Pontine tubercular abscess: A rare presentation of CNS tuberculosis masquerading as glioma in a child.

Tuberculous brain abscess (TBA) in a child was initially misdiagnosed as glioma. Two craniotomies, abscess drainage, and anti-tubercular therapy led to recovery. Pontine TBA, though rare and atypical, can have better outcome with timely intervention.

Targeting MYC effector functions in pancreatic cancer by inhibiting the ATPase RUVBL1/2.

OBJECTIVE: The hallmark oncogene MYC drives the progression of most tumours, but direct inhibition of MYC by a small-molecule drug has not reached clinical testing. MYC is a transcription factor that depends on several binding partners to function. We therefore explored the possibility of targeting MYC via its interactome in pancreatic ductal adenocarcinoma (PDAC). DESIGN: To identify the most suitable targets among all MYC binding partners, we constructed a targeted shRNA library and performed screens in cultured PDAC cells and tumours in mice. RESULTS: Unexpectedly, many MYC binding partners were found to be important for cultured PDAC cells but dispensable in vivo. However, some were also essential for tumours in their natural environment and, among these, the ATPases RUVBL1 and RUVBL2 ranked first. Degradation of RUVBL1 by the auxin-degron system led to the arrest of cultured PDAC cells but not untransformed cells and to complete tumour regression in mice, which was preceded by immune cell infiltration. Mechanistically, RUVBL1 was required for MYC to establish oncogenic and immunoevasive gene expression identifying the RUVBL1/2 complex as a druggable vulnerability in MYC-driven cancer. CONCLUSION: One implication of our study is that PDAC cell dependencies are strongly influenced by the environment, so genetic screens should be performed in vitro and in vivo. Moreover, the auxin-degron system can be applied in a PDAC model, allowing target validation in living mice. Finally, by revealing the nuclear functions of the RUVBL1/2 complex, our study presents a pharmaceutical strategy to render pancreatic cancers potentially susceptible to immunotherapy.

Evaluating aortomesenteric parameters in a tertiary center of Nepal for superior mesenteric artery syndrome diagnosis and risk factors: cross-sectional study.

Background and objectives: This study examines aortomesenteric angle (AMA) and distance (AMD), which are critical in superior mesenteric artery (SMA) syndrome. Addressing the scarcity of SMA cases, the research explores potential links with lower BMI and aims to establish normative data for diagnostic and predictive purposes, using contrast-enhanced computed tomography (CT) scans across various BMI and sex categories. Methodology: A retrospective quantitative cross-sectional study was conducted on 189 patients undergoing abdominal contrast-enhanced CT scans between December 2019 and December 2020. Ethical clearance was obtained, and participants provided informed consent. Exclusion criteria targeted specific medical histories. Patient demographics, BMI categories, and imaging data were recorded. Helical 128-slice CT scans were employed, with sagittal-oblique multiplanar reconstructions for parameter assessments. Statistical analysis utilized SPSS 26.0, including Pearson correlation coefficients and mean calculations. Results: The study reveals a mean AMA of 54.07°±8.53° and a mean distance of 16.25±3.44 mm. Elevated BMI is found to positively correlate with AMA and distance, indicating that higher BMI values may augment these parameters, with an additional positive correlation observed between AMA and distance. No significant correlations are found with patient age or sex. Conclusion: The study concludes that decreased BMI may pose a potential risk for SMA syndrome, as evidenced by the observed correlations with aortomesenteric parameters. Understanding these normal values in the Nepalese population is critical for accurate diagnoses and predictions using CT scans. The research highlights the impact of demographic factors on these parameters and emphasizes their significance in clinical assessments related to SMA syndrome.

Implications of irregular shelterwood system on regeneration and species diversity of Sal (Shorea robusta Gaertn. f.) forest in Nepal.

Silvicultural systems are essential for effective forest management and utilize the resources by conserving biodiversity, health, and valuable services forests offer to society. However, Nepal faces a significant knowledge gap due to the limited data on the effect of silvicultural systems and forest management practices on tree diversity and regeneration. Therefore, this study was conducted to assess the effects of canopy opening on natural regeneration and species diversity of Sal (Shorea robusta Gaertn. f.) forest in comparison to managed and control blocks in the southern plains of Nepal under irregular shelterwood systems. The vegetation sampling was carried out by the quadrat method (plot of 10 m* 10 m) for studying 48 plots in both managed and control forest areas. The Shannon-Wiener Index and the Simpson Index were used to measure species diversity, whereas Margalef's index was used to measure species richness. Dominant tree species in both managed and control forest areas were identified through the Important Value Index (IVI). The seedling and sapling density of Sal was found to be significantly higher (p < 0.05) in managed blocks. Seedlings of Sal from the seed origin were notably more abundant in the managed block (p < 0.01), whereas those from coppice origin exhibited higher numbers in the control block (p < 0.01). Sal was found to be dominant species in both managed block (IVI = 199.94) and control (IVI = 108.34). The species diversity and richness were significantly declining in the managed forest (p < 0.01) with higher species dominance in comparison to the control blocks. Our study found a positive correlation of canopy cover with species diversity (r = 0.69, p < 0.01) and richness (r = 0.59, p < 0.01) whereas a negative correlation with seedling (r = -0.43, p < 0.01) and sapling density (r = -0.16, p < 0.01). The application of the irregular shelterwood system in study area has effectively promoted natural Sal regeneration while concurrently reducing species diversity. To strike a balance between timber production and biodiversity conservation in these forests, further research focusing on moderating felling intensity within the irregular shelterwood system is strongly recommended.

Carbon footprint of Nepalese healthcare system: A study of Dhulikhel Hospital.

Background: Though direct greenhouse gas emissions cannot be observed in health care sectors, there can exist indirect emissions contributing to global climate change. This study addresses the concept of the carbon footprint and its significance in understanding the environmental impact of human activities, with a specific emphasis on the healthcare sector through gate-to-gate (GtoG) life cycle assessment. Transportation, energy consumption, and solid waste generated by hospitals are the primary sources of carbon emissions. Methods: Different standards, guidelines and parameters were used to estimate emissions from both the primary and secondary data. All steps and sub-steps involved in GtoG were accessed and analyzed within the standard ISO 14040:44 guideline. An extensive review of existing literature was carried out for the evaluation and verification of secondary data. Results: The total carbon footprint of generators, electricity consumption, transportation activities, LPG cylinders, PV systems was found to be 58,780 kg-CO2-eq/yr, 519,794 kg-CO2-eq/yr, 272,375 kg-CO2-eq/yr, 44,494 kg-CO2-eq/yr, 35,283 kg-CO2-eq/yr respectively and the emissions from non-biodegradable solid waste was found to be 489,835 kg-CO2/yr. Local air pollutants such as PM 10, CO, SO 2, NO X, and VOCs generated by generators and transportation were also estimated. The CH 4 emissions from liquid waste were 1177.344 kg CH 4/BOD yr, and those from biodegradables were 3821.6954 kg CH4/yr. Conclusions: Healthcare professionals and policymakers can take action to reduce the sector's carbon footprint by implementing best practices and encouraging sustainable behavior. This study can be taken as foundation for further exploration of indirect emissions from healthcare sectors not only in Nepal but also in south Asian scenario.

Feasibility of bubble non-invasive positive pressure ventilation, a first-in-human study.

PURPOSE: Infant respiratory distress is  a significant cause of mortality globally. Bubble continuous positive airway pressure (CPAP) is a simple and effective therapy, but sicker infants may require additional support such as non-invasive positive-pressure ventilation (NIPPV). We investigated the feasibility of a simple, low-cost, non-electric bubble NIPPV device. METHODS: In this cross-over feasibility study, seven newborns with moderate respiratory distress (Downes score ≥ 3), weight > 1500 g and gestational age > 32 weeks were randomized to  4 h of treatment with bubble CPAP (5-8 cm H2O) vs. bubble NIPPV (Phigh 8-10 cm H2O/Plow 5-8 cm H2O) followed by 4 h of the alternate treatment. Treatment order (CPAP vs. NIPPV) was randomized. Outcome measures included hourly vital signs, Downes score and O2 saturation. Adverse events including pneumothorax, nasal septal necrosis, necrotizing enterocolitis and death before discharge were also recorded. RESULTS: It took nurses 39 (7.3) s to assemble the bubble NIPPV device. Patients had similar vital signs and Downes scores on both treatments; median (IQR) values on bubble CPAP vs. bubble NIPPV were: heart rate 140 (134.5, 144), 140 (134.5, 144); respiratory rate 70 (56, 80), 65 (58, 82), Downes score 4 (3, 5.75), 4 (3, 5), O2 96 (94, 98), 97 (96, 98). All newborns survived to discharge and there were no adverse events. . CONCLUSIONS: A simple, low-cost, non-electric method of providing NIPPV for newborns with respiratory distress is feasible in limited resource settings. Randomized-controlled trials comparing bubble CPAP and bubble NIPPV are justified.

Innovations and adaptations in neonatal and pediatric respiratory care for resource constrained settings.

Respiratory disease is a leading cause of death in children under 5 years of age worldwide, and most of these deaths occur in low- to middle-income countries (LMICs) where advanced respiratory care technology is often limited. Much of the equipment required to provide advanced respiratory care is unavailable in these areas due to high costs, the need for specialty trained personnel, and myriad other resource constraints that limit uptake and sustainable use of these devices, including reliable access to electricity, sensitive equipment needing frequent maintenance, single-patient-use supplies, and lack of access to sterilization equipment. Compounding the problem, pediatrics is uniquely challenging in that one size does not fit all, or even most patients. Despite these substantial barriers, numerous innovations in respiratory care technology have been made in recent years that have brought increasing access to high quality respiratory care in some of the most remote areas of the world. In this article, we intend to review the global burden of respiratory diseases for children, highlight the prototypical innovations that have been made in bringing respiratory care to LMICs, spotlight some of the technologies being actively developed to improve respiratory care in resource-constrained settings, and conclude with a discussion highlighting areas where further innovation is still needed.

Waterlogging during the reproductive growth stage causes physiological and biochemical modifications in the leaves of cowpea (Vigna unguiculata L.) genotypes with contrasting tolerance.

Waterlogging causes various metabolic, physiological, and morphological changes in crops, resulting in yield loss of most legumes in rainfed and irrigated agriculture. However, research on cowpea genotypes using physiological and biochemical traits as a measure of tolerance to waterlogging stress is limited. We evaluated the impacts of 7 days of waterlogging (DOW) and 7 days of recovery (DOR) on the physiology and biochemistry of two cowpea (Vigna unguiculata (L.) Walp) genotypes (UCR 369 and EpicSelect.4) with contrasting waterlogging tolerance. Cowpea genotypes were grown in a controlled environment until the R2 stage and then subjected to 7 DOW. Later, the waterlogged plants were reoxygenated for an additional 7 DOR. Overall, cowpea genotypes had a contrasting response to waterlogging using different mechanisms. Compared to the control, the photosynthetic parameters of both cowpea genotypes were impaired under 7 DOW and could not recover at 7 DOR, with a larger decline in EpicSelect.4.7 DOW caused significant loss in the chlorophyll and carotenoid content of both genotypes. However, only waterlogged UCR 369 was not photo-inhibited and able to restore the levels of chlorophyll and carotenoids at 7 DOR. In addition, 7 DOW induced intense stress in UCR 369 with increased zeaxanthin, sucrose, and flavonoid content, while these metabolites were decreased in EpicSelect.4. On the other hand, glucose, fructose, and phenolic content were increased in EpicSelect.4 but decreased in UCR 369 at 7 DOR. In summary, compared to EpicSelect.4, UCR 369 restored their photosynthetic pigments and metabolites to the control levels at 7 DOR, indicating a likely tolerance to waterlogging stress.

Growth and Photosynthetic Responses of Cowpea Genotypes under Waterlogging at the Reproductive Stage.

Waterlogging is an important environmental stress limiting the productivity of crops worldwide. Cowpea (Vigna unguiculata L.) is particularly sensitive to waterlogging stress during the reproductive stage, with a consequent decline in pod formation and yield. However, little is known about the critical processes underlying cowpea's responses to waterlogging during the reproductive stage. Thus, we investigated the key parameters influencing carbon fixation, including stomatal conductance (gs), intercellular CO2 concentration, chlorophyll content, and chlorophyll fluorescence, of two cowpea genotypes with contrasting waterlogging tolerance. These closely related genotypes have starkly contrasting responses to waterlogging during and after 7 days of waterlogging stress (DOW). In the intolerant genotype ('EpicSelect.4'), waterlogging resulted in a gradual loss of pigment and decreased photosynthetic capacity as a consequent decline in shoot biomass. On the other hand, the waterlogging-tolerant genotype ('UCR 369') maintained CO2 assimilation rate (A), stomatal conductance (gs), biomass, and chlorophyll content until 5 DOW. Moreover, there was a highly specific downregulation of the mesophyll conductance (gm), maximum rate of Rubisco (Vcmax), and photosynthetic electron transport rate (Jmax) as non-stomatal limiting factors decreasing A in EpicSelect.4. Exposure of EpicSelect.4 to 2 DOW resulted in the loss of PSII photochemistry by downregulating the PSII quantum yield (Fv/Fm), photochemical efficiency (ΦPSII), and photochemical quenching (qP). In contrast, we found no substantial change in the photosynthesis and chlorophyll fluorescence of UCR 369 in the first 5 DOW. Instead, UCR 369 maintained biomass accumulation, chlorophyll content, and Rubisco activity, enabling the genotype to maintain nutrient absorption and photosynthesis during the early period of waterlogging. However, compared to the control, both cowpea genotypes could not fully recover their photosynthetic capacity after 7 DOW, with a more significant decline in EpicSelect.4. Overall, our findings suggest that the tolerant UCR 369 genotype maintains higher photosynthesis under waterlogging stress attributable to higher photochemical efficiency, Rubisco activity, and less stomatal restriction. After recovery, the incomplete recovery of A can be attributed to the reduced gs caused by severe waterlogging damage in both genotypes. Thus, promoting the rapid recovery of stomata from waterlogging stress may be crucial for the complete restoration of carbon fixation in cowpeas during the reproductive stage.

Short waterlogging events differently affect morphology and photosynthesis of two cucumber (Cucumis sativus L.) cultivars.

Waterlogging induces growth and developmental changes in sensitive crops such as cucumber (Cucumis sativus L.) during early plant development. However, information on the physiological mechanisms underpinning the response of cucumber plants to waterlogging conditions is limited. Here, we investigated the effects of 10-day waterlogging stress on the morphology, photosynthesis, and chlorophyll fluorescence parameters in two cultivars of cucumber seedlings. Waterlogging stress hampered cultivars' growth, biomass accumulation, and photosynthetic capacity. Both cultivars also developed adventitious roots (ARs) after 10 days of waterlogging (DOW). We observed differential responses in the light- and carbon-dependent reactions of photosynthesis, with an increase in light-dependent reactions. At the same time, carbon assimilation was considerably inhibited by waterlogging. Specifically, the CO2 assimilation rate (A) in leaves was significantly reduced and was caused by a corresponding decrease in stomatal conductance (gs). The downregulation of the maximum rate of Rubisco efficiency (Vcmax) and the maximum rate of photosynthetic electron transport (Jmax) were non-stomatal limiting factors contributing to A reduction. Exposure of cucumber to 10 DOW affected the PSII photochemistry by downregulating the PSII quantum yield (ΦPSII). The redox state of the primary quinone acceptor in the lake model (1-qL), a measure of the regulatory balance of the light reactions, became more oxidized after 10 DOW, indicating enhanced electron sink capacity despite a reduced A. Overall, the results suggest that waterlogging induces alterations in the photochemical apparatus efficiency of cucumber. Thus, developing cultivars that resist inhibition of PSII photochemistry while maintaining carbon metabolism is a potential approach for increasing crops' tolerance to waterlogged environments.

Enhanced seedling growth by 3-n-pentadecylphenolethanolamide is mediated by fatty acid amide hydrolases in upland cotton (Gossypium hirsutum L.).

Fatty acid amide hydrolase (FAAH) is a conserved amidase that is known to modulate the levels of endogenous N-acylethanolamines (NAEs) in both plants and animals. The activity of FAAH is enhanced in vitro by synthetic phenoxyacylethanolamides resulting in greater hydrolysis of NAEs. Previously, 3-n-pentadecylphenolethanolamide (PDP-EA) was shown to exert positive effects on the development of Arabidopsis seedlings by enhancing Arabidopsis FAAH (AtFAAH) activity. However, there is little information regarding FAAH activity and the impact of PDP-EA in the development of seedlings of other plant species. Here, we examined the effects of PDP-EA on growth of upland cotton (Gossypium hirsutum L. cv Coker 312) seedlings including two lines of transgenic seedlings overexpressing AtFAAH. Independent transgenic events showed accelerated true-leaf emergence compared with non-transgenic controls. Exogenous applications of PDP-EA led to increases in overall seedling growth in AtFAAH transgenic lines. These enhanced-growth phenotypes coincided with elevated FAAH activities toward NAEs and NAE oxylipins. Conversely, the endogenous contents of NAEs and NAE-oxylipin species, especially linoleoylethanolamide and 9-hydroxy linoleoylethanolamide, were lower in PDP-EA treated seedlings than in controls. Further, transcripts for endogenous cotton FAAH genes were increased following PDP-EA exposure. Collectively, our data corroborate that the enhancement of FAAH enzyme activity by PDP-EA stimulates NAE-hydrolysis and that this results in enhanced growth in seedlings of a perennial crop species, extending the role of NAE metabolism in seedling development beyond the model annual plant species, Arabidopsis thaliana.

Screening of cowpea (Vigna unguiculata (L.) Walp.) genotypes for waterlogging tolerance using morpho-physiological traits at early growth stage.

The majority of cowpea (Vigna unguiculata (L.) Walp.) produced in the U.S. is planted shortly after the summer rains and subsequently depends on rain or artificial irrigation. Therefore, excessive precipitation and poor soil drainage will cause cowpea plants to suffer temporary waterlogging, reducing the submerged tissue's oxygen level. Although cowpea is sensitive to waterlogging, excessive moisture can induce several morpho-physiological changes with adverse impacts on yield in its early stages of development. The current study subjected 30 cowpea genotypes to 10-days of waterlogging at the seedling stage under a controlled environment. The dynamic changes of 24 morpho-physiological parameters under waterlogging and optimal water conditions were analyzed to understand cowpea's response to waterlogging. Significant waterlogging treatment, cowpea genotypes, and their interactions (P < 0.001) were observed for most of the measured parameters. The results indicated that plant height (PH), leaf area (LA), fresh (FW) and dry weight (DW) of cowpea genotypes were significantly decreased under waterlogging compared to the control treatments. Similar results were obtained for net photosynthesis (Pn), stomatal conductance (gs), intercellular CO2 concentration (Ci), and transpiration rate (E). However, the water use efficiency (WUE) and adventitious roots (ARs) increased linearly under waterlogging conditions. Waterlogging also declined chlorophyll fluorescence parameters except non-photochemical quenching (qN), which increased with excess soil moisture. In addition, waterlogging tolerance coefficient (WTC) and multivariate analysis (MCA) methods were used to characterize cowpea genotypes for waterlogging tolerance. Accordingly, the cowpea genotype Dagupan Pangasinan, UCR 369, and Negro were classified as waterlogging tolerant, while EpicSelect.4 and ICARDA 140071, as the most waterlogging sensitive. The cowpea genotypes and morpho-physiological traits determined from this study may be useful for genetic engineering and breeding programs that integrate cowpea waterlogging tolerance.

Generation of auxin inducible degron (AID) knock-in cell lines for targeted protein degradation in mammalian cells.

Targeted protein degradation using degrons, such as the mini-Auxin-inducible degron (mAID), has an advantage over genetic silencing/knockout. However, the efficiency of sgRNA, homologous recombination, tedious expansion, and screening single clones makes the process of tagging endogenous proteins long and laborious. This protocol describes a practical and economical way to obtain AID-tagged endogenous proteins using CRISPR/Cas9-mediated homology-directed repair (HDR). We use the generation of endogenously AID-tagged SPT6 in U2OS cells as an example but provide sufficient details for usage in other cell types. For complete details on the use and execution of this protocol, please refer to Narain et al. (2021).

LC-HRMS Profiling and Antidiabetic, Antioxidant, and Antibacterial Activities of Acacia catechu (L.f.) Willd.

Acacia catechu (L.f.) Willd is a profoundly used traditional medicinal plant in Asia. Previous studies conducted in this plant are more confined to extract level. Even though bioassay-based studies indicated the true therapeutic potential of this plant, compound annotation was not performed extensively. This research is aimed at assessing the bioactivity of different solvent extracts of the plant followed by annotation of its phytoconstituents. Liquid chromatography equipped with high resolution mass spectrometry (LC-HRMS) is deployed for the identification of secondary metabolites in various crude extracts. On activity level, its ethanolic extract showed the highest inhibition towards α-amylase and α-glucosidase with an IC50 of 67.8 ± 1 µg/mL and 10.3 ± 0.1 µg/mL respectively, inspected through the substrate-based method. On the other hand, the plant extract showed an antioxidant activity of 23.76 ± 1.57 µg/mL, measured through radical scavenging activity. Similarly, ethyl acetate and aqueous extracts of A. catechu showed significant inhibition against Staphylococcus aureus with a zone of inhibition (ZoI) of 13 and 14 mm, respectively. With the LC-HRMS-based dereplication strategy, we have identified 28 secondary metabolites belonging to flavonoid and phenolic categories. Identification of these metabolites from A. catechu and its biological implication also support the community-based usage of this plant and its medicinal value.

Targeted protein degradation reveals a direct role of SPT6 in RNAPII elongation and termination.

SPT6 is a histone chaperone that tightly binds RNA polymerase II (RNAPII) during transcription elongation. However, its primary role in transcription is uncertain. We used targeted protein degradation to rapidly deplete SPT6 in human cells and analyzed defects in RNAPII behavior by a multi-omics approach and mathematical modeling. Our data indicate that SPT6 is a crucial factor for RNAPII processivity and is therefore required for the productive transcription of protein-coding genes. Unexpectedly, SPT6 also has a vital role in RNAPII termination, as acute depletion induced readthrough transcription for thousands of genes. Long-term depletion of SPT6 induced cryptic intragenic transcription, as observed earlier in yeast. However, this phenotype was not observed upon acute SPT6 depletion and therefore can be attributed to accumulated epigenetic perturbations in the prolonged absence of SPT6. In conclusion, targeted degradation of SPT6 allowed the temporal discrimination of its function as an epigenetic safeguard and RNAPII elongation factor.

Antidiabetic, Antimicrobial, and Molecular Profiling of Selected Medicinal Plants.

Natural products have been the center of attraction ever since they were discovered. Among them, plant-based natural products were popular as analgesics, anti-inflammatory, antidiabetic, and cosmetics and possess widespread biotechnological applications. The use of plant products as cosmetics and therapeutics is deep-rooted in Nepalese society. Although there are few ethnobotanical studies conducted, extensive research of these valuable medicinal plants has not been a priority due to the limitation of technology and infrastructure. Here, we selected 4 traditionally used medicinal plants to examine their bioactive properties and their enzyme inhibition potential. α-Glucosidase and α-amylase inhibitory activities were investigated using an in vitro model followed up by antioxidant and antimicrobial activities. The present study shows that ethyl acetate fraction of Melastoma melabathrium (IC50 9.1 ± 0.3 µg/mL) and water fraction Acacia catechu (IC50 9.0 ± 0.6 µg/mL) exhibit strong α-glucosidase inhibition. Likewise, the highest α-amylase inhibition was shown by crude extracts of Ficus religiosa (IC50 29.2 ± 1.2 µg/mL) and ethyl acetate fractions of Shorea robusta (IC50 69.3 ± 1.1 µg/mL), and the highest radical scavenging activity was shown by F. religiosa with an IC50 67.4 ± 0.6 µg/mL. Furthermore, to identify the metabolites within the fractions, we employed high-resolution mass spectrometry (LC-HRMS) and annotated 17 known metabolites which justify our assumption on activity. Of 4 medicinal plants examined, ethyl acetate fraction of S. robusta, ethyl acetate fraction of M. melabathrium, and water or ethyl acetate fraction of A. catechu extracts illustrated the best activities. With our study, we set up a foundation that provides authentic evidence to the community for use of these traditional plants. The annotated metabolites in this study support earlier experimental evidence towards the inhibition of enzymes. Further study is necessary to explore the clinical efficacy of these secondary molecules, which might be alternatives for the treatment of diabetes and pathogens.

Design, Synthesis, and Evaluation of WD-Repeat-Containing Protein 5 (WDR5) Degraders.

Histone H3K4 methylation serves as a post-translational hallmark of actively transcribed genes and is introduced by histone methyltransferase (HMT) and its regulatory scaffolding proteins. One of these is the WD-repeat-containing protein 5 (WDR5) that has also been associated with controlling long noncoding RNAs and transcription factors including MYC. The wide influence of dysfunctional HMT complexes and the typically upregulated MYC levels in diverse tumor types suggested WDR5 as an attractive drug target. Indeed, protein-protein interface inhibitors for two protein interaction interfaces on WDR5 have been developed. While such compounds only inhibit a subset of WDR5 interactions, chemically induced proteasomal degradation of WDR5 might represent an elegant way to target all oncogenic functions. This study presents the design, synthesis, and evaluation of two diverse WDR5 degrader series based on two WIN site binding scaffolds and shows that linker nature and length strongly influence degradation efficacy.

Overcoming Barriers to Accessing Surgery and Rehabilitation in Low and Middle-Income Countries: An Innovative Model of Patient Navigation in Nepal.

BACKGROUND: Injury and disability are prominent public health concerns, globally and in the country of Nepal. Lack of locally available medical infrastructure, socioeconomic barriers, social marginalization, poor health literacy, and cultural barriers prevent patients from accessing surgical and rehabilitative care. Overcoming these barriers is an insurmountable challenge for the most vulnerable and marginalized, resulting in absence of treatment or even death. METHODS: Sundar Dhoka Saathi Sewa (SDSS), a non-government organization, provides a patient navigation service which facilitates referrals to tertiary centers from Nepal's most remote areas. Specific criteria ensure that patient referrals are appropriate in regard to clinical and socioeconomic need, while comprehensive counselling helps guide the patient and family. The SDSS staff meet patients upon arrival in Kathmandu and facilitate admission to the appropriate tertiary hospital. They advocate for the patient, provide medicine, supply food and cover all treatment costs. RESULTS: This project has enabled access to treatment for more than 1200 children for conditions leading to long-term disability and/or congenital heart disease. Interventions include a wide range of surgical and rehabilitative procedures such as complex orthopedics, cleft lip and palate, congenital talipes equinovarus, burn contractures, neurological cases, and cardiac surgery for valvular disease, septal defects and other congenital malformations. DISCUSSION: The SDSS model of patient navigation is effective in overcoming the barriers to access surgical care and rehabilitation in Nepal. The success is owed to committed international donors, capacity building, effective counselling, advocacy, compassion, and community. We believe that this model could be replicated in other LMICs.

Potential natural inhibitors of xanthine oxidase and HMG-CoA reductase in cholesterol regulation: in silico analysis.

BACKGROUND: Hypercholesterolemia has posed a serious threat of heart diseases and stroke worldwide. Xanthine oxidase (XO), the rate-limiting enzyme in uric acid biosynthesis, is regarded as the root of reactive oxygen species (ROS) that generate atherosclerosis and cholesterol crystals. ß-Hydroxy ß-methylglutaryl-coenzyme A reductase (HMGR) is a rate-limiting enzyme in cholesterol biosynthesis. Although some commercially available enzyme inhibiting drugs have effectively reduced cholesterol levels, most of them have failed to meet potential drug candidates' requirements. Here, we have carried out an in-silico analysis of secondary metabolites that have already shown good inhibitory activity against XO and HMGR in a wet lab setup. METHODS: Out of 118 secondary metabolites reviewed, sixteen molecules inhibiting XO and HMGR were selected based on the IC50 values reported in in vitro assays. Further, receptor-based virtual screening was carried out against secondary metabolites using GOLD Protein-Ligand Docking Software, combined with subsequent post-docking, to study the binding affinities of ligands to the enzymes. In-silico ADMET analysis was carried out to explore their pharmacokinetic properties, followed by toxicity prediction through ProTox-II. RESULTS: The molecular docking of amentoflavone (GOLD score 70.54, ∆G calc. = - 10.4 Kcal/mol) and ganomycin I (GOLD score 59.61, ∆G calc. = - 6.8 Kcal/mol) displayed that the drug has effectively bound at the competitive site of XO and HMGR, respectively. Besides, 6-paradol and selgin could be potential drug candidates inhibiting XO. Likewise, n-octadecanyl-O-α-D-glucopyranosyl (6' → 1″)-O-α-D-glucopyranoside could be potential drug candidates to maintain serum cholesterol. In-silico ADMET analysis has shown that these sixteen metabolites were optimal within the categorical range compared to commercially available XO and HMGR inhibitors, respectively. Toxicity analysis through ProTox-II revealed that 6-gingerol, ganoleucoin K, and ganoleucoin Z are toxic for human use. CONCLUSION: This computational analysis supports earlier experimental evidence towards the inhibition of XO and HMGR by natural products. Further study is necessary to explore the clinical efficacy of these secondary molecules, which might be alternatives for the treatment of hypercholesterolemia.

Evaluation of Breast Mass by Mammography and Ultrasonography with Histopathological Correlation.

BACKGROUND: Mammography, ultrasound and Magnetic Resonance Imaging are the available modalities for the evaluation of breast masses. Advances and ongoing improvements in imaging technologies have improved the sensitivity of breast cancer detection and diagnosis, but each modality is most beneficial when utilized according to individual traits such as age, risk factors, and breast density. However, pathological diagnosis is most crucial for the treatment of breast masses. METHODS: A cross-sectional study were conducted from January 2017 to April 2018. There were total of 50 patients with clinically diagnosed palpable breast lumps who attended Gynaecological OPD/surgical OPD/medicine OPD in the study period. The patients above 30 years were evaluated by mammography and ultrasound in Department of Radiology, National Academy of Medical Sciences, Bir Hospital. The patients were then send for FNAC/biopsy and histopathology examination. Data were collected and analyzed using SPSS version 16. Specificity and sensitivity of MG and USG individually and in combination to determine the nature of breast lump in relation to histopathological findings were calculated. RESULTS: Ultrasound had 88.90% sensitivity and 68.80% specificity whereas mammogram had 94.40% and 87.50% sensitivity and specificity respectively. When combined, both sensitivity of diagnosing malignant lesions increases up to 94.4% and specificity decreases up to 31.2%. Most of the variables of ultrasound and mammography (except density of the lesion) had significance in predicting nature of the lesion (p< 0.05). CONCLUSIONS: Combined Mammography and Ultrasound had higher sensitivity than sensitivity rate observed for either single modality. A combined Mammography and Ultrasound approach to detect breast diseases was significantly more helpful in accurate evaluation of breast pathologies.