consists of 13 members. The governor and the Board of Governors each select six members and FAMU Student Body President fills the thirteenth seat.
The change came two weeks away from the first Board of Trustees meeting of 2005, which was scheduled for March 3. That meeting has been cancelled.
Corbin's replacement has already been named.
W. George Allen, 68, an attorney from Fort Lauderdale, got the job. The 1958 FAMU alumnus applied for the position in December and learned Thursday he was selected to replace Corbin.
With Corbin's experience and familiarity with FAMU, Allen must be able to handle a heightened level of media attention or public scrutiny.
Allen admitted that he doesn't know a lot about the University's problems and that he isn't sure how he will even handle them. But he said his heart is in it.
"I don't know what I can bring accept that I love FAMU and I have some energy and some time," said Allen, whose term is through 2010.
For the past two months, Bryant has been in the process of settling into her new job and defining her relationship with the trustees – the same group that voted 9-4 to oust Gainous last September.
However, she said her focus is on the University.
"How we operate with the board is with legislation so I don't care who's on it," Bryant said.
Bryant said she doesn't expect Corbin's dedication to diminish regardless of his role.
"There is no person with a more focused commitment than Jim Corbin," she said. "I don't expect his commitment to change whether he's on the board or not."
SGA President Virgil A. Miller was not sure why the governor had denied Corbin's request for reappointment. He said Corbin was dedicated to the University, in spite of a reputation that branded him an agitator.
"Sometimes he was seen as a controversial figure," Miller said. "But he was certainly an advocate for the University. I can only hope that attorney Allen will come and bring that same level of commitment."
Miller said with the new president and new chairman, the dynamics of the decision-making may shift.
With all that has happened in the past few months, Miller said FAMU's future is beyond the power of any one person. And just like in show business, one setback should not disrupt the school's performance.
"The business of the university must go on," Miller said. "And it will go on."
Contact Russell Nichols at russell_nichols@hotmail.com.


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Prepare now for the 2021 Atlantic hurricane season
The 2021 Atlantic hurricane season began on June 1 and will extend through Nov. 30.
Forecasters predict a very busy 2021 Atlantic hurricane season, which began June 1 and ends on Nov. 30. Florida Polytechnic University urges its students and employees to take early actions to prepare for possible storm impacts.
The National Oceanic and Atmospheric Administration predicts a high probability of 13 to 20 named storms this season. Of those, six to 10 are expected to become hurricanes with top winds of at least 74 miles per hour, and three to five are predicted to be major categories at Category 3 or above.
Acting now can prevent stress and help avoid a potentially dangerous situation if a hurricane impacts the region. The following links are useful to prepare and stay informed.
Sign up or update your Florida Poly Alerts contact information to receive important messages if a hurricane or other serious event could affect Florida Poly. This is the primary method of official University communication in the event of an emergency. Email will serve as a secondary means of communication.
The annual Florida Disaster Preparedness Sales Tax Holiday is now through June 6. Visit this link to learn about what items are included in the event.
Create an emergency kit. The Florida Division of Emergency Management developed a guide to assist you in creating an emergency supplies kit to last you and your family for at least seven days.
Make a plan. Those who have a disaster plan in place can minimize confusion and worry during a hurricane. Forbes has created an extensive checklist that can help you be prepared.
Stay informed. In addition to listening to the battery-operated radio in your emergency kit, it's important to monitor resources such as the National Weather Service, the National Hurricane Center, and local weather resources. You also can call 211 during a disaster to get information about emergency shelters, food distribution, grief counseling, clean up, and more.
For more local information, visit Polk County's disaster preparedness website.
Monitor Florida Poly's website and social media for important information that may affect you as storms approach throughout the season. Follow us on Facebook, Twitter, and Instagram.
Florida Poly AlertsHurricane Season


Dimensions: 1.25" X 3.5" X 2.75"
High quality mold, very sturdy. Very good impression of sea waves or snow swirls. Good size bar.
My first time using this mold was last weekend. I mixed Evergreen mica with green color drops, Christmas Spice scent and a glycerin based M & P. The heating mixture smelled like the holidays. I dipped a Q-tip into bronze metallic mica and lightly swirled it into the grooves of this design, then poured the soap base. I filled the molds to the top. I waited 28 hours and then gently pulled the sides of each mold space to clear the intrinsic soap seal. With a gentle nudge from the top, the soaps dropped down onto my cutting board. Yeah! They evoke Christmas! Even my husband said " wow, you are getting good at this" (I've been making soap for 4 weekends). I would have provided a picture if there was a way. Thanks for a great mold, Bulk A!


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import javax.tools.StandardLocation;

/**
 * Annotation processor to store certain annotations from auto-configuration classes in a
 * property file.
 *
 * @author Madhura Bhave
 * @author Phillip Webb
 */
@SupportedAnnotationTypes({ "org.springframework.context.annotation.Configuration",
		"org.springframework.boot.autoconfigure.condition.ConditionalOnClass",
		"org.springframework.boot.autoconfigure.condition.ConditionalOnBean",
		"org.springframework.boot.autoconfigure.condition.ConditionalOnSingleCandidate",
		"org.springframework.boot.autoconfigure.condition.ConditionalOnWebApplication",
		"org.springframework.boot.autoconfigure.AutoConfigureBefore",
		"org.springframework.boot.autoconfigure.AutoConfigureAfter",
		"org.springframework.boot.autoconfigure.AutoConfigureOrder" })
public class AutoConfigureAnnotationProcessor extends AbstractProcessor {

	protected static final String PROPERTIES_PATH = "META-INF/"
			+ "spring-autoconfigure-metadata.properties";

	private final Map<String, String> annotations;

	private final Map<String, ValueExtractor> valueExtractors;

	private final Properties properties = new Properties();

	public AutoConfigureAnnotationProcessor() {
		Map<String, String> annotations = new LinkedHashMap<>();
		addAnnotations(annotations);
		this.annotations = Collections.unmodifiableMap(annotations);
		Map<String, ValueExtractor> valueExtractors = new LinkedHashMap<>();
		addValueExtractors(valueExtractors);
		this.valueExtractors = Collections.unmodifiableMap(valueExtractors);
	}

	protected void addAnnotations(Map<String, String> annotations) {
		annotations.put("Configuration",
				"org.springframework.context.annotation.Configuration");
		annotations.put("ConditionalOnClass",
				"org.springframework.boot.autoconfigure.condition.ConditionalOnClass");
		annotations.put("ConditionalOnBean",
				"org.springframework.boot.autoconfigure.condition.ConditionalOnBean");
		annotations.put("ConditionalOnSingleCandidate",
				"org.springframework.boot.autoconfigure.condition.ConditionalOnSingleCandidate");
		annotations.put("ConditionalOnWebApplication",
				"org.springframework.boot.autoconfigure.condition.ConditionalOnWebApplication");
		annotations.put("AutoConfigureBefore",
				"org.springframework.boot.autoconfigure.AutoConfigureBefore");
		annotations.put("AutoConfigureAfter",
				"org.springframework.boot.autoconfigure.AutoConfigureAfter");
		annotations.put("AutoConfigureOrder",
				"org.springframework.boot.autoconfigure.AutoConfigureOrder");
	}

	private void addValueExtractors(Map<String, ValueExtractor> attributes) {
		attributes.put("Configuration", ValueExtractor.allFrom("value"));
		attributes.put("ConditionalOnClass", new OnClassConditionValueExtractor());
		attributes.put("ConditionalOnBean", new OnBeanConditionValueExtractor());
		attributes.put("ConditionalOnSingleCandidate",
				new OnBeanConditionValueExtractor());
		attributes.put("ConditionalOnWebApplication", ValueExtractor.allFrom("type"));
		attributes.put("AutoConfigureBefore", ValueExtractor.allFrom("value", "name"));
		attributes.put("AutoConfigureAfter", ValueExtractor.allFrom("value", "name"));
		attributes.put("AutoConfigureOrder", ValueExtractor.allFrom("value"));
	}

	@Override
	public SourceVersion getSupportedSourceVersion() {
		return SourceVersion.latestSupported();
	}

	@Override
	public boolean process(Set<? extends TypeElement> annotations,
			RoundEnvironment roundEnv) {
		for (Map.Entry<String, String> entry : this.annotations.entrySet()) {
			process(roundEnv, entry.getKey(), entry.getValue());
		}
		if (roundEnv.processingOver()) {
			try {
				writeProperties();
			}
			catch (Exception ex) {
				throw new IllegalStateException("Failed to write metadata", ex);
			}
		}
		return false;
	}

	private void process(RoundEnvironment roundEnv, String propertyKey,
			String annotationName) {
		TypeElement annotationType = this.processingEnv.getElementUtils()
				.getTypeElement(annotationName);
		if (annotationType != null) {
			for (Element element : roundEnv.getElementsAnnotatedWith(annotationType)) {
				Element enclosingElement = element.getEnclosingElement();
				if (enclosingElement != null
						&& enclosingElement.getKind() == ElementKind.PACKAGE) {
					processElement(element, propertyKey, annotationName);
				}
			}
		}
	}

	private void processElement(Element element, String propertyKey,
			String annotationName) {
		try {
			String qualifiedName = Elements.getQualifiedName(element);
			AnnotationMirror annotation = getAnnotation(element, annotationName);
			if (qualifiedName != null && annotation != null) {
				List<Object> values = getValues(propertyKey, annotation);
				this.properties.put(qualifiedName + "." + propertyKey,
						toCommaDelimitedString(values));
				this.properties.put(qualifiedName, "");
			}
		}
		catch (Exception ex) {
			throw new IllegalStateException(
					"Error processing configuration meta-data on " + element, ex);
		}
	}

	private AnnotationMirror getAnnotation(Element element, String type) {
		if (element != null) {
			for (AnnotationMirror annotation : element.getAnnotationMirrors()) {
				if (type.equals(annotation.getAnnotationType().toString())) {
					return annotation;
				}
			}
		}
		return null;
	}

	private String toCommaDelimitedString(List<Object> list) {
		StringBuilder result = new StringBuilder();
		for (Object item : list) {
			result.append((result.length() != 0) ? "," : "");
			result.append(item);
		}
		return result.toString();
	}

	private List<Object> getValues(String propertyKey, AnnotationMirror annotation) {
		ValueExtractor extractor = this.valueExtractors.get(propertyKey);
		if (extractor == null) {
			return Collections.emptyList();
		}
		return extractor.getValues(annotation);
	}

	private void writeProperties() throws IOException {
		if (!this.properties.isEmpty()) {
			FileObject file = this.processingEnv.getFiler()
					.createResource(StandardLocation.CLASS_OUTPUT, "", PROPERTIES_PATH);
			try (OutputStream outputStream = file.openOutputStream()) {
				this.properties.store(outputStream, null);
			}
		}
	}

	@FunctionalInterface
	private interface ValueExtractor {

		List<Object> getValues(AnnotationMirror annotation);

		static ValueExtractor allFrom(String... names) {
			return new NamedValuesExtractor(names);
		}

	}

	private abstract static class AbstractValueExtractor implements ValueExtractor {

		@SuppressWarnings("unchecked")
		protected Stream<Object> extractValues(AnnotationValue annotationValue) {
			if (annotationValue == null) {
				return Stream.empty();
			}
			Object value = annotationValue.getValue();
			if (value instanceof List) {
				return ((List<AnnotationValue>) value).stream()
						.map((annotation) -> extractValue(annotation.getValue()));
			}
			return Stream.of(extractValue(value));
		}

		private Object extractValue(Object value) {
			if (value instanceof DeclaredType) {
				return Elements.getQualifiedName(((DeclaredType) value).asElement());
			}
			return value;
		}

	}

	private static class NamedValuesExtractor extends AbstractValueExtractor {

		private final Set<String> names;

		NamedValuesExtractor(String... names) {
			this.names = new HashSet<>(Arrays.asList(names));
		}

		@Override
		public List<Object> getValues(AnnotationMirror annotation) {
			List<Object> result = new ArrayList<>();
			annotation.getElementValues().forEach((key, value) -> {
				if (this.names.contains(key.getSimpleName().toString())) {
					extractValues(value).forEach(result::add);
				}
			});
			return result;
		}

	}

	private static class OnBeanConditionValueExtractor extends AbstractValueExtractor {

		@Override
		public List<Object> getValues(AnnotationMirror annotation) {
			Map<String, AnnotationValue> attributes = new LinkedHashMap<>();
			annotation.getElementValues().forEach((key, value) -> attributes
					.put(key.getSimpleName().toString(), value));
			if (attributes.containsKey("name")) {
				return Collections.emptyList();
			}
			List<Object> result = new ArrayList<>();
			extractValues(attributes.get("value")).forEach(result::add);
			extractValues(attributes.get("type")).forEach(result::add);
			return result;
		}

	}

	private static class OnClassConditionValueExtractor extends NamedValuesExtractor {

		OnClassConditionValueExtractor() {
			super("value", "name");
		}

		@Override
		public List<Object> getValues(AnnotationMirror annotation) {
			List<Object> values = super.getValues(annotation);
			Collections.sort(values, this::compare);
			return values;
		}

		private int compare(Object o1, Object o2) {
			return Comparator.comparing(this::isSpringClass)
					.thenComparing(String.CASE_INSENSITIVE_ORDER)
					.compare(o1.toString(), o2.toString());
		}

		private boolean isSpringClass(String type) {
			return type.startsWith("org.springframework");
		}

	}

}

redpajama_set_name: RedPajamaGithub


Bookcases and bookshelves offer a safe place to display prized novels, photos or anything else you love. Buying the right fit for your home is essential, and it begins with knowing whether to purchase a bookshelf or bookcase.
Bookcase vs. Bookshelf: What's the Difference?
Although many people use the two terms interchangeably, bookshelves and bookcases are two different types of furnishings. Which one you should buy depends on your space, needs and preferences.
Most bookcases are large free standing furniture pieces and feature multiple shelves. As such, furniture websites may describe a bookcase as a shelving unit. A traditional model has three closed sides, though modern designs may have a more open look with no back or feature glass doors. Bookcases usually sit on the floor, making them perfect for heavy items such as vases and stacks of hardbacks.
On the other hand, bookshelves typically refer to a single, wall-mounted shelf, a small grouped set of wall-mounted shelves or a ladder-style piece. A wall-mounted bookshelf is typically affixed high on the wall, making it a great place to keep fragile objects away from curious children and pets.
Since larger models tend to be a little bulky, bookcases may pose more of a challenge when it comes to rearranging furniture or moving. However, unlike bookshelves, they are not permanently bolted to the wall. As a result, a bookcase may be the best option for renters. To prevent tipping however, it is recommended to strap tall bookcases to the wall, as you would with any other tall or top heavy furnishing. This is especially important if you have small children or live in an area prone to earthquakes.
Alternately, there are advantages to owning a bookshelf verses a bookcase. These pieces free up floor space, keeping your room less cluttered. In addition, hanging bookshelves over mantles and doorways makes it easy to draw attention to design features or add creative flair to otherwise blank walls.
Before selecting a bookshelf or bookcase, think about your existing decor. For an elegant living room or timeless office, bookcases fit the bill. Upscale pieces with etched glass barrister doors, deep wood tones or carved detailing instantly add a classic touch. If a minimalist vibe is more your scene, ladder bookshelves provide simple shapes and clean lines that will blend with your decor.
The cost of bookcases verses bookshelves varies depending on the material. Plywood or pressboard models are a less expensive option, but they are prone to damage. Solid wood bookcases and bookshelves have a higher price point, but their durability is worth every penny.
Making the Decision: Bookshelf or Bookcase?
When it comes down to it, deciding on bookshelves or bookcases is a personal choice. For classic, movable storage, bookcases are the way to go. If you want a contemporary style that stays fixed to the wall, look at bookshelves instead. No matter which you choose, your books, decor and collectibles will have a beautiful new home.


2010 WG1 asteroid magnitude is 23 H and asteroid diameter is between 67 and 149 meters. Asteroid 2010 WG1 closest near miss earth distance is 15,335,893 kilometers on 9 December 2010.
List of approaches near Earth of asteroid 2010 WG1 with distance and velocity information.


"Portrait of a Poet Sage" 10.875x 9" overall, painting 7.5x5.5". A smaller size imagined antique, created to be a perfect entry point for first time collectors wishing to own a Dankquart collection original. Acrylic on panel, artist crafted distressed wood frame. A flat panel painted to have a distinct trompe l'oeil faux fresco look, finished with a warm toned varnish. Signed on the back of the panel and on the brown paper backing. SALE! Was $575.00 Now $475.00+ $18.00 US shipping. "Buy It Now" purchase option US only. Buyers outside the US please contact me for additional shipping information.


In this auto reliability ratings interview, you'll learn how Consumer Reports, one of the world's most renowned car rating publications, performs test drives and rates vehicles based on a number of important factors. Find out which cars are the best, which ones are the worst, and some surprising information about vehicle testing and rating.
In this interview, Consumer Reports associate editor Jim Travers shares a great deal of insight with LoveToKnow readers about the sort of factors that truly make a vehicle a good value. With a wide range of experience and a depth of knowledge in automobiles, Jim Travers brings a wealth of insight to Consumer Reports. In this auto reliability ratings interview, Jim shares details about Consumer Reports tests and offers tips about how you can determine value the next time you're shopping for a new car.
LoveToKnow (LTK): How often does Consumer Reports do test drives and rankings?
Jim Travers (JT): We do ratings all the time. We test upwards of 100 cars a year.
LTK: Do the annual tests cover all different classes of vehicles?
JT: Correct. we'll do family sedans, small SUVs, sporty cars, compact cars - and generally speaking, we'll touch on each of those categories once or twice a year depending upon the popularity of the category and how many new models have come out in that category.
LTK: So, you try to focus on the most popular vehicles for that year?
JT: Well, we focus on new vehicles as they come out, and then also as changes get made. For example, if the Nissan Ultima gets a new engine, we'll retest it just to keep our ratings and our information current.
Generally speaking, new cars are usually redesigned about once every five years by most manufacturers. In the course of that five years, they'll make a couple of revisions. If it's a styling tweak, we don't retest. If it's something that is a mechanical difference or a safety difference, we'll retest it.
LTK: So you try to focus on things that affect performance, handling and things like that?
JT: Performance, safety, fuel economy and all around liveability. Reliability is another big one with us, of course.
LTK: Do you find that every year there's a model that seems to be a predictable winner?
JT: You know, it's been interesting in the past few years. For a long time, Japanese car makers, particularly Toyota and Honda, led the reliability ratings and scored very well for their fuel economy and packaging, and just quality. That has been changing in recent years. Things have gotten a lot more competitive and we found that a lot of the domestic car makers, Ford in particular, have made some real strides in their ratings overall. They're making some really good sedans. The Fusion is an excellent choice and very competitive within its category. And the new Flex is just a great package as an alternative to a minivan or a big SUV, as it's got lots of room and lots of versatility. Their reliability has improved across the board as well. General Motors has also made some real strides and has some very competitive models that we like very much, like the Chevy Malibu.
But, you know, they're still kind of spotty. Some of the older GM designs that haven't been redesigned as recently don't do as well in our scoring. If somebody is shopping for a car, we certainly suggest that they look at our ratings, which are divided by category, and it'll give you a pretty good idea of how cars score.
LTK: You mentioned that top contenders seem to be changing from Asian car makers to domestic. Has that switched or is it just a general trend?
JT: I don't know that it's necessarily switched. However, the domestics are a whole lot more competitive and putting out some excellent products. The Fusion is a really good car. The Chevy Traverse and GMC Acadia SUV are also very highly recommended. In fact, in terms of family SUVs, the Chevy Traverse was our top pick this year.
LTK: Do you find that each year there's a brand or model that seems to be a predictable loser?
JT: Certainly with the domestics. For example, Chrysler has been struggling in recent years due to financial difficulties and lack of development money for new product. They've gotten a whole lot less competitive. The Ram pickups do very well in our testing, but their sedans have just fallen behind the competition, unfortunately.
LTK: A lot of our readers drive minivans; do you see the minivan market as still very strong?
JT: There's been a lot of shakeout in the minivan market. Basically, the domestic manufacturers, with the exception of Chrysler, have pulled out of it altogether within the past three or four years, but the companies that are still in the market do very well. The Toyota Sienna and the Honda Odyssey are both excellent vehicles, and you can't beat a minivan for the utility. It gets better gas mileage than an SUV, and with the amount of passenger room and cargo room, the versatility is just unbeatable.
LTK: What are the features that you think add the most value to a vehicle?
JT: First, you want to get something that has good reliability ratings and scores well in our testing, obviously. You also want something with all of the latest safety equipment, particularly if you're carrying a family. Curtain airbags are a big life saver, and not all cars have those. Electronic stability control is often said to be the most significant safety improvement feature since the advent of the safety belt.
LTK: Stability control really makes that much of a difference?
JT: Yes, all cars are mandated to have it by 2012, and most cars do at this point. It can make a huge difference, especially if people have kids learning to drive. We basically suggest don't buy anything that doesn't have it.
LTK: Does stability control tend to impact performance tests in Consumer Reports trials?
JT: We do about 50 tests on every car that we drive. We buy the cars and keep them from six months to a year - it's not just a one week quick test around town. We also do have our own test track (a 327 acre facility) and we do all kinds of testing out there.
One of the tests is called the avoidance maneuver, which basically simulates a quick swerve. That's a situation where electronic stability control can really help a car that is not necessarily the best handling car in the world. What it does is it'll selectively apply the brakes and cut the throttle some. That can really make a big difference with keeping a car on course.
Now, if you're looking to save money and still get a really good car, and if it's something that you're going to keep for a long time and don't mind a low resale value, we've noticed that Hyundai and Kia have really improved in our scoring and are making some really competitive cars these days.
LTK: So do you think that the low resale is just name recognition?
JT: I think that the name recognition is a lot of it. Back in the 80's, when Hyundai first came on the scene in the states, they did have some quality issues. The cars were just regarded as throw away cars, and I think that they're still living down that reputation. The Hyundai Elantra is actually the top rated car in its category.
LTK: Do you have advice for what readers should look for when they test drive a new vehicle?
JT: The first thing that we suggest is to not rush the process. You want to spend at least thirty minutes on a test drive, and you want to drive on a variety of roads - both on side streets and on the highway. You want to see how easy it is for you to park and maneuver the car, how well you can see out of the car, and that it's a car that you are comfortable in.
If you have a family and they will be riding in the vehicle, you want to bring them along and make sure they fit and that they're comfortable. You really have to look at the test drive as a snapshot of what you're going to be doing with that car for the next several years.
As Jim noted in this interview, there is a great deal of effort and care that goes into the testing and rating of new and used vehicles, so when you read vehicle ratings at Consumer Reports, you know that you're getting an accurate and fair review of the vehicle.


Too much tendon stress results in tears and overuse conditions such as tendinitis. These injuries often occur as a result of exercise. Injuries sustained in the pursuit of fitness can come back to haunt you. They present themselves as nagging aches and pains that compromise your fitness as you get older.
To minimize risk of injury, the goal is to exercise enough to produce positive change in your your muscles, joints, and connective tissue, not to see how much stress they can withstand . At our Austin Strength Training facility, we have years of experience determining the minimum effective dose of exercise (the amount that safely produces ongoing optimal improvement). Anything beyond that will at best result in a diminishing marginal return and at worst result in injury.
If you do nothing your muscles, bones, and connective tissue will become weaker and make an injury more likely. Is it worth a half hour of strength training each week to help avoid injuries and to live an active life? We think it is.


Site of the Week: Awwwards | Greenfield Belser LTD.
The 3D style is what drew me to the Awwwards' conference site right off the bat. It's nothing that we haven't all seen before, but maybe that's why I was drawn to it. This is a modern website that incorporates old tech. It resonates with me as the creative approach we abide by here at Greenfield Belser. Making the familiar fresh.
The site itself is very simple and links speakers to their individual Twitter pages. I like the simple parallax and the fact that the bio shots are a mix between video loops and still shots. All have various styles, but the black and white and 3D effect pulls them together.
This neat little gimmick may just retain your attention for long enough to further engage you in the site and prompt you to continue clicking through. Which, of course, is the goal for almost any website. Maybe it'll even entice you to put the old pair of 3D glasses from your kitchen junk drawer to use. That said, even without the glasses, I think the site is visually interesting. And who doesn't like 3D stuff?


A man has been arrested in Pakistan for allegedly assisting in solemnising the wedding of two Hindu minor girls, who were reportedly abducted and forcefully converted to Islam, as the teenagers approached a court in the country's Punjab province seeking protection.
According to Geo TV, the teenagers approached a court in Bahawalpur in Pakistan's Punjab province seeking protection. "Police have arrested a man from Khanpur who is suspected to have assisted in the nikah (marital contract) of the girls," it said. However, it is not confirmed whether the arrested man is the cleric who performed their marriage. Earlier, there were reports that the cleric who performed the minor girls' marriage was arrested from Khanpur in Sindh.
The draft resolution demands that the most unfortunate incidents of kidnappings and forced conversions must be condemned unanimously by all honourable members of Parliament. "The bill against forced conversions which was unanimously passed by Sindh Assembly in 2016 and then reverted due to pressure of extremist elements, must be resurrected and passed in the Assembly on priority basis, " says the draft resolution. The resolution would seek strict action against controversial religious elements for supporting such inhuman practice.
A war of words broke out between India's External Affairs Minister Sushma Swaraj and Pakistan's Information Minister Fawad Chaudhry over the reported abduction, forced conversion and underage marriages of the two Hindu teenagers. The spat started soon after Swaraj sought details from the Indian envoy in Pakistan into the reported abduction of two Hindu teenaged girls. Swaraj, while tagging a media report about the incident, tweeted that she has asked the Indian High Commissioner in Pakistan to send a report on the matter.
Pakistan's Information Minister Fawad Chaudhry responded to her tweet, saying it was his country's "internal issue". In a Twitter post in Urdu on Sunday, Chaudhry said the prime minister has asked the Sindh chief minister to look into reports that the girls in question have been taken to Rahim Yar Khan in Punjab. He said the prime minister has also ordered the Sindh and Punjab governments to devise a joint action plan in light of the incident, and to take concrete steps to prevent such incidents from happening again.
Last year, Khan during his election campaign had said his party's agenda was to uplift the various religious groups across Pakistan and said they would take effective measures to prevent forced marriages of Hindu girls. Rights activist Jibran Nasir tweeted that the sisters were converted at the Dargah Barchundi Sharif and were taken to Rahim Yar Khan in Punjab following their marriages.


Just three months after its official debut, Samsung's GS II smartphone has seen record sales at more than 5 million units across parts of Europe and the Asia Pacific region.
Samsung's Galaxy S II smartphone has racked up record sales even before it's hit the hot U.S. market.
The Korean mobile-phone maker said yesterday that it sold more than 5 million units of the Galaxy S II in the 85 days following its debut. Announcing the sales on its Samsung Tomorrow page (Google Translate English version), Samsung said that the phone has captured the top market share among more than 10 countries in Europe.
In comparison, the original Galaxy S took 125 days to reach the same 5-million-unit sales mark.
The GS II launched in its home base of South Korea on April 29 before reaching Japan and several European countries in May. The popular phone claimed more than 3 million in unit sales just one month after its release, according to Samsung, with 2 million selling in some of the larger markets.
Reaching Chinese customers earlier this week, the GS II is slated to make its U.S. debut in August where it will be sold by three of the major carriers, each of which will give it a new name. The phone will be available through Sprint as the Samsung Within, through Verizon Wireless as the Samsung Function, and through AT&T as the Samsung Attain.
"Since being launched into the retail market in late April, the Galaxy S II has seen tremendous growth," J.K. Shin, president and head of Samsung's Mobile Communications Business, said in a statement. "This reflects the strong support from carrier partners globally, who in choosing the Galaxy S II as their flagship device have reaffirmed the device's status as a premium, market-defining smartphone."
Aiming to launch the GS2 in 120 countries through 140 mobile carriers, Samsung is looking to sell 10 million units by the end of the year, according to the Yonhap News Agency.
The phone has impressed consumers and reviewers alike with its aggressive array of features, including a dual-core 1.2GHz processor, a 4.3-inch Super AMOLED Plus display, an 8-megapixel camera in back, and a 2-megapixel camera in front. Currently running Android 2.3 Gingerbread, the GS2 also sports Samsung's customized TouchWiz 4.0 interface.
Samsung has been on a roll lately climbing up the charts among the world's leading smartphone vendors. A June report from Nomura Securities predicted that Samsung would overtake longtime market king Nokia by the second quarter.
Helped by heavy demand for the GS II, Samsung sold 18 million to 21 million smartphones in the second quarter, according to Strategy Analytics analyst Neil Mawston. At just 18 million, Samsung did outsell Nokia; assuming the high end, then Samsung also outshined Apple as the quarter's top smartphone vendor.


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Providing quality is our top priority. Our customers can expect nothing less than total quality, which is guaranteed by our employees in all aspects of their day-to-day work. These essentially simple principles were first formulated by Karl Berrang when the company was established more than 60 years ago.
Our work is governed by an unerring focus on the particular requirements of each of our customers. Working together with our clients, we develop customized solutions for every aspect of a project. With a broad network of offices in Germany, the USA, France, Poland, and China, we are able to establish direct contact and offer intensive support to our customers – straightforward and with minimal waiting times thanks to our fast and flexible approach.
Our employees are the key to our success, since it is they who develop, improve, and implement our various solutions. For this reason, it is particularly important for us to ensure that our staff members are satisfied and motivated at work. In this respect, it is an inestimable advantage that we are an independent, family-run business in which employees have a direct line to the management.