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Human papillomavirus (HPV) infections can cause common warts, which usually resolve spontaneously or become recalcitrant, resistant to multiple treatments. In rare cases, they transform into cutaneous giant horns resulting in the tree-man syndrome (TMS). Defective beta-HPVs can cause flat warts in epidermodysplasia verruciformis (EV), a genetic disorder. In typical EV, limited to the skin, the mutated genes are critical for keratinocyte-intrinsic immunity, whereas atypical, syndromic EV involves genes controlling T cells. Inborn errors of immunity due to mutations in distinct genes underlying recalcitrant warts and the alpha-HPV2-driven TMS have been identified, all disrupting T-cell immunity. Collectively, these observations attest to the wide phenotypic spectrum of cutaneous infections caused by different HPV types at the intersection of the genetic diversity of the viral and human genomes.

C. elegans neurons were thought to be non-spiking until our recent discovery of action potentials in the sensory neuron AWA; however, the extent to which the C. elegans nervous system relies on analog or digital coding is unclear. Here we show that the enteric motor neurons AVL and DVB fire synchronous all-or-none calcium-mediated action potentials following the intestinal pacemaker during the rhythmic C. elegans defecation behavior. AVL fires unusual compound action potentials with each depolarizing calcium spike mediated by UNC-2 followed by a hyperpolarizing potassium spike mediated by a repolarization-activated potassium channel EXP-2. Simultaneous behavior tracking and imaging in free-moving animals suggest that action potentials initiated in AVL propagate along its axon to activate precisely timed DVB action potentials through the INX-1 gap junction. This work identifies a novel circuit of spiking neurons in C. elegans that uses digital coding for long-distance communication and temporal synchronization underlying reliable behavioral rhythm. Most neurons in the nematode C. elegans communicate in an analog manner. Here, the authors demonstrate that enteric motor neurons can fire all-or-none action potentials, and that this digital communication is important for defecation.

Background: Total hip arthroplasty (THA) and total knee arthroplasty (TKA) are cost-effective procedures that decrease pain and improve health-related quality of life for patients with advanced symptomatic arthritis, including rheumatoid arthritis (RA). Patients with RA have a longer length of stay (LOS) after THA or TKA than patients with osteoarthritis, yet the factors contributing to LOS have not been investigated. Purpose: We sought to identify the factors contributing to LOS for patients with RA undergoing THA and TKA at a single tertiary care orthopedic specialty hospital. Methods: We retrospectively reviewed data from a prospectively collected cohort of 252 RA patients undergoing either THA or TKA. Demographics, RA characteristics, medications, serologies, and disease activity were collected preoperatively. Linear regression was performed to explore the relationship between LOS (log-transformed) and possible predictors. A multivariate model was constructed through backward selection using significant predictors from a univariate analysis. Results: Of the 252 patients with RA, 83% were women; they had a median disease duration of 14 years and moderate disease activity at the time of arthroplasty. We had LOS data on 240 (95%) of the cases. The mean LOS was 3.4 +/- 1.5 days. The multivariate analysis revealed a longer LOS for RA patients who underwent TKA versus THA, were women versus men, required a blood transfusion, and took preoperative opioids. Conclusion: Our retrospective study found that increased postoperative LOS in RA patients undergoing THA or TKA was associated with factors both non-modifiable (type of surgery, sex) and modifiable (postoperative blood transfusion, preoperative opioid use). These findings suggest that preoperative optimization of the patient with RA might focus on improving anemia and reducing opioid use in efforts to shorten LOS. More rigorous study is warranted.

Emerging resistance to currently used antibiotics is a global public health crisis. Because most of the biosynthetic capacity within the bacterial kingdom has remained silent in previous antibiotic discovery efforts, uncharacterized biosynthetic gene clusters found in bacterial genome-sequencing studies remain an appealing source of antibiotics with distinctive modes of action. Here, we report the discovery of a naturally inspired lipopeptide antibiotic called cilagicin, which we chemically synthesized on the basis of a detailed bioinformatic analysis of the cil biosynthetic gene cluster. Cilagicin's ability to sequester two distinct, indispensable undecaprenyl phosphates used in cell wall biosynthesis, togethDer with the absence of detectable resistance in laboratory tests and among multidrug-resistant clinical isolates, makes it an appealing candidate for combating antibiotic-resistant pathogens.

Spina bifida (SB) is the second most common nonlethal congenital malformation. The existence of monogenic SB mouse models and human monogenic syndromes with SB features indicate that human SB may be caused by monogenic genes. We hypothesized that whole exome sequencing (WES) allows identification of potential candidate genes by (i) generating a list of 136 candidate genes for SB, and (ii) by unbiased exome-wide analysis. We generated a list of 136 potential candidate genes from three categories and evaluated WES data of 50 unrelated SB cases for likely deleterious variants in 136 potential candidate genes, and for potential SB candidate genes exome-wide. We identified 6 likely deleterious variants in 6 of the 136 potential SB candidate genes in 6 of the 50 SB cases, whereof 4 genes were derived from mouse models, 1 gene was derived from human nonsyndromic SB, and 1 gene was derived from candidate genes known to cause human syndromic SB. In addition, by unbiased exome-wide analysis, we identified 12 genes as potential candidates for SB. Identification of these 18 potential candidate genes in larger SB cohorts will help decide which ones can be considered as novel monogenic causes of human SB.

Predatory animals pursue prey in a noisy sensory landscape, deciding when to continue or abandon their chase. The mosquito Aedes aegypti is a micropredator that first detects humans at a distance through sensory cues such as carbon dioxide. As a mosquito nears its target, it senses more proximal cues such as body heat that guide it to a meal of blood. How long the search for blood continues after initial detection of a human is not known. Here, we show that a 5 s optogenetic pulse of fictive carbon dioxide induced a persistent behavioral state in female mosquitoes that lasted for more than 10 min. This state is highly specific to females searching for a blood meal and was not induced in recently blood-fed females or in males, who do not feed on blood. In males that lack the gene fruitless, which controls persistent social behaviors in other insects, fictive carbon dioxide induced a long-lasting behavior response resembling the predatory state of females. Finally, we show that the persistent state triggered by detection of fictive carbon dioxide enabled females to engorge on a blood meal mimic offered up to 14 min after the initial 5 s stimulus. Our results demonstrate that a persistent internal state allows female mosquitoes to integrate multiple human sensory cues over long timescales, an ability that is key to their success as an apex micropredator of humans.

STUDY QUESTION Does intraovarian injection of platelet-rich plasma (PRP) change ovarian function in patients with extremely low functional ovarian reserve (LFOR) who, otherwise, would likely only have a chance of pregnancy through third-party oocyte donation? SUMMARY ANSWER No clinically significant effects of PRP treatment on ovarian function were observed over 1 year of follow-up. WHAT IS KNOWN ALREADY Several investigators have reported improved responses to ovulation induction after treatment with PRP. However, previous published reports have involved, at most, only small case series. Whether PRP actually improves ovarian performance is, therefore, still unknown. PRP is nevertheless widely offered as an 'established' fertility treatment, often under the term 'ovarian rejuvenation'. STUDY DESIGN, SIZE, DURATION We are reporting a prospective cohort study of 80 consecutive patients at ages 28-54 with LFOR, defined by anti-Mullerian hormone <1.1 ng/ml, FSH >12 mIU/ml or at least one prior IVF cycle with <= 3 oocytes within 1 year. The women were followed for 1 year after an intraovarian PRP procedure. PARTICIPANTS/MATERIALS, SETTING, METHODS PRP (1.5 ml) was injected into the cortex of ovaries with an average of 12 injections per ovary. Study participants were followed every 3 days for 2 weeks after PRP treatment with estradiol and FSH measurements and vaginal ultrasound to observe follicle growth and thereafter followed weekly. Beginning 1 month after their PRP treatment, participants underwent one or more cycles of ovarian stimulation for IVF. Outcome measures were endocrine response, and numbers of oocytes and embryos produced in response to a maximal gonadotropin stimulation before and after PRP treatment. MAIN RESULTS AND THE ROLE OF CHANCE In this study, women failed to demonstrate statistically significant outcome benefits from intraovarian PRP. However, two 40-year-old very poor-prognosis patients, with prior failed IVF cycles that never reached embryo transfer at other centers, achieved pregnancy, resulting in an ongoing pregnancy rate of 4.7% among patients who, following PRP, produced at least one oocyte (n = 42). LIMITATIONS, REASONS FOR CAUTION As an observational study of patients who performed poorly in past ovarian stimulation cycles, the improvement may be accounted for by regression to the mean. Similar considerations may also explain the occurrence of the two pregnancies. WIDER IMPLICATIONS OF THE FINDINGS This study demonstrates that, even in extremely poor prognosis patients due to LFOR, sporadic pregnancies are possible. The study, however, does not allow for the conclusion that those pregnancies were the consequence of PRP treatments. A case series, indeed, does not allow for such conclusions, even if results are more suggestive than here. This registered study, therefore, must be viewed as a preliminary report, with further data expected from this study but also from two other prospectively randomized ongoing registered studies with more controlled patient selection. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by intramural funds from The Center for Human Reproduction and the not-for-profit research Foundation for Reproductive Medicine, both in New York, NY, USA. N.G. and D.H.B. are listed as co-inventors on several US patents. Some of these patents relate to pre-supplementation of hypo-androgenic infertile women with androgens, such as dehydroepiandrosterone and testosterone and, therefore, at least peripherally relate to the subject of this manuscript. They, as well as D.F.A. , have also received research support, travel funds and speaker honoraria from several pharmaceutical and medical device companies, though none related to the here presented subject and manuscript. N.G. is a shareholder in Fertility Nutraceuticals and he and D.H.B. receive royalty payments from Fertility Nutraceuticals LLC. E.M. has no conflicts of interest to declare.

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in hospitals in Portugal is worrisome and among the highest in Europe. Surprisingly, MRSA prevalence in the community was described as very low (<2%) based on studies that used classical culture-based methods (CCBM). We investigated whether the apparent limited spread of MRSA in the community in Portugal might result from low sensitivity of CCBM. Nasopharyngeal- and oropharyngeal-paired samples obtained from senior adults living in nursing (n = 299) or family homes (n = 300) previously characterized by CCBM were reanalyzed. Samples were inoculated in a semi-selective enrichment medium, and those showing visible growth were evaluated by qPCR targeting nuc, mecA, and mecC genes (SSE+qPCR). By SSE+qPCR, 34 of the 1,198 (2.8%) samples were MRSA positive compared with 21 (1.8%) by CCBM. SSE+qPCR improved non-significantly detection of MRSA carriers from 5.4% to 8.0% (p = 0.12) in the nursing home collection, and from 0.3% to 1.7% (p = 0.13) in the family home collection. MRSA isolates belonged to three HA-MRSA clones widely disseminated in Portuguese hospitals. In conclusion, use of semi-selective medium combined with qPCR did not change the overall scenario previously described. In Portugal, MRSA circulation in the community among senior adults is low.

Double-strand break (DSB) repair relies on DNA damage response (DDR) factors including BRCA1, BRCA2, and RAD51, which promote homology-directed repair (HDR); 53BP1, which affects single-stranded DNA formation; and proteins that mediate end-joining. Here we show that the CRL4/DDB1/WDR70 complex (CRL4(WDR70)) controls the expression of DDR factors. Auxin-mediated degradation of WDR70 led to reduced expression of BRCA1, BRCA2, RAD51, and other HDR factors; 53BP1 and its downstream effectors; and other DDR factors. In contrast, cNHEJ factors were generally unaffected. WDR70 loss abrogated the localization of HDR factors to DSBs and elicited hallmarks of genomic instability, although 53BP1/RIF1 foci still formed. Mutation of the DDB1-binding WD40 motif, disruption of DDB1, or inhibition of cullins phenocopied WDR70 loss, consistent with CRL4, DDB1, and WDR70 functioning as a complex. RNA-sequencing revealed that WDR70 degradation affects the mRNA levels of DDR and many other factors. The data indicate that CRL4(WDR70) is critical for expression of myriad genes including BRCA1, BRCA2, and RAD51.