Impacts of Climate Change on the Health of Older People in District Nowshera- Pakistan

The study was carried out in district Nowshera  in 2017, in order to examine the effects of  climate change  on the health of older people . The Universe of the study was District Nowshera which consist of three tehsil namely Phabbi, Nowshera and Jehangira while in the first stage purposively two tehsil Phabbi and Nowshera  were selected on the basis of more climate affection. On the same methodology in the second stage villages Kheshgi Bala and Cant union councils were selected from Nowshera  while Mohib Banda, Pashtung Ghari and Jabba Khansa were chosen from tehsil Phabbi. The number of total respondents were 117 in the total villages   while   number of male was 54 and women  was 63. The data was collected through focused group discussion, Key Informant interview and consultation meeting with Elder people of the study area. The results indicate that climate change has severely affected the health of the older people which cause multiple disease such as Heart, Skin irritation, Malaria infection, respiratory infection, diarrhea,psychological disorder, dengue and dehydration which was not severe as compared to  20 years ago in the study area. The climate has changed the temperature, which has affected the rain pattern annually in the study area and disturbs the ecosystem for all living organism in district Nowshera.  Mosquito, heat stress, flood and degradation of the land, deforestation and population pressure problems were observed in the study area. On the basis of problems the following recommendations were suggested for future control measurement. More plantation strategy should be applied for soil erosion because through soil erosion the more mud come into the river which fulfill river from mud which increase the chances of flood in the rainy season which  push community destruction in the study area. Cleanness of the river is required and community should be also informed through awareness program to not put plastic bags in the river which block the river water and cause the flood. Drainage system should be developed in the study area. Health services should be provided for control of diseases measurement.  Transportation system should be developed for the facilitation of marketing which play key role in pushing the economy of the study area. Similarly older people women and men should be facilitated in a proper way in District Nowshera. Keywords: - Climate, Impact, Older People, Health, District Nowshera DOI: 10.7176/JAAS/57-01 Publication date: August 31st 201

Impacts of Climate Change on Social Life of Older People in District Nowshera- Pakistan

The study was carried out in district Nowshera  in 2017, in order to examine the effects of  climate change  on social life of older people . The Universe of the study was District Nowshera which consist of three tehsil namely Phabbi, Nowshera and Jehangira while in the first stage purposively two tehsil Phabbi and Nowshera  were selected on the basis of more climate affection. On the same methodology in the second stage villages Kheshgi Bala and Cant union councils were selected from Nowshera  while Mohib Banda, Pashtung Ghari and Jabba Khansa were chosen from tehsil Phabbi on the same analogy. The number of  respondents were 117 in the selected villages   while   number of male was 54 and women  was 63. The data was collected through focused group discussion, Key Informant interview and consultation meeting with older people of the study area. The results indicate that climate change has affected the pattern of the rainfall and flood and temperature which has disturbed the social life of the older people. The flood has destroyed the land and houses which affected the livelihood of the younger people, so the yournger for the purpose of their livelihood left their houses from district Nowshera and left older people at their home for care of the families. The look after responsibilities fell on older people shoulder which latter on affect their health. Government has arranged different programs for helping the communities while the poor older people of the communities have no access to these programs and the rich old people get the benefit of the program very easily due to their good approaches. Load shedding is the serious problems which affect the function of the fans and AC. Due to fans and AC the mosquitoes at night disturb the older people sleepiness which make the environment unfavorable for the older people which latter on affect their health and daily activities. Crimes and poverty also increased, lack of livelihood in the study area.  On the basis of problems credit should be provided to older people for their financial problems on free interest basis from the bank. Safety network should be established in the study area for solving the problems. Rescue team should be arranged for emergency problems of the older people in the study area. Health services should be facilitated in the study area for older people for social life improvement. Keywords: - Climate, Impact, Social Life,  Older People,  District Nowshera DOI: 10.7176/DCS/9-4-03 Publication date: April 30th 201

Neue Ansätze des molekularen Targetings bei der Philadelphia-Chromosom-positiven Leukämie

In Philadelphia Chromosome (Ph) positive ALL and CML the fusion between BCR and ABL leads to the BCR/ABL fusion proteins, which induces the leukemic phenotype because of the constitutive activation of multiple signaling pathways down-stream to the aberrant BCR/ABL fusion tyrosine kinase. Targeted inhibition of BCR/ABL by ABL-kinase inhibitors induces apoptosis in BCR/ABL transformed cells and leads to complete remission in Ph positive leukemia patients. However, a large portion of patients with advanced Ph+ leukemia relapse and acquire resistance. Kinase domain (KD) mutations interfering with inhibitor binding represent the major mechanism of acquired resistance in patients with Ph+ leukemia. Tetramerization of BCR/ABL through the N-terminal coiled-coil region (CC) of BCR is essential for the ABL-kinase activation. Targeting the CC-domain forces BCR/ABL into a monomeric conformation, reduces its kinase activity and increases the sensitivity for Imatinib. Here we show that i.) targeting the tetramerization by a peptide representing the Helix-2 of the CC efficiently reduced the autophosphorylation of both WT BCR/ABL and its mutants; ii.) Helix-2 inhibited the transformation potential of BCR/ABL independently of the presence of mutations; iii.) Helix-2 efficiently cooperated with Imatinib as revealed by their effects on the transformation potential and the factor-independence related to BCR/ABL with the exception of mutant T315I. These findings suggest that BCR/ABL harboring the T315I mutation have a transformation potential which is at least partially independent from its kinase activity. Targeted inhibition of BCR/ABL by small molecule inhibitors reverses the transformation potential of BCR/ABL. We definitively proved that targeting the tetramerization of BCR/ABL mediated by the N-terminal coiled-coil domain (CC) using competitive peptides, representing the Helix-2 of the CC, represents a valid therapeutic approach for treating Ph+ leukemia. To further develop competitive peptides for targeting BCR/ABL, we created a membrane permeable Helix-2 peptide (MPH-2) by fusing the Helix-2 peptide with a peptide transduction tag. In this study, we report that the MPH-2: (i) interacted with BCR/ABL in vivo; (ii) efficiently inhibited the autophosphorylation of BCR/ABL; (iii) suppressed the growth and viability of Ph+ leukemic cells; and (iv) was efficiently transduced into mononuclear cells (MNC) in an in vivo mouse model. The T315I mutation confers resistance against all actually approved ABL-kinase inhibitors and competitive peptides. It seems not only to decrease affinity for kinase inhibitors but to confer additional features to the leukemogenic potential of BCR/ABL. To determine the role of T315I in resistance to the inhibition of oligomerization and in the leukemogenic potential of BCR/ABL, we investigated its influence on loss-of-function mutants with regard to the capacity to mediate factor-independence. Thus we studied the effects of T315I on BCR/ABL mutants lacking functional domains in the BCR portion indispensable for the oncogenic activity of BCR/ABL such as the N-terminal coiled coil (CC), the tyrosine phosphorylation site Y177 and the serine/threonine kinase domain (ST), as well as on the ABL portion of BCR/ABL (#ABL-T315I) with or without the inhibitory SH3 (delta SH3-ABL) domain. Here we report that i.) T315I restored the capacity to mediate factor independence of oligomerization_deficient p185BCR/ABL; ii.) resistance of p185-T315I against inhibition of the oligomerization depends on the phosphorylation at Y177; iii.) autophosphorylation at Y177 is not affected by the oligomerization inhibition, but phosphorylation at Y177 of endogenous BCR parallels the effects of T315I; iv.) the effects of T315I are associated with an intact ABL_kinase activity; v.) the presence of T315I is associated with an increased ABL_kinase activity also in mutants unable to induce Y177 phosphorylation of endogenous BCR; vi.) there is no direct relationship between the ABL-kinase activity and the capacity to mediate factor_independence induced by T315I as revealed by the #ABL-T315I mutant, which was unable to induce Y177 phosphorylation of BCR only in the presence of the SH3 domain. In contrast to its physiological counterpart c-ABL, the BCR/ABL kinase is constitutively activated, inducing the leukemic phenotype. The N-terminus of c-ABL (Cap region) contributes to the regulation of its kinase function. It is myristoylated, and the myristate residue binds to a hydrophobic pocket in the kinase domain known as the myristoyl binding pocket in a process called “capping”, which results in an auto-inhibited conformation. Because the cap region is replaced by the N-terminus of BCR, BCR/ABL “escapes” this auto-inhibition. Allosteric inhibition by myristate “mimics”, such as GNF-2, is able to inhibit unmutated BCR/ABL, but not the BCR/ABL that harbors the “gatekeeper” mutation T315I. Here we investigated the possibility of increasing the efficacy of allosteric inhibition by blocking BCR/ABL oligomerization. We demonstrate that inhibition of oligomerization was able not only to increase the efficacy of GNF-2 on unmutated BCR/ABL, but also to overcome the resistance of BCR/ABL-T315I to allosteric inhibition. These results strongly suggest that the response to allosteric inhibition by GNF-2 is inversely related to the degree of oligomerization of BCR/ABL. Taken together these data suggest that the inhibition of tetramerization inhibits BCR/ABL-mediated transformation and can contribute to overcome Imatinib-resistance. The study provides the first evidence that an efficient peptide transduction system facilitates the employ-ment of competitive peptides to target the oligomerization interface of BCR/ABL in vivo. Further the data show that T315I confers additional leukemogenic activity to BCR/ABL, which might explain the clinical behavior of patients with BCR/ABL -T315I-positive blasts. In summary, our observations establish a new approach for the molecular targeting of BCR/ABL and its resistant mutants represented by the combination of oligomerization and allosteric inhibitors.In der Philadelphia Chromosome (Ph) positiven ALL und CML hat die Fusion von BCR und ABL die Bildung eines BCR/ABL Fusionsprotein zur Folge. Dieses Fusionsprotein ist für den leukämischen Phänotypen aufgrund der konstitutiven Aktivierung vieler Signalwege unterhalb/Downstream der veränderten BCR/ABL fusionierten Tyrosinkinase.Eine zielgerichtete Inhibierung von BCR/ABL mittels ABL-Kinase-Inhibitoren induziert Apoptose in BCR/ABL transformierten Zellen und hat eine komplette Remission in Ph+ Leukämie Patienten zur Folge. Eine große Anzahl an Patienten mit fortgeschrittener Ph+ Leukämie erleiden einen Rückfall und entwickeln Resistenzen. Die Mutation der Kinasedomäne verhindert die Bindung von Inhibitoren und stellt somit den häufigsten Mechanimus von erworbenen Resistenzen in Patienten mit Ph+ Leukämie. Die Tetramerizierung von BCR/ABL mittels der N-Terminalen coiled-coil region (CC) von BCR ist notwendig für die Aktivierung der ABl-Kinase. Das Targeting der CC-Domäne zwingt BCR/ABL in eine monomere Konformation, was zu einer Reduzierung der Kinasaktivität und einer erhöhten Imatinib-Sensitivität führt. Wir können zeigen, daß i) das Angreifen der Tetramerisierung mittels einem Peptide, welches die Helix2 der CC-Domäne repräsentiert, reduziert die Autophosphorylierung sowohl von WT BCR/ABL, als auch seinen Mutanten. ii) Die Helix-2 inhibiert unabhängig von vorkommenden Mutationen das transformierende Potential von BCR/ABL. iii) Aufgrund der Effekte auf das transformierende Potential und dem Faktor unabhängigen Wachstum von BCR/ABL, mit Ausnahme der T315I-Mutation, konnte eine effektive Kooperation zwischen Helix-2 und Imatinib gezeigt werden. Die gezielte Hemmung von BCR/ABL durch Inhibitoren in Form kleiner Moleküle macht das Potential zur Transformation von BCR/ABL rückgängig. Wir haben eindeutig bewiesen, dass das Zielen auf die, durch die N-terminale coiled-coil Domäne (CC) vermittelte, Tetramerisierung von BCR/ABL mithilfe kompetitiver Peptide, welche die Helix-2 von CC repräsentieren, ein wirkungsvoller therapeutischer Ansatz zur Behandlung der Ph+Leukämie ist. Um die kompetitiven Peptide zum Angriff auf BCR/ABL weiter zu entwickeln, erzeugten wir eine Membran permeables Helix-2 Peptid (MPH-2), indem wir die Helix-2 Peptide mit einem Peptid-Transduktions-Tag fusionierten. In dieser Studie berichten wir, dass MPH-2: (i) mit BCR/ABL in vivo interagierte; (ii) effizient die Autophosphorylierung von BCR/ABL hemmte; (iii) Wachstum und Viabilität von Ph+ leukämischen Zellen unterdrückte; und (iv) in einem in vivo Maus-Modell effizient in mononukleäre Zellen (MNC) transduziert wurde. Die T315I Mutation von BCR/ABL weist eine Resistenz gegen alle momentan sich in medizinischen Studien befindlichen ABL-kinase Inhibitoren und kompetitiven Peptiden auf. Es scheint nicht nur die Bindungsaffinität der Kinase Inhibitoren zu vermindern sondern erzeugt zusätzliche Eigenschaften, die das leukämogene Potential von BCR/ABL verstärken. Um die Rolle der T315I Mutation auf dessen fehlender Inhibition der für das leukämogene Potential wichtigen Oligomerisierung von BCR/ABL näher zu bestimmen, untersuchten wir seinen Einfluß auf zusätzliche “loss-of-function” Mutanten von BCR/ABL in bezug auf deren Fähigkeit eine Faktor-Unabhängigkeit zu erzeugen. Entsprechend erzeugten wir BCR/ABL Mutanten, denen notwendige funktionale Domänen bezüglich des onkogenen Potenzials fehlen. Im BCR-Anteil deletierten wir die N-terminale coiled coil (CC) Domäne, die Tyrosine Phosphorylierungs Stelle Y177 und die Serine/Threonine Kinase Domäne (ST) sowie im ABL_Anteil die inhibitorische SH3 (delta SH3-ABL) Domäne. Aus den vorliegenden Arbeiten ergaben sich folgende Ergebnisse i.) T315I stellt die fehlende Faktor Unabhängigkeit von hämatopoetischen Zellen mit Oligomerizations defizienten p185BCR/ABL Mutanten wieder her; ii.) Die Resistenz von p185-T315I gegen die Inhibition der Oligomerisation ist abhängig von der Phosphorylierung am Y177; iii.) Die Autophosphorylierung am Y177 wird durch die Inhibition der Oligomerisierung nicht beeinträchtigt, jedoch die Phosphorylierung am Y177 von endogenem BCR wird durch die T315I Mutation verstärkt; iv.) Die Effekte von T315I sind mit einer intakten ABL_Kinase Aktivität assoziiert; v.) Das Vorhandensein der T315I Mutation ist assoziiert mit einer verstärkten ABL_kinase Aktivität, welches sich auch in Mutanten zeigt, die die Y177 Phosphorylierung von endogenem BCR nicht induzieren; vi.) Es gibt keinen direkten Zusammenhang zwischen der ABL-Kinase Aktivität und der durch T315I induzierten Faktorunabhängigkeit. Im Gegensatz zu der ABL-T315I Mutante, die nur in der Anwesenheit der SH3 Domäne nicht in der Lage war eine Phosphorylierung am Y177 von endogenem BCR zu induzieren. Im Gegensatz zu seinem physiologischen Pendant c-Abl, ist die BCR/ABL Kinase, die den leukämischen Phänotyp induziert, konstitutiv aktiviert. Der N-Terminus von c-ABL (Cap region) wirkt an der Regulation seiner Kinasefunktion mit. Er ist myristoyliert und in einem Prozess, genannt „capping“ bindet der Myristinsäurerest an eine hydrophobe Tasche in der Kinasedomäne, bekannt als Myristinsäurebindungstasche. Daraus resultiert eine autoinhibitorische Konformation. Da die Cap-region durch den N-terminus von BCR/ABL ersetzt wurde, entgeht BCR/ABL dieser Autoinhibition. Allosterische Inhibition durch Myristeinimitatoren, wie GNF-2, sind in der Lage nicht mutiertes BCR/ABL zu inhibieren, nicht jedoch BCR/ABL, das die „Gatekeeper“-Mutation T315I beherbergt. Wir untersuchen hier die Möglichkeit die Effizienz der allosterischen Inhibtion durch Blockierung der BCR/ABL-Oligomerisierung zu erhöhen. Wir demonstrieren, dass die Inhibtion der Oligomerisierung nicht nur in der Lage war die Effizienz von GNF-2 auf das nicht mutierte BCR/ABL zu erhöhen, sondern auch die Resistenz von BCR/ABL-T315I zu überwinden hin zur allosterischen Hemmung. Diese Ergebnisse lassen stark annehmen, dass das Ansprechen der allosterischen Hemmung durch GNF-2 in umgekehrtem Verhältnis zum Grad der Oligomerisierung von BCR/ABL steht. Zusammengenommen deuten diese Daten auf eine Inhibierung der Tetramerizierung hin, welsche die BCR/ABL vermittelte Transformation hemmt. Diese führt zu einer Überwindung der Imatinib Resistenz. Diese Studie bietet erste Evidenz, dass ein effizientes Peptid-Transduktions-System die Anwendung von kompetitiven Peptiden, um auf die Oligomerisierungs-Schnittstelle von BCR/ABL zu zielen, in vivo unterstützt. Des weitern zeigen die Daten, daß T315I zusätzliche leukämische Aktivität von BCR/ABL induziert, welches eine mögliche Erklärung für klinische Prognose von Patienten mit BCR/ABL-T315I positiven Blasten darstellt. Zusammenfassend lässt sich sagen, dass unsere Beobachtungen einen neuen Ansatz für molekulare Angriffspunkte für BCR/ABL und seine resistenten Mutanten etablieren, bestehend aus der Kombination von Oligomerisierungs- und allosterischen Inhibitoren

Investigation of semi-solid metal processing route

Two main objectives were complete during this work. One was the design and construction of a high temperature capillary viscometer and the second was the modelling of semi-solid metal flow with a view to aiding the design and providing data for comparison purposes. The high temperature capilla ry viscometer has been constructed and has been used for preliminary testing. This device will be used to measure the viscosity of semi-solid metals under high temperature and shear rate conditions, similar to those found in industry. The capillary viscometer is a single point system that can be used to calculate the v isco s ity b y measuring the flow rate and pressure difference between the two end o f the capillary tube as the v isco s ity directly proportional to the pressure drop and inversely proportional to the flow rate. Design criteria included a requirement for a highly controllable temperature up to 800 °C, injection shear rates above 10 ,0 0 0 s '1, and controllable injection profiles. A 2D , two phase theoretical unsteady state model using a computational fluid dynamics (CFD) software F LU E N T was developed. This was used to evaluate the v isco s ity o f semi-solid metals passing through the designed capillary viscometer at injection speeds o f 0.075, 0.5, and 1 m/s. The effects o f fractions solid (fs) o f the metal from 0 .25 to 0.50 were also investigated. Strong correlations between these parameters and the resulting v iscosity were noted for the power law viscosity equations which were used to develop the Fluent models

SBS-based Tunable Microwave Photonic Notch Filter and Amplifier Simultaneously with Enhanced Gain, Bandwidth, and Polarisation Control up to 50 GHz

Stimulated Brillouin Scattering (SBS) based filters can provide high gain, narrow bandwidth, and wideband tunability, which are critical for modern radio frequency systems. However, it is important to optimise all performance parameters to obtain stable response over wideband along with high gain. We present a novel SBS-based Tuneable Microwave Photonics Notch Filter and Amplifier (TMWPNFA) configuration that can perform notch filtering, selective amplification or both simultaneously by exploiting additional Brillouin gain modes and using both SBS stokes and anti-stokes in single-mode fibre. The TMWPNFA amplification and notch suppression are shown for maximum of 50 GHz in Radio Domain, which is the highest reported tunability to our knowledge. The TMWPNFA exhibits high gain of ≃35dB by employing Radio Frequency Amplifier. The TMWPNFA achieves SBS gains from 24 to 4 dB over the range. The suppression achieved by TMWPNFA ranges from 12 to 3 dB. We demonstrated the SBS pump's RF Mixing approach for increasing the -3dB bandwidth of TMWPNFA to 35 MHz, resulting in greater separation of the amplification and suppression bands. The TMWPNFA phase noise distortion caused by SBS is measured to be < -8.6dBc/Hz at 125 kHz Spacing. The filter achieved sharp -3 dB bandwidth of 20 MHz and Q factor of 200 to 2500. The Degree of Polarisation of the SBS pump is shown to be the source of 6 dB gain control. It is shown that additional sound modes produced by SBS, separated by ≈2 x Bandwidth of SBS can be used for notch filtering while simultaneously achieving selective amplification. The proposed 50GHz TMWPNFA would provide unique benefits for satellite, aerospace and beyond communication technologies

User Transmit Power Minimization through Uplink Resource Allocation and User Association in HetNets

The popularity of cellular internet of things (IoT) is increasing day by day and billions of IoT devices will be connected to the internet. Many of these devices have limited battery life with constraints on transmit power. High user power consumption in cellular networks restricts the deployment of many IoT devices in 5G. To enable the inclusion of these devices, 5G should be supplemented with strategies and schemes to reduce user power consumption. Therefore, we present a novel joint uplink user association and resource allocation scheme for minimizing user transmit power while meeting the quality of service. We analyze our scheme for two-tier heterogeneous network (HetNet) and show an average transmit power of -2.8 dBm and 8.2 dBm for our algorithms compared to 20 dBm in state-of-the-art Max reference signal received power (RSRP) and channel individual offset (CIO) based association schemes

p185(BCR/ABL) has a lower sensitivity than p210(BCR/ABL) to the allosteric inhibitor GNF-2 in Philadelphia chromosome-positive acute lymphatic leukemia

Background: The t(9;22) translocation leads to the formation of the chimeric breakpoint cluster region/c-abl oncogene 1 (BCR/ABL) fusion gene on der22, the Philadelphia chromosome. The p185(BCR/ABL) or the p210(BCR/ABL) fusion proteins are encoded as a result of the translocation, depending on whether a "minor" or "major" breakpoint occurs, respectively. Both p185(BCR/ABL) and p210(BCR/ABL) exhibit constitutively activated ABL kinase activity. Through fusion to BCR the ABL kinase in p185(BCR/ABL) and p210(BCR/ABL) "escapes" the auto-inhibition mechanisms of c-ABL, such as allosteric inhibition. A novel class of compounds including GNF-2 restores allosteric inhibition of the kinase activity and the transformation potential of BCR/ABL. Here we investigated whether there are differences between p185(BCR/ABL) and p210(BCR/ABL) regarding their sensitivity towards allosteric inhibition by GNF-2 in models of Philadelphia chromosome-positive acute lymphatic leukemia. Design and methods: We investigated the anti-proliferative activity of GNF-2 in different Philadelphia chromosome-positive acute lymphatic leukemia models, such as cell lines, patient-derived long-term cultures and factor-dependent lymphatic Ba/F3 cells expressing either p185(BCR/ABL) or p210(BCR/ABL) and their resistance mutants. Results: The inhibitory effects of GNF-2 differed constantly between p185(BCR/ABL) and p210(BCR/ABL) expressing cells. In all three Philadelphia chromosome-positive acute lymphatic leukemia models, p210(BCR/ABL)-transformed cells were more sensitive to GNF-2 than were p185BCR/ABL-positive cells. Similar results were obtained for p185(BCR/ABL) and the p210(BCR/ABL) harboring resistance mutations. Conclusions: Our data provide the first evidence of a differential response of p185(BCR/ABL)- and p210(BCR/ABL)- transformed cells to allosteric inhibition by GNF-2, which is of importance for the treatment of patients with Philadelphia chromosome-positive acute lymphatic leukemia