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This study provides insights into conformational changes that lead to phospho-ubiquitin-induced PARKIN activation and how PARKIN is recruited to phospho-ubiquitin chains on mitochondria; the crystal structure of PARKIN in complex with phospho-ubiquitin also indicates that the pocket within PARKIN where phospho-ubiquitin binds carries amino acid residues that are mutated in patients with autosomal-recessive juvenile Parkinsonism. PARKIN activation mechanism revealed The enzymatic duo PARKIN and PINK1 are notable not only because they regulate the process of mitophagy, whereby the cell degrades its damaged mitochondria, but also because they are mutated in autosomal-recessive juvenile Parkinson disease (AR-JP). At a molecular level, PINK1 activates PARKIN by phosphorylating both the ubiquitin (Ub)-like (Ubl) domain of PARKIN and Ub molecules. David Komander and colleagues provide insights into conformational changes that lead to phosphoUb-induced PARKIN activation and how PARKIN recruits phosphoUb chains on mitochondria. The crystal structure of PARKIN in complex with phosphoUb also indicates that the pocket within PARKIN where phosphoUb binds carries amino acid residues that are mutated in patients with AR-JP. The E3 ubiquitin ligase PARKIN (encoded by PARK2 ) and the protein kinase PINK1 (encoded by PARK6 ) are mutated in autosomal-recessive juvenile Parkinsonism (AR-JP) and work together in the disposal of damaged mitochondria by mitophagy 1 , 2 , 3 . PINK1 is stabilized on the outside of depolarized mitochondria and phosphorylates polyubiquitin 4 , 5 , 6 , 7 , 8 as well as the PARKIN ubiquitin-like (Ubl) domain 9 , 10 . These phosphorylation events lead to PARKIN recruitment to mitochondria, and activation by an unknown allosteric mechanism 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 . Here we present the crystal structure of Pediculus humanus PARKIN in complex with Ser65-phosphorylated ubiquitin (phosphoUb), revealing the molecular basis for PARKIN recruitment and activation. The phosphoUb binding site on PARKIN comprises a conserved phosphate pocket and harbours residues mutated in patients with AR-JP. PhosphoUb binding leads to straightening of a helix in the RING1 domain, and the resulting conformational changes release the Ubl domain from the PARKIN core; this activates PARKIN. Moreover, phosphoUb-mediated Ubl release enhances Ubl phosphorylation by PINK1, leading to conformational changes within the Ubl domain and stabilization of an open, active conformation of PARKIN. We redefine the role of the Ubl domain not only as an inhibitory 13 but also as an activating element that is restrained in inactive PARKIN and released by phosphoUb. Our work opens up new avenues to identify small-molecule PARKIN activators.

Background Head louse females secrete liquid glue during oviposition, which is solidified to form the nit sheath over the egg. Recently, two homologous proteins, named louse nit sheath protein (LNSP) 1 and LNSP 2, were identified as adhesive proteins but the precise mechanism of nit sheath solidification is unknown. Methods We determined the temporal transcriptome profiles of the head louse accessory glands plus oviduct, from which putative major structural proteins and those with functional importance were deduced. A series of RNA interference (RNAi) experiments and treatment of an inhibitor were conducted to elucidate the function and action mechanism of each component. Results By transcriptome profiling of genes expressed in the louse accessory glands plus uterus, the LNSP1 and LNSP2 along with two hypothetical proteins were confirmed to be the major structural proteins. In addition, several proteins with functional importance, including transglutaminase (TG), defensin 1 and defensin 2, were identified. When LNSP1 was knocked down via RNA interference, most eggs became nonviable via desiccation, suggesting its role in desiccation resistance. Knockdown of LNSP2 , however, resulted in oviposition failure, which suggests that LNSP2 may serve as the basic platform to form the nit sheath and may have an additional function of lubrication. Knockdown of TG also impaired egg hatching, demonstrating its role in the cross-linking of nit sheath proteins. The role of TG in cross-linking was further confirmed by injecting or hair coating of GGsTop, a TG inhibitor. Conclusions Both LNSP1 and LNSP2 are essential for maintaining egg viability besides their function as glue. The TG-mediated cross-linking plays critical roles in water preservation that are essential for ensuring normal embryogenesis. TG-mediated cross-linking mechanism can be employed as a therapeutic target to control human louse eggs, and any topically applied TG inhibitors can be exploited as potential ovicidal agents. Graphical abstract

Human head lice Pediculus humanus capitis (De Geer) (Phthiraptera: Pediculidae) are insect parasites closely associated with humans, feeding on the blood of their hosts and causing them skin irritation and probable secondary infections. Despite being a severe nuisance, very few studies have reported on intraspecific chemical communication in head lice. Here, we evaluated the attractive response of head lice to the volatile compounds and solvent extracts from their feces. We also chemically analyzed the main volatile components of these feces and those of the feces' extracts. Head lice were attracted to the methanol extract of their feces but not to the hexane or dichloromethane extracts, suggesting the polar nature of bioactive chemicals present in head louse feces. Follow-up chemical identifications, in fact, showed the presence of hypoxanthine, uric acid, and another purine tentatively identified as either guanine or iso-guanine. Additionally, head lice were significantly attracted by volatiles emitted from samples containing feces. The volatiles emanated from feces alone contained 19 identified substances: 2-pentanone, hexanal, heptanal, 3-methyl-3-buten-1-ol, octanal, sulcatone, nonanal, acetic acid, 2-ethyl-1-hexanol, decanal, 1-octanol, butyric acid, 1-nonanol, hexanoic acid, octanoic acid, 2,6-dimethyl-7-octen-2-ol, 2-undecanone, geranylacetone, and hexadecane. The major compounds found were decanal, nonanal, hexanal, and acetic acid, together representing approximately 60% of the identified compounds. This work represents the first chemical evidence of intraspecies communication among head lice. The results support the existence of active substances present in the feces of P. humanus capitis that may be involved in its aggregation behavior.

•Insects found at a crime scene can provide a contribution to forensic investigations.•The analysis of human genetic material obtained from entomological samples is proposed.•NGS technology was used to analyze human DNA from the gastrointestinal tract of lice.•Lice found at the crime scenes can be valuable forensic allies. Rapid and progressive advances in molecular biology techniques and the advent of Next Generation Sequencing (NGS) have opened new possibilities for analyses also in the identification of entomological matrixes. Insects and other arthropods are widespread in nature and those found at a crime scene can provide a useful contribution to forensic investigations. Entomological evidence is used by experts to define the postmortem interval (PMI), which is essentially based on morphological recognition of the insect and an estimation of its insect life cycle stage. However, molecular genotyping methods can also provide an important support for forensic entomological investigations when the identification of species or human genetic material is required. This case study concerns a collection of insects found in the house of a woman who died from unknown causes. Initially the insects were identified morphologically as belonging to the Pediculidae family, and then, human DNA was extracted and analyzed from their gastrointestinal tract. The application of the latest generation forensic DNA assays, such as the Quantifiler® Trio DNA Quantification Kit and the HID-Ion AmpliSeq™ Identity Panel (Applied Biosystems®), individuated the presence of human DNA in the samples and determined the genetic profile.

Flash pyrolysis-gas chromatography/mass spectrometry was used to assess the chemical composition of the head louse's nit sheath. The pyrolyzate of the female insect's secretions, which form a cement-like cylinder holding the egg onto the hair, is dominated by amino acid derivatives and fatty acids. No chitin-specific compounds were detected in the sheath. These results, contrary to previous reports, show that the polymeric complex of the sheath is composed of proteinaceous moieties, possibly cross-linked to aliphatic components. This study constitutes the first chemical characterization of the pyrolysis products of insect (louse) glue and unequivocally confirms that louse sheaths are not chitinous, as suggested by earlier histochemical studies. Development of agents that might loosen nits from the hair shaft is dependent on research that addresses the chemical composition of the nit sheath.

Protein and lipid compositions were studied at different developmental stages of Pediculus capitis De Geer 1778. Phosphatidylcholine was found to be the predominant lipid at all stages and in both sexes. Palmitic and oleic acids were the main fatty acids throughout the 3 stages studied. A marked decline was observed in the total lipid content and triacylglyceride concentration during development, suggesting that their consumption is an energy source. The electrophoretic mobility revealed the predominance of a 320-kDa protein in eggs and adult females, whereas 2 major proteins of 514 and 439 kDa were found in nymphs, as well as in male and female adults. Two very high density lipoprotein fractions were isolated by ultracentrifugation of egg cytosol in a density gradient of NaBr. Both reserve lipoproteins contained phospholipids and triacylglycerols as the predominant lipids and a protein band of around 320 kDa. The structure of this band is likely to be similar to that found in females in a vitellogenic state.

The human head louse, Pediculus humanus capitis, is subdivided into several significantly divergent mitochondrial haplogroups, each with particular geographical distributions. Historically, they are among the oldest human parasites, representing an excellent marker for tracking older events in human evolutionary history. In this study, ancient DNA analysis using real-time polymerase chain reaction (qPCR), combined with conventional PCR, was applied to the remains of twenty-four ancient head lice and their eggs from the Roman period which were recovered from Israel. The lice and eggs were found in three combs, one of which was recovered from archaeological excavations in the Hatzeva area of the Judean desert, and two of which found in Moa, in the Arava region, close to the Dead Sea. Results show that the head lice remains dating approximately to 2,000 years old have a cytb haplogroup A, which is worldwide in distribution, and haplogroup B, which has thus far only been found in contemporary lice from America, Europe, Australia and, most recently, Africa. More specifically, this haplogroup B has a B36 haplotype, the most common among B haplogroups, and has been present in America for at least 4,000 years. The present findings confirm that clade B lice existed, at least in the Middle East, prior to contacts between Native Americans and Europeans. These results support a Middle Eastern origin for clade B followed by its introduction into the New World with the early peoples. Lastly, the presence of Acinetobacter baumannii DNA was demonstrated by qPCR and sequencing in four head lice remains belonging to clade A.

Autosomal-recessive juvenile Parkinsonism (AR-JP) is caused by mutations in a number of PARK genes, in particular the genes encoding the E3 ubiquitin ligase Parkin ( PARK2 , also known as PRKN ) and its upstream protein kinase PINK1 (also known as PARK6 ). PINK1 phosphorylates both ubiquitin and the ubiquitin-like domain of Parkin on structurally protected Ser65 residues, triggering mitophagy. Here we report a crystal structure of a nanobody-stabilized complex containing Pediculus humanus corporis ( Ph )PINK1 bound to ubiquitin in the ‘C-terminally retracted’ (Ub-CR) conformation. The structure reveals many peculiarities of PINK1, including the architecture of the C-terminal region, and reveals how the N lobe of PINK1 binds ubiquitin via a unique insertion. The flexible Ser65 loop in the Ub-CR conformation contacts the activation segment, facilitating placement of Ser65 in a phosphate-accepting position. The structure also explains how autophosphorylation in the N lobe stabilizes structurally and functionally important insertions, and reveals the molecular basis of AR-JP-causing mutations, some of which disrupt ubiquitin binding. Stabilization of a transient protein kinase–substrate complex using a nanobody provides molecular details about how the Parkinson’s disease-linked protein kinase PINK1 phosphorylates ubiquitin, and suggests new pharmacological strategies. A study in PINK1 The kinase enzyme PINK1 is known mainly for two reasons. At an organism level, mutations of PINK1 have been associated with autosomal-recessive juvenile Parkinsonism (AR-JP). At a cellular level, PINK1 phosphorylates both ubiquitin and a ubiquitin-like domain within its partner enzyme Parkin to trigger mitophagy, the process by which cells get rid of dysfunctional mitochondria. David Komander and co-authors report the structure of a complex between louse PINK1 and ubiquitin, which they obtained using nanobody-based stabilization. The structure provides molecular insights not only into PINK1–ubiquitin interactions and therefore the mechanism of PINK1 activity, but also into AR-JP-associated mutations, some of which disrupt ubiquitin binding.

Yersinia pestis , the causative agent of plague, is a highly lethal vector-borne pathogen responsible for killing large portions of Europe’s population during the Black Death of the Middle Ages. In the wild, Y . pestis cycles between fleas and rodents; occasionally spilling over into humans bitten by infectious fleas. For this reason, fleas and the rats harboring them have been considered the main epidemiological drivers of previous plague pandemics. Human ectoparasites, such as the body louse ( Pediculus humanus humanus ), have largely been discounted due to their reputation as inefficient vectors of plague bacilli. Using a membrane-feeder adapted strain of body lice, we show that the digestive tract of some body lice become chronically infected with Y . pestis at bacteremia as low as 1 × 10 5 CFU/ml, and these lice routinely defecate Y . pestis . At higher bacteremia (≥1 × 10 7 CFU/ml), a subset of the lice develop an infection within the Pawlowsky glands (PGs), a pair of putative accessory salivary glands in the louse head. Lice that developed PG infection transmitted Y . pestis more consistently than those with bacteria only in the digestive tract. These glands are thought to secrete lubricant onto the mouthparts, and we hypothesize that when infected, their secretions contaminate the mouthparts prior to feeding, resulting in bite-based transmission of Y . pestis . The body louse’s high level of susceptibility to infection by gram-negative bacteria and their potential to transmit plague bacilli by multiple mechanisms supports the hypothesis that they may have played a role in previous human plague pandemics and local outbreaks.

The head louse Pediculus humanus capitis (De Geer) (Phthiraptera: Pediculidae) is a cosmopolitan human ectoparasite causing pediculosis, one of the most common arthropod parasitic conditions of humans. The mechanisms and/or chemicals involved in host environment recognition by head lice are still unknown. In this study, we evaluated the response of head lice to volatiles that emanate from the human scalp. In addition, we identified the volatile components of the odor and evaluated the attractive or repellent activity of their pure main components. The volatiles were collected by means of Solid Phase microextraction and the extract obtained was chemically analyzed by gas chromatograph-mass spectrometer. Twenty-four volatile were identified in the human scalp odor, with the main compounds being the following: nonanal, sulcatone, geranylacetone, and palmitic acid. Head lice were highly attracted by the blend human scalp volatiles, as well as by the individual major components. A significant finding of our study was to demonstrate that nonanal activity depends on the mass of the compound as it is repellent at high concentrations and an attractant at low concentrations.The results of this study indicate that head lice may use chemical signals in addition to other mechanisms to remain on the host.