AbstractPurpose: Hexokinase II (HK2) protein expression is elevated in glioblastoma (GBM), and we have shown that HK2 could serve as an effective therapeutic target for GBM. Here, we interrogated compounds that target HK2 effectively and restrict tumor growth in cell lines, patient-derived glioma stem cells (GSCs), and mouse models of GBM. Experimental Design: We performed a screen using a set of 15 drugs that were predicted to inhibit the HK2-associated gene signature. We next determined the EC50 of the compounds by treating glioma cell lines and GSCs. Selected compounds showing significant impact in vitro were used to treat mice and examine their effect on survival and tumor characteristics. The effect of compounds on the metabolic activity in glioma cells was also assessed in vitro. Results: This screen identified the azole class of antifungals as inhibitors of tumor metabolism. Among the compounds tested, ketoconazole and posaconazole displayed the greatest inhibitory effect on GBM both in vitro and in vivo. Treatment of mice bearing GBM with ketoconazole and posaconazole increased their survival, reduced tumor cell proliferation, and decreased tumor metabolism. In addition, treatment with azoles resulted in increased proportion of apoptotic cells. Conclusions: Overall, we provide evidence that azoles exert their effect by targeting genes and pathways regulated by HK2. These findings shed light on the action of azoles in GBM. Combined with existing literature and preclinical results, these data support the value of repurposing azoles in GBM clinical trials.

Supplemental Figure 1. Gene-set enrichment analysis (GSEA). Based on the list of top 200 differentially expressed genes with HK2 knockdown in the two cell lines (U87 and GSC30), a GSEA using the molecular signature database identified oncogenic signatures downregulated (A) or upregulated (B) with HK2 knockdown.

The assessment of groundwater quality is crucial for ensuring its safe and sustainable use for domestic and agricultural purposes. The Kurukshetra district in the Indian state of Haryana relies heavily on groundwater to meet household and agricultural needs. Sustainable groundwater management must be assessed in terms of suitability for domestic and agricultural needs in a region. The current study analyzed pre-monsoon geochemical data from groundwater samples in the study area for 1991, 2000, 2010, and 2020. A Geographic Information System (GIS) was used to create spatial distribution maps for hydrogen ion concentration, total hardness, total dissolved solids, electrical conductivity, sodium adsorption ratio, percent sodium, and residual sodium carbonate. The study area was divided into different groundwater quality zones for domestic and agricultural use as per Bureau of Indian Standards and World Health Organization norms. The integrated maps for agriculture and domestic use were prepared by weighted overlays of these parameters in GIS for 2020, highlighting spatial variations across the district. In 2020, approximately 0.52% of the district's area fell under the good class, while 94.41% was classified as permissible, and 5.07% as the doubtful class in terms of groundwater quality for domestic use. This indicates that the majority of the district falls under the permissible category for domestic water consumption. An area of 51.18% was found as good class, 48.43% as permissible class, and 0.39% as doubtful class for agricultural suitability, which indicates that almost the entire district's water is suitable for agricultural use. These results suggest that a significant portion of the district's groundwater is of acceptable quality for both domestic and agricultural purposes, although certain areas may require closer monitoring and management due to water quality issues. This study offers valuable insights into local water resource management and the promotion of sustainable agricultural practices at the district level.

Supplemental Figure 2. Ketoconazole and Posaconazole inhibit GBM growth in a U87 xenograft model.

The availability of groundwater is vital for the overall development of society. The rapid increase in human population, urbanization, and industrialization has caused intense deterioration of groundwater regime, especially in developing countries. Hence, assessment of the spatio-temporal distribution of groundwater is crucial for the prudent management of the water resources of a region, as it helps in the identification of critical zones and formulating appropriate strategies to deal with the problem. The objective of the study is to monitor the spatio-temporal changes in groundwater depth in Kurukshetra district, Haryana, using a Geographical Information System. The data of ninety-seven observation wells, from 1985 to 2020, were used for spatio-temporal analysis of depth to water level and water level fluctuation over a five-year interval. Inverse Distance Weighted interpolation technique was used to generate depth-to-water level and fluctuation maps. Vertical Electrical Sounding (VES) survey was conducted to understand the subsurface resistivity distribution for assessing groundwater conditions in the district. It was observed that 91

Groundwater is vital for meeting water demands in India, especially for agriculture, but faces stress from industrialization, urbanization, and climate change. Sustainable management, including understanding aquifers and recharge zones like palaeochannels, is essential to ensure long-term groundwater availability. The present research explored the applications of surface geophysical Dar-Zarrouk (D–Z) parameters, estimated from Vertical Electrical Sounding (VES) surveys conducted at seventeen locations, to assess hydrogeological conditions and correlate the findings with the identified palaeochannels within the alluvial area of Saraswati Nagar block of district Yamuna Nagar, Haryana, India. Further, as the study area is occupied with fresh groundwater, the estimated D–Z parameters including Transverse Resistance (T) and Longitudinal Conductance (S) values should be relatively on the higher side in comparison to the saline groundwater-occupied areas. In the study area, S values vary between 0.2025 (Sahabpur) and 2.49 (Talakaur) mho with an average value of 0.9364 mho, and T values vary between 922.96 (Bhamboli) and 5505 (Kabulpur) Ωm2 with an average value of 3000.75 Ωm2 respectively. The results of the electrical resistivity survey have been used for estimating the hydraulic conductivity (K) and transmissivity (t) . Hydraulic parameters such as hydraulic conductivity and transmissivity are pivotal in evaluating and controlling groundwater resources. The findings highlight the valuable insights gained for groundwater resource management. This type of study has not been attempted before by any researcher in this regions hence, it will greatly help in understanding the groundwater regime in the area.

Haryana is one of the dominant agrarian states of India but salinity in the groundwater is one of the major concerns in the state. The salinity in groundwater is observed from top itself in the central part of Haryana consisting of Hisar, Jind, Rohtak, and Jhajjar districts. As a result, local inhabitants are facing severe problems with the nonavailability of fresh drinking water. In some places, shallow aquifers are having marginally saline water which is used by the local inhabitants in dry months. Groundwater even in shallow aquifers also becomes saline due to less rainfall and intrusion of saline water from lower layers. In some areas, the thickness of freshwater columns has been reduced significantly due to the excessive withdrawal of fresh water and intrusion from underlying saline groundwater aquifers. It is therefore pertinent to study fresh/saline groundwater interface to solve these problems on scientific basis. The geophysical methods especially electrical resistivity method has proved very useful for the estimation of fresh/ saline groundwater interface. The present paper deals with the findings of electrical resistivity survey conducted in Adampur and Agroha blocks of district Hisar, Haryana, India. Thirty-five Vertical Electrical Soundings (VES) were conducted in these areas for this purpose. The results indicate that the entire study area is occupied with marginally saline to highly saline groundwater. The study shows the presence of a thin layer of marginally saline groundwater almost uniformly distributed in the entire study area.

The palaeochannel is one of the promising features to hold a considerable amount of groundwater and acts as an underground reservoir for supplementing groundwater resources. There is a need for site-specific studies for exploring new areas for further groundwater prospecting in the wake of dwindling groundwater resources. The groundwater exploration studies have been conducted along and across the possible Saraswati River palaeochannel in a part of the Kurukshetra district of Haryana to understand the subsurface groundwater regime. Electrical resistivity tomography (ERT) surveys were conducted at Garhi Roran and Indbari villages of Kurukshetra district, Haryana. The ERT results indicate broadly three distinct lithological units up to the explored depth of 20 meters (m). The third layer showed relatively higher resistivity in comparison to the second layer. Therefore, vertical electrical sounding (VES) surveys were conducted in the study area at eight villages in the Kurukshetra district, including Garhi Roran and Indbari villages. The inverted model was correlated with the available lithological information for various lithological units. The maximum depth of investigation derived from the VES surveys was found to be 120 m. Further, a palaeo-path of high resistivity was delineated from 15 to 50 m depth and the width of the palaeochannel was interpreted as about 10–12 km. The hydrological data analysis of nearby bore wells shows a highly productive zone of good-quality groundwater. The analysis of Dar–Zarrouk ( D–Z ) parameters also indicates the presence of palaeochannel in the study area.

The magnetotelluric (MT) method is a passive geophysical technique based on using time variations in the geoelectric and geomagnetic field to measure the electrical resistivity of the surface layer. It is one of the most effective geophysical techniques to study the deep structure of the Earth's crust, particularly in steep terrain like the Garhwal Himalaya region. MT responses are distorted as a result of undulating/rugged terrain. Such responses, if not corrected, can lead to the misinterpretation of MT data with respect to geoelectrical structures. In this study, two different correction procedures were used to compute the topography distortion for a synthetic model of the Garhwal Himalaya region from the Roorkee to the Gangotri section. A finite-difference algorithm was used to compute the MT responses (apparent resistivity and phase) for irregular terrain. The accuracy of the terrain correction procedures was checked using the results of different topography models for various periods from the literature. The relative errors between two terrain correction procedures were calculated with respect to the flat earth surface and were almost equal to zero for most of the sites along the Roorkee–Gangotri profile except at the foothill, where the error was high for shorter periods. The similar topography procedures of two terrain-corrected responses (TCR1 and TCR2) showed that there is no need for topography correction along the Roorkee–Gangotri profile because the slope angle is less than 1°.

Palaeochannels are remnants of rivers or stream channels filled with younger sediments over the period of time. In ancient times, these rivers/channels were thriving in phenomenal conditions, but due to frequent tectonic activities, they lost the direction of their original path and were gradually either lost or buried under thick beds of younger alluvium. Palaeochannels act as reservoirs for fresh groundwater since they are made up of coarser sediments and were formerly flowing rivers. Depending on the groundwater regime and local topography, these could either be saturated or dry. The palaeochannels have high groundwater potential if saturated. These are ideal sites for artificial groundwater recharge, if dry. The identification of palaeochannels becomes quite challenging if they are buried under thick deposits of finer younger sediments. In the present study, an attempt has been made to characterize the Saraswati River Palaeochannel in parts of Yamuna Nagar and Kurukshetra districts of Haryana by using surface and subsurface geophysical methods. Till date, the palaeochannels in this area were mainly discerned on the basis of remote sensing only; therefore, geophysical characterization of these palaeochannels has been attempted in this study. In surface geophysical methods, electrical resistivity surveys, especially gradient resistivity profiling (GRP) and vertical electrical sounding (VES), were conducted in the study area, while electrical and natural gamma logging was used as subsurface geophysical approaches to identify the coarser sands of buried palaeochannels. The main objective of the study was to characterize the Saraswati River palaeochannel and analyze the quality of the groundwater stored in the palaeochannel in the study area. The findings were compared with the well-log data and were found in good agreement.

The Western Himalaya is one of the most complex and heterogeneous seismotectonic units of the Alpide-Himalaya seismic belt. The region has distinctive physiographic characteristics because of the way that they have changed and evolved over the course of time. The purpose of the present investigation is to understand the seismotectonic architecture beneath the study area which is seismically very active. Twenty broad-band seismic stations have been employed to record the surface wave data to study the crustal structure beneath the western Himalayas. We find phase and group velocities of Rayleigh waves for the region with periods between 4 and 30s. To obtain layered S wave velocity models, the dispersion curves are inverted. The crustal velocity structure beneath the region is found to vary significantly. The average estimated S-wave velocity is ~ 3.8 km/s down to 30 km depth. We also observed a low-velocity layer in the middle crust of the higher Himalayas section and the interpretation from the present analysis is consistent with available geological data.

Snow avalanches cause danger to human lives and property worldwide in high-altitude mountainous regions. Mathematical models based on past data records can predict the danger level. In this paper, we are proposing a neural network model for predicting avalanches. The model is trained with a quality-controlled sub-dataset of the Swiss Alps. Training accuracy of 79.75 % and validation accuracy of 76.54 % have been achieved. Comparative analysis of neural network and random forest models concerning metrics like precision, recall, and F1 has also been carried out.This paper is organized as follows. Related literature is briefly overviewed in Sect. 2. The dataset used for the training of neural networks is described in Sect. 3. After that, in Sect. 4, we explain the neural network model, tuning of hyperparameters, and evaluation metrics. Random forest machine learning method details applied to the same dataset are described in Sect. 5. Results from both methods are compared and analysed in Sect. 6. The paper is concluded in Sect. 7.

AbstractThe optimum 1D velocity model is calculated for the Kinnaur sector of the NW Himalaya utilizing the arrival time information of the local earthquakes (137 no.) recorded with 12 broadband seismic network within the azimuthal gap of ≤180°. This optimum 1D velocity model is a five-layer model and ranges from the surface to 90 km in the shallow mantle. P velocity varies from 5.5 km/s to 8.6 km/s in the crust and upper mantle, and S-wave velocity varies between 3.2 km/s and 4.9 km/s for the same range. When we relocated the earthquakes with the Joint Hypocenter Determination program incorporating the optimum 1D velocity model, it resulted in a lower RMS residual error of 0.23 s for the hypocenter locations compared to initial hypo71 locations. A total of 1274 P and 1272 S arrival times were utilized to compute station delays. We observed positive variations in P-station delays from -0.19 s below the PULG station to 0.11 s below the SRHN station. Similarly, for S-station delays, we observed negative delays at each individual site from -0.65 s at LOSR station to -0.16 s at the SRHN station. This large variation in P- and S-station delays corresponds to the 3D nature of the subsurface below the Kinnaur Himalaya. The relocated seismicity is clustered along the STD fault at sub-Moho and Moho depths ranging between 40 km and 80 km. The seismicity distribution aligned across the strike of the STD and along the strike of the Kaurik-Chango fault (KCF) can be attributed to the cross-fault interactions of the KCF and the STD fault in the area. We also observed bimodal depth distribution of seismicity in the Higher and Tethys Himalayas. The occurrence of earthquakes down to a depth of ~0-40 km and 50-80 km in the study area can be interpreted in terms of stress contribution from interseismic stress loading associated with the India-Eurasia collision tectonics. The presence of hypocentres in the shallow mantle at 120 km depth highlights the strength of the mantle, which seems to be deforming in a brittle manner below the region. The computed focal mechanisms exhibit generally the flexing of the Indian plate below the Lesser Himalaya with shear parallel to the strike of the MCT and extension orthogonal to it. This study shows deformation over the entire crust and shallow upper mantle levels, with differential stress conditions. Thus, we can consider the crust and the shallow upper mantle down to depths of 120 km to be seismogenic in nature and is capable of producing the microseismicity beneath the Kinnaur Himalaya.

On 7 February 2021, Chamoli district (Uttarakhand, India) was devastated by a deadly rock-ice avalanche that led to a large causality of more than 200 people and a huge economic loss. We found noteworthy sequence of precursory signals of main failure/detachment preceded by a dynamic nucleation phase. The rock-ice avalanche appears to have been initiated by seismic precursors which were continuously active for 2:30 h prior to main detachment. The seismic amplitude, frequency characteristics and signal-to-noise ratio variation of detected tremors indicate static to dynamic changes in nucleation phase located at the source of detached wedge. The characteristics of seismic data distinguished debris flow and hitting obstacles from other seismic sources and allowed the estimations of debris flow speed. We analyzed and verified the seismic signals with field evidences to estimate the associated impacts and velocity of dynamic flow. The proximal high-quality seismic data allowed us to reconstruct the complete chronological sequence and evaluate impacts since the initiation of nucleation phase to its advancement. Furthermore, we suggest that real-time seismic monitoring with existing network and future deployment of integrated dense network can be used for forecasting of flow events and hazard mitigation in the downstream.

The converted wave seismological data across the Doda-Kishtwar region in the Kashmir seismic gap of North-West Himalaya has been used in this study. The results based on inversion of receiver functions (RFs) reveals, for the first time, the crustal velocity-structure with a Low-Velocity Layer (LVL). The crustal thickness varies from 47 km to 58 km from south to north, and the Main Himalayan Thrust exists at depth between 21 to 26 km. The LVL with its top lying at 11 to 13 km extends downward up to a depth of 29 km, and shows Vp/Vs of 1.9. This high value of Vp/Vs may be explained by the presence of fluid/fractional melt in the depth range between 10 to 15 km. We suggest that the LVL and hence the fluids/melts could be one of the possible reasons for the generation of upper-to-mid-crustal earthquakes. Interestingly, the LVL coincides with the focal depths of most of the earthquakes, observed in this region.

The Sikkim Himalaya is the eastern division of the Himalayan arc and is located between the Nepal and Bhutan Himalaya. Due to the complex geology, the abnormal trend of Main Central Thrust (MCT) and duplex structure in Higher Himalayan Crystalline (HHC) zone, the magnetotelluric (MT) data in Sikkim Himalayan region is modeled using topographic correction. In the present research, the three-dimensional (3-D) topographic correction using impedance tensor correction algorithm was applied to eight sites from the Sikkim Himalayan region and then inverted on the flat terrain. This paper presents the effectiveness of the 3-D topographic correction on two dimensional (2-D) modeling by comparing inversion models (a) model with distorted data on flat terrain, (b) distorted data with topography, (c) 3-D topography corrected data on flat terrain, to mitigate the effects of topography in MT data. The major outcome of the present study is in the form deciphering much bigger dimension in case of topography corrected data of the overlying resistive block (∼9000 ohm.m) having depth up to 15 km between the sites Manglay and Lema, which correlate with the exposures of the Daling Formation in the northern Lesser Himalayan Sequence (LHS) and Lingste granite in the MCT zone. The topography corrected MT data brought out the topography of the resistive Indian crust more clearly.

Teleseismic earthquakes data recorded by 8 broadband digital seismic stations deployed in the Kumaun-Garhwal and adjoining area of NW Himalaya are analyzed to investigate the seismic anisotropy in the upper mantle. Shear-wave splitting parameters (ɸ and ∂t) derived from the analysis of core-refracted SKS/SKKS phases provide first hand information about seismic anisotropy and deformation in the upper mantle beneath the region. A total, 209 good measurements of seismic anisotropy have been obtained from the two years of collected high-quality teleseismic data in the study region. The analysis shows considerable strength of anisotropy (delay time(∂t) 0.6–2.8 s) with average ENE–WSW oriented fast polarization orientation at most of the stations while other one either along with the absolute plate motion (APM) of the Indian plate or parallel to strike of the Himalayan mountain belt. The Fast axis direction observed at stations close to between the MBT and MCT aligns parallel to the strike of local geological faults and orthogonal to absolute plate motion (APM) direction of the Indian plate. The large variation in the splitting strength and fast polarization trends around the Kumaun-Gharwal and adjacent in NW Himalaya have invoked both lithospheric and asthenospheric anisotropy.

The Anderson?s theory (Anderson, 1951) can be utilized to understand the allocation of principal stresses. For various tectonic regimes, the global seismicity trend for crustal earthquakes of less than 20 km depth suggests that the source fault inclination also plays a critical part in the propagation of the aftershocks in the subsurface rupture with respect to the mainshock earthquake. It has also been observed that majority of the compression earthquakes that display upward seismicity migration typically occur along steep faults. However, in the context of Himalaya seismicity, the opposite migratory behaviour of the aftershock sequence is observed even along the gentle dipping source faulting. The failure envelope Mohr?s diagram is used to understand the alteration in the dynamics of the subsurface locked zone of Himalayan Seismic Belt (HSB). This study discusses the alteration in the effective strength of the rock mass which imply the variation in the crustal hydrostatic fluid pressure at shallow depth (0?15 km). Different earthquakes and their aftershocks sequence of Himalayan terrain have been incorporated to corroborate the role of orientation of tectonic principal stresses, subsurface morphology and fluids/partial melts if present. In addition, topography contributes to the vertical loads and development of the subsurface geometry, therefore its role and its influence on seismicity has been discussed. This study highlights the controlling factors and the trend of the principal applied stresses and subsurface fluids in the distribution of aftershock sequences along tectonic regime of the Himalayan arc.