A massive rock and ice avalanche caused the 2021 disaster at Chamoli, Indian Himalaya.

On 7 February 2021, a catastrophic mass flow descended the Ronti Gad, Rishiganga, and Dhauliganga valleys in Chamoli, Uttarakhand, India, causing widespread devastation and severely damaging two hydropower projects. More than 200 people were killed or are missing. Our analysis of satellite imagery, seismic records, numerical model results, and eyewitness videos reveals that ~27 × 106 cubic meters of rock and glacier ice collapsed from the steep north face of Ronti Peak. The rock and ice avalanche rapidly transformed into an extraordinarily large and mobile debris flow that transported boulders greater than 20 meters in diameter and scoured the valley walls up to 220 meters above the valley floor. The intersection of the hazard cascade with downvalley infrastructure resulted in a disaster, which highlights key questions about adequate monitoring and sustainable development in the Himalaya as well as other remote, high-mountain environments.

Jumpstarting post-conflict strategic water resources protection from a changing global perspective: gaps and prospects in Afghanistan.

Notwithstanding ambiguities, long-term economic resurgence in Afghanistan amidst water insecurity exacerbated by climate change decisively requires a water protection strategy that will complement a multitude of agroindustrial and socioeconomic activities in an environmentally sustainable and climate resilient manner. In this paper, we begin with a perspective on institutions, legislation, and key issues in the water sector of Afghanistan. We then embark on linking the integrated water resources management (IWRM) and strategic environmental assessment (SEA) approaches as a novel framework for strategic water management and subsequently propose a strategy for post-conflict water protection based on the coalesced IWRM and SEA. Context relevant good practices worldwide are presented to provide empirical evidence for this approach whereas perceived opportunities and vulnerabilities in the Afghan context are discussed. Examination of post-conflict water sector initiatives in Afghanistan reveals the critical role of foreign assistance in both water infrastructure rehabilitation and modernization of the institutional aspect of water management. The introduction of IWRM as the basis for a progressive water sector strategy has been seen as a major milestone which is detrimentally matched by substantial deficiency in national capacity for implementation. Concurrently, the role of extra-national actors in relevant policy interventions has been considered catalytic despite criticisms of proposed regulations as being anachronistic to field realities. Therefore the view is maintained to practicable policies by accelerating policy learning in the country's water and environment sectors to encourage homegrown water strategy innovations. Demonstratively, mainstreaming IWRM-SEA coalescence will bridge institutional gaps for better feedback between local and national water stakeholders, providing a venue for improved delivery of water services to sustain post-conflict socioeconomic recovery and promote environmental stewardship.

Development of protegrins for the treatment and prevention of oral mucositis: structure-activity relationships of synthetic protegrin analogues.

Protegrin antimicrobial peptides possess activity against gram-positive and gram-negative bacteria and yeasts. An extensive structure-activity relationship (SAR) study was conducted on several hundred protegrin analogues to gain understanding of the relationship between the primary and secondary structure of the protegrins and their antimicrobial activities, and to identify a protegrin analogue for clinical development. Native sequence protegrins are cationic, amphiphilic peptides that are characterized by the presence of a beta-sheet structure that is maintained by two disulfide bridges. The presence of the beta-sheet is key to the stability of the protegrin structure; linearized analogues or analogues that have amino acid substitutions that eliminate hydrogen bonding across the beta-sheet have reduced activity, especially in the presence of physiological concentrations of NaCl. Also, maintaining amphiphilicity of the beta-sheet is key; analogues with substitutions of polar amino acids in the hydrophobic face have reduced activity. Analogues with reduced positive charge tend to be less active, an observation that is more marked for gram-negative than gram-positive bacteria, and may implicate binding to lipopolysaccharide as a key mechanistic step in the killing of gram-negative bacteria. A very large number of amino acid substitutions are tolerated by the protegrin structure, implying that overall structural features such as amphiphilicity, charge, and shape are more important to activity than the presence of specific amino acids. This lack of importance of specific stereochemistry is supported by the fact that completely D-amino acid substituted protegrins are fully potent. Based on the SAR studies, and on the microbiological data from an animal model, one protegrin analogue, IB-367, was selected for clinical development as a topical agent to prevent the oral mucositis associated with cancer therapy.

Protegrin antimicrobial peptides.

Protegrins are 16 to 18 amino acid, cationic antimicrobial peptides that are produced by porcine neutrophils, and are activated extracellularly by cleavage of the pro-protegrin molecule by neutrophil elastase. Biologically, the protegrins are characterized by broad-spectrum antimicrobial activity, rapid microbicidal action and low inherent ability to induce microbial resistance.Structurally, the protegrins form amphiphilic beta-sheets maintained by two intramolecular disulfides that are key for optimal biological activity. A synthetic protegrin analog, IB-367, is in clinical development as a locally administered agent in one program to prevent oral mucositis, a significant side effect of high dose chemotherapy and radiotherapy, and in another program to prevent nosocomial pneumonia in patients undergoing mechanically assisted ventilation.

Effect of local application of the antimicrobial peptide IB-367 on the incidence and severity of oral mucositis in hamsters.

OBJECTIVE: The purpose of this animal study was to determine whether IB-367, an antimicrobial peptide, is able to ameliorate oral mucositis by reducing microflora densities on the mucosal surfaces of the mouth. STUDY DESIGN: Oral mucositis was induced in hamsters by intraperitoneal injection of 5-fluorouracil followed by superficial abrasion of the buccal mucosa. A test formulation was applied topically to the buccal mucosa 5 or 6 times per day starting 6 to 8 hours before abrasion. RESULTS: Mucositis scores were significantly lower (P < .05) in hamsters given formulations containing 0.5 or 2.0 mg/mL of IB-367 than in placebo-treated controls. Treatment with IB-367 produced a more than 100-fold reduction in oral microflora densities. In a second experiment, treatment of hamsters with a formulation containing IB-367 at 0.12, 0.5 or 2.0 mg/mL resulted in a dose-dependent reduction in mucositis severity. CONCLUSION: The results indicate that reduction of local microflora densities through use of IB-367 may improve clinical outcomes in patients at risk for the development of oral mucositis.

Protegrin-1: a broad-spectrum, rapidly microbicidal peptide with in vivo activity.

Protegrin-1 (PG-1) is a cysteine-rich, 18-residue beta-sheet peptide isolated from porcine leukocytes with antimicrobial activity against a broad range of microorganisms. The MICs of PG-1 against representative gram-positive and gram-negative bacteria ranged from 0.12 to 2 microg/ml. At these levels, PG-1 was rapidly bactericidal in vitro, reducing the number of viable CFU of either methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa by more than three log units in less than 15 min. Resistance to PG-1 did not develop after 11 subculturings of P. aeruginosa or 18 subcultures of MRSA in Mueller-Hinton broth containing PG-1 at one-half the MIC. Under similar conditions of serial passage, the MICs of norfloxacin and gentamicin against P. aeruginosa increased 10 and 190 times, respectively. Similarly, the MIC of norfloxacin against MRSA increased 85 times. Immunocompetent mice inoculated intraperitoneally (i.p.) with P. aeruginosa or S. aureus exhibited 93 to 100% mortality in the vehicle control group compared with 0 to 27% mortality in animals that received a single i.p. injection of PG-1 (0.5 mg/kg of body weight). Mice inoculated with S. aureus by intravenous (i.v.) injection and dosed 0 to 60 min later with a single i.v. injection of PG-1 (5 mg/kg) had a mortality of 7 to 33%, compared to a mortality of 73 to 93% in the vehicle controls. In leukopenic mice inoculated i.v. with vancomycin-resistant Enterococcus faecium, mortality was 87% in the vehicle control group and 33% in animals that received a single i.v. injection of PG-1 (2.5 mg/kg). Taken together, these data indicate that PG-1 has potential for use as an antimicrobial agent in the treatment of local or systemic infections caused by clinically relevant pathogens.

Integrated care for asthma: matching care to the patient.

The purpose of the present study was to investigate whether criteria associated with assignment of asthma patients between general practice (GP) care alone, integrated care (shared between GP care and hospital clinic) or conventional specialist review could be identified, and whether outcomes for these patients differed over the next 12 months. Seven hundred and sixty four patients with a diagnosis of asthma and previously assigned to either integrated care or clinic care were reviewed after 1 year and reassigned. These patients were then followed for another 12 months and clinical data were collected over this time. After 12 months in clinic care or integrated care, assignment to integrated care was predicted by previous participation in integrated care (OR 2.94), patient preference for integrated care (OR 3.7), no admission (OR 1.56), fewer steroid courses during the previous year (OR 0.88) and nonattendance at review (OR 0.43) in the previous 12 months. Patient discharge to GP care was predicted by higher level of forced expiratory volume in one second (FEV1) (OR 1.49), lower number of GP consultations for troublesome asthma (OR 0.78), and nonattendance for review in the preceding year (OR 2.15). In the following 12 months, the three groups of patients differed significantly in hospital admissions (Discharged = 0.008; Integrated = 0.12; Clinic = 0.31), bronchodilators prescribed (Discharged = 8.5; Integrated = 10.2; Clinic = 13.9), GP consultations (Discharged = 1.3; Integrated = 3.0; Clinic = 4.1) and oral steroid courses (Discharged = 0.62; Integrated = 1.7; Clinic = 2.4). Patients assigned to integrated care, clinic care or discharged to general practice care form three distinct patient populations differing retrospectively and prospectively in morbidity and admission risk. In particular, patients assigned to integrated care fall midway in risk and morbidity between those discharged or those retained in clinic care. These results suggest that integrated care provides general practitioners with a system of management for asthma patients, for whom they do not wish frequent specialist review but who they do not believe can safely be discharged to general practice care only.

Fibroblast growth factor reserves the bacterial retardation of wound contraction.

Chronic granulating wounds were established in rats by excising burns inoculated with Escherichia coli. Recombinant human basic fibroblast growth factor was applied at dosages of 1, 10, and 100 micrograms/cm2 to the wounds of three groups of 20 animals on days 5, 9, 12, 15, and 18 after injury. The rate of wound closure was compared with that of similarly wounded animals treated with saline vehicle alone. High levels of bacteria caused significant retardation of wound contraction. The addition of basic fibroblast growth factor at the 100 micrograms/cm2 dosage level markedly improved the rate of wound closure whereas inert vehicles applied alone were ineffective. Since bacterial counts did not decrease in the basic fibroblast growth factor treated wounds, basic fibroblast growth factor was not inherently bactericidal. Histologic examination of the wounds treated with basic fibroblast growth factor showed increased cellularity with increased numbers of fibroblasts and round cells. These results suggest basic fibroblast growth factor can overcome the defect in healing created by bacterial infection, and this peptide may have efficacy in the management of the contaminated wound.

The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing.

Vascular endothelial growth factor (VEGF) is an apparently endothelial cell-specific mitogen that is structurally related to platelet-derived growth factor. By Northern blot and protein analyses, we show that VEGF is produced by cultured vascular smooth muscle cells. Analysis of VEGF transcripts in these cells by polymerase chain reaction and cDNA cloning revealed three different forms of the VEGF coding region, as had been reported in HL60 cells. The three forms of the human VEGF protein chain predicted from these coding regions are 189, 165, and 121 amino acids in length. Comparison of cDNA nucleotide sequences with sequences derived from human VEGF genomic clones indicates that the VEGF gene is split among eight exons and that the various VEGF coding region forms arise from this gene by alternative splicing: the 165-amino-acid form of the protein is missing the residues encoded by exon 6, whereas the 121-amino-acid form is missing the residues encoded by exons 6 and 7. Analysis of the VEGF gene promoter region revealed a single major transcription start, which lies near a cluster of potential Sp1 factor binding sites. The promoter region also contains several potential binding sites for the transcription factors AP-1 and AP-2; consistent with the presence of these sites, Northern blot analysis demonstrated that the level of VEGF transcripts is elevated in cultured vascular smooth muscle cells after treatment with the phorbol ester 12-O-tetradecanoyl-phorbol-13-acetate.

A heparin-binding growth factor secreted by macrophage-like cells that is related to EGF.

Macrophage-like U-937 cells secrete a 22-kilodalton heparin-binding growth factor that is mitogenic for BALB-3T3 fibroblasts and smooth muscle cells, but not endothelial cells. The amino acid sequence predicted from complementary DNA clones indicates that the mitogen is a new member of the epidermal growth factor (EGF) family. This heparin-binding EGF-like growth factor (HB-EGF) binds to EGF receptors on A-431 epidermoid carcinoma cells and smooth muscle cells, but is a far more potent mitogen for smooth muscle cells than is EGF. HB-EGF is also expressed in cultured human macrophages and may be involved in macrophage-mediated cellular proliferation.

Basic fibroblast growth factor stimulation of epidermal wound healing in pigs.

Basic fibroblast growth factor (bFGF) has recently been shown to be a mitogen for keratinocytes. This observation has now been extended in a porcine model of epidermal wound healing. A single application of recombinant human bFGF given at the time of injury to healthy animals accelerated the rate of epithelialization by 20%; multiple applications gave no greater effect than the single application. Histologic analysis of biopsies of these partial-thickness wounds taken during bFGF-mediated healing supported the assessment of an enhanced rate of epithelialization and an earlier onset of dermal healing. Because no histologic abnormalities were observed, bFGF induced an acceleration of what appears to be the normal healing process.

The human basic fibroblast growth factor gene (FGFB) is assigned to chromosome 4q25.

In situ hybridization was used to localize a cDNA probe for the basic fibroblast growth factor gene (FGFB) to human metaphase and prometaphase chromosomes. In this communication we report the localization of this gene to 4q25.

Vascular endothelial growth factor: a new member of the platelet-derived growth factor gene family.

Using applications of the polymerase chain reaction (PCR) technique, cDNA clones have been isolated encoding bovine vascular endothelial growth factor (VEGF), a mitogen with specificity for vascular endothelial cells. Analysis of the clones indicates that VEGF can exist in two forms, probably due to alternative RNA splicing. The amino acid sequences predicted from the clones also show that VEGF shares homologies of about 21% and 24% respectively with the A and B chains of human platelet-derived growth factor (PDGF), and has complete conservation of the eight cysteine residues found in both mature PDGF chains. The homology is not reflected in function, however, since the cell types responsive to VEGF are distinct from those responsive to homo- and heterodimers of the PDGF chains.

Structural analysis of the gene for human acidic fibroblast growth factor.

Genomic clones derived from the gene for human acidic fibroblast growth factor (aFGF) have been isolated. Nucleotide sequence analysis of these clones revealed that the coding region of the human aFGF gene is interrupted by two introns, located at precisely homologous locations to introns in four other members of the FGF gene family, strongly indicating a common evolutionary origin for these genes. Northern blot analyses of the multiple aFGF transcripts found in serum-stimulated human foreskin fibroblasts indicated that the aFGF gene also contains a third intron, lying in the 5' untranslated region.

Addition of growth hormone secretion signal to basic fibroblast growth factor results in cell transformation and secretion of aberrant forms of the protein.

Basic fibroblast growth factor (bFGF) is a potent mitogen for a wide variety of cell types. Unlike most growth factors, the primary translation product for bFGF appears to lack a secretory signal peptide. To explore the normal mode of bFGF release, as well as to investigate the growth factor's oncogenic potential, expression vectors were created for a bFGF cDNA and for a chimeric molecule in which the bFGF coding sequence was linked to the human growth hormone signal peptide sequence. Transfection of NIH3T3 cells with the bFGF cDNA vectors caused the synthesis of high levels of biologically active, cell-associated bFGF, but no evidence of transformation was detected. In contrast, the chimeric bFGF-signal peptide expression vector induced foci of transformation at a very high frequency. The transformed cells grew in soft agar and were tumorigenic in nude mice. The majority of the immunoreactive bFGF species made by the transformed cells was found in the conditioned medium and appeared to be posttranslationally modified, indicating that the chimeric bFGF-signal peptide molecule was processed through the secretory pathway. The secreted bFGF exhibited little mitogenic activity, suggesting that interaction of bFGF with its receptor likely occurs while the fusion protein is being processed along the secretory pathway.