In Vitro Susceptibility to Ceftazidime-Avibactam and Comparator Antimicrobial Agents of Carbapenem-Resistant Enterobacterales Isolates.

The emergence of carbapenem-resistant Enterobacterales (CRE) has been recognized as a significant concern globally. Ceftazidime/avibactam (CZA) is a novel ß-lactam/ß-lactamase inhibitor that has demonstrated activity against isolates producing class A, C, and D ß-lactamases. Here-in, we evaluated the in vitro activity of CZA and comparator antimicrobial agents against 858 CRE isolates, arising from the Southeast Asian region, collected from a large tertiary hospital in Singapore. These CRE isolates mainly comprised Klebsiella pneumoniae (50.5%), Escherichia coli (29.4%), and Enterobacter cloacae complex (17.1%). Susceptibility rates to levofloxacin, imipenem, meropenem, doripenem, aztreonam, piperacillin/tazobactam, cefepime, tigecycline, and polymyxin B were low. CZA was the most active ß-lactam agent against 68.9% of the studied isolates, while amikacin was the most active agent among all comparator antibiotics (80% susceptibility). More than half of the studied isolates (51.4%) identified were Klebsiella pneumoniae carbapenemase (KPC)-2 producers, 25.9% were New Delhi metallo-ß-lactamase (NDM) producers, and Oxacillinase (OXA)-48-like producers made up 10.7%. CZA was the most active ß-lactam agent against KPC-2, OXA-48-like, and Imipenemase (IMI) producers (99.3% susceptible; MIC50/90: ≤1/2 mg/L). CZA had excellent activity against the non-carbapenemase-producing CRE (91.4% susceptible; MIC50/90: ≤1/8 mg/L). Expectedly, CZA had no activity against the metallo-ß-lactamases (MBL)-producing CRE (NDM- and Imipenemase MBL (IMP) producers; 27.2% isolates), and the carbapenemase co-producing CRE (NDM + KPC, NDM + OXA-48-like, NDM + IMP; 3.0% isolates). CZA is a promising addition to our limited armamentarium against CRE infections, given the reasonably high susceptibility rates against these CRE isolates. Careful stewardship and rational dosing regimens are required to preserve CZA's utility against CRE infections.

Comparative Activities of Novel Therapeutic Agents against Molecularly Characterized Clinical Carbapenem-Resistant Enterobacterales Isolates.

Limited treatment options exist for the treatment of carbapenem-resistant Enterobacterales (CRE) bacteria. Fortunately, there are several recently approved antibiotics indicated for CRE infections. Here, we examine the in vitro activity of various novel agents (eravacycline, plazomicin, ceftazidime-avibactam, imipenem-relebactam, and meropenem-vaborbactam) and comparators (tigecycline, amikacin, levofloxacin, fosfomycin, polymyxin B) against 365 well-characterized CRE clinical isolates with various genotypes. Nonduplicate isolates collected from the largest public health hospital in Singapore between 2007 and 2020 were subjected to antimicrobial susceptibility testing (broth microdilution or antibiotic gradient test strips). Susceptibilities were defined using Clinical and Laboratory Standards Institute (CLSI) or Food and Drug Administration (FDA) interpretative criteria. Sequence types and resistance mechanisms were characterized using short-read whole-genome sequencing. Overall, tigecycline and plazomicin exhibited the highest susceptibility rates (89.6% and 80.8%, respectively). However, the tigecycline susceptibility breakpoint utilized here may be outdated in view of prevailing pharmacokinetic-pharmacodynamic (PK/PD) data. Susceptibility varied by carbapenemase genotype; the ß-lactam/ß-lactamase inhibitor combinations were equally active (92.3 to 99.2% susceptible) against KPC producers, but only ceftazidime-avibactam retained high susceptibility (98.7%) against OXA-48-like producers. Against metallo-ß-lactamase producers, only plazomicin exhibited moderate activity (77.0% susceptible). Aminoglycoside activity was also influenced by carbapenemase genotypes. This work provides an insight into the comparative activity and presumptive utility of novel agents in this geographic region. IMPORTANCE This study determined the susceptibilities of carbapenem-resistant Enterobacterales isolates to various novel antimicrobial agents (ceftazidime-avibactam, imipenem-relebactam, meropenem-vaborbactam, eravacycline, and plazomicin). Whole-genome sequencing was performed for all strains. Our study findings provide insights into the comparative activities of novel agents in this geographic region. Plazomicin and ceftazidime-avibactam exhibited the lowest nonsusceptibility rates and may be considered promising agents in the management of carbapenem-resistant Enterobacterales infections. We note also that antibiotic activity is influenced by genotypes and that understanding the geographic region's molecular epidemiology could aid in the definition of the presumptive utility of novel agents and contribute to antibiotic decision-making.

Generational effect on nurses' work values, engagement, and satisfaction in an acute hospital.

BACKGROUND: The present nursing workforce comprises four generational of nurses working side-by-side. While such a generation blend adds invaluable diversity to the workforce, it also brings added complexity. The study aimed to describe and summarise work values and attitudes of four nursing generations, namely Baby boomers, Generation X, Y and Z. METHOD: A cross-sectional questionnaire study was adopted. A total of 778 nurses from an acute hospital in Singapore completed the online questionnaire. The Work Value and Attitude scale measuring seven constructs (Work Centrality, Non-compliance, Technology Challenge, Work life balance, leadership, Power, and Recognition) was employed for data collection. RESULTS: The Cronbach's alpha was 0.714 for the overall instrument. Statistically significant differences amongst the four generations of nurses emerged in the Work Value and Attitude scale in the construct of non-compliance (p = 0.007), technology challenge (p = 0.027), work-life balance (p < 0.001), and recognition (p < 0.001). No statistically significant differences were noted for the rest of the constructs. DISCUSSION AND CONCLUSION: The findings of this study highlight that differences in work values and attitudes exist among nurses of different generations. Generation X are less likely to challenge the conventional norm and supervisors. Generation Y and Z are the most tech-savvy generations and can adapt quickly to new technology. There is also a greater emphasis on work-life balance as the generation gets younger. Generation Y and Z nurses perceived that younger nurses do not get due respect and recognition from their colleagues. Acknowledging the generational differences in work values and attitudes can facilitate nursing management to tailor strategies to improve individual and organisation performance while creating a work environment that enhances intergeneration harmony and teamwork.

Comparison of BACTEC versus conventional enrichment medium for peritoneal dialysate fluid culture.

BACKGROUND: Bacterial peritonitis remains a significant cause of mortality in patients on peritoneal dialysis (PD). Early detection of causative organisms and targeted antimicrobial treatment allow for better clinical outcomes. This study compares bacterial growth results from peritoneal dialysate in the BACTEC blood culture system vs. conventional culture. MATERIALS AND METHODS: We conducted a prospective study on 46 patients with 63 consecutive episodes of suspected PD peritonitis between August 2020 and August 2021. PD dialysate was simultaneously sent to the laboratory in both BACTEC and sterile bottles. BACTEC bottles were incubated in the BD BACTEC FX system for 5 days. PD effluent transported from the sterile bottles was centrifuged at 3,000 rpm for 15 minutes; the supernatant was inoculated into cooked-meat broth for enrichment. Both incubation methods were extended to 14 days if microorganisms were seen on the Gram-stained smear. Recovery of isolated micro-organisms and time to detection (TTD) were compared. RESULTS: 26 episodes of suspected PD peritonitis based on clinical criteria were identified during the study period. The sensitivity of the BACTEC and the conventional culture methods was 50% and 42.3%, respectively (p = 0.45). Seven samples had partial concordance or discordant results. McNemar's χ2-test revealed no statistical difference between either method (p = 0.45). TTD was 18.9 ± 24.4 hours via the BACTEC method vs. 37 ± 16.5 hours in conventional cultures (p = 0.014). CONCLUSION: The comparable sensitivities and similar yield in identifying pathogens could be due to the enrichment medium and prolonged incubation period. The shorter TTD for the BACTEC method could facilitate earlier confirmation of bacteriological diagnosis and subsequent treatment strategies.

Handheld ultrasound-guided cannulation of difficult hemodialysis arteriovenous access: A randomized controlled trial.

INTRODUCTION: Cannulation of complex arteriovenous fistula (AVF) or graft (AVG) frequently poses challenges to renal nursing practice. Ultrasound (US) guidance on visualizing central and peripheral venous access has been widely adopted in nephrology, reducing vascular intervention complications. Renal nurses could acquire this point-of-care technique to increase the successful cannulation rate while facilitating confidence build-up during practice. We aim to evaluate the use of handheld US on difficult AVF/AVG cannulation in a hospital-based dialysis unit. METHODS: We conducted a single-center randomized controlled trial from January 2021 to January 2022. Ten renal nurses were trained by an interventional nephrologist before patient recruitment and had completed a pre- and posttraining questionnaire on their confidence level. Fifty hemodialysis patients with complex AVF were randomized to US-guided or conventional cannulation. The total time spent on cannulation and patients' pain scores were also collected. FINDINGS: Renal nurses increased their confidence level after training (pretraining score 26.6 ± 6.9 vs. posttraining score 36.4 ± 3.0; p = 0.014). There was a higher success rate (only one cannulation attempt required) for US-guided (96%) versus conventional (72.0%) cannulation (p = 0.049). US-guided cannulation had a lower pain score than the conventional method (1.48 ± 0.73 vs. 2.13 ± 0.95, p = 0.012). The pre-cannulation assessment time and time spent on cannulation were comparable between the two groups. DISCUSSION: Our study showed that US-guided cannulation increased renal nurses' confidence level in difficult cannulation and improved success rate. Larger scale studies are required to further assess the applications of handheld US in AVF cannulation, particularly in different clinical settings (e.g., chronic dialysis centers).

Genomic Surveillance of Carbapenem-Resistant Klebsiella pneumoniae from a Major Public Health Hospital in Singapore.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global public health threat. In this study, we employed whole-genome sequencing (WGS) to determine the genomic epidemiology of a longitudinal collection of clinical CRKP isolates recovered from a large public acute care hospital in Singapore. Phylogenetic analyses, a characterization of resistance and virulence determinants, and plasmid profiling were performed for 575 unique CRKP isolates collected between 2009 and 2020. The phylogenetic analyses identified the presence of global high-risk clones among the CRKP population (clonal group [CG] 14/15, CG17/20, CG147, CG258, and sequence type [ST] 231), and these clones constituted 50% of the isolates. Carbapenemase production was common (n = 497, 86.4%), and KPC was the predominant carbapenemase (n = 235, 40.9%), followed by OXA-48-like (n = 128, 22.3%) and NDM (n = 93, 16.2%). Hypervirulence was detected in 59 (10.3%) isolates and was most common in the ST231 carbapenemase-producing isolates (21/59, 35.6%). Carbapenemase genes were associated with diverse plasmid replicons; however, there was an association of blaOXA-181/232 with ColKP3 plasmids. This study presents the complex and diverse epidemiology of the CRKP strains circulating in Singapore. Our study highlights the utility of WGS-based genomic surveillance in tracking the population dynamics of CRKP. IMPORTANCE In this study, we characterized carbapenem-resistant Klebsiella pneumoniae clinical isolates collected over a 12-year period in the largest public acute-care hospital in Singapore using whole-genome sequencing. The results of this study demonstrate significant genomic diversity with the presence of well-known epidemic, multidrug-resistant clones amid a diverse pool of nonepidemic lineages. Genomic surveillance involving comprehensive resistance, virulence, and plasmid gene content profiling provided critical information for antimicrobial resistance monitoring and highlighted future surveillance priorities, such as the emergence of ST231 K. pneumoniae strains bearing multidrug resistance, virulence elements, and the potential plasmid-mediated transmission of the blaOXA-48-like gene. The findings here also reinforce the necessity of unique infection control and prevention strategies that take the genomic diversity of local circulating strains into consideration.

In vitro Bactericidal Activities of Combination Antibiotic Therapies Against Carbapenem-Resistant Klebsiella pneumoniae With Different Carbapenemases and Sequence Types.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) is becoming increasingly problematic due to the limited effectiveness of new antimicrobials or other factors such as treatment cost. Thus, combination therapy remains a suitable treatment option. We aimed to evaluate the in vitro bactericidal activity of various antibiotic combinations against CRKP with different carbapenemase genotypes and sequence types (STs). Thirty-seven CRKP with various STs and carbapenemases were exposed to 11 antibiotic combinations (polymyxin B or tigecycline in combination with ß-lactams including aztreonam, cefepime, piperacillin/tazobactam, doripenem, meropenem, and polymyxin B with tigecycline) in static time-kill studies (TKS) using clinically achievable concentrations. Out of the 407 isolate-combination pairs, only 146 (35.8%) were bactericidal (≥3 log10CFU/mL decrease from initial inoculum). Polymyxin B in combination with doripenem, meropenem, or cefepime was the most active, each demonstrating bactericidal activity in 27, 24, and 24 out of 37 isolates, respectively. Tigecycline in combination with ß-lactams was rarely bactericidal. Aside from the lower frequency of bactericidal activity in the dual-carbapenemase producers, there was no apparent difference in combination activity among the strains with other carbapenemase types. In addition, bactericidal combinations were varied even in strains with similar STs, carbapenemases, and other genomic characteristics. Our findings demonstrate that the bactericidal activity of antibiotic combinations is highly strain-specific likely owing to the complex interplay of carbapenem-resistance mechanisms, i.e., carbapenemase genotype alone cannot predict in vitro bactericidal activity. The availability of WGS information can help rationalize the activity of certain combinations. Further studies should explore the use of genomic markers with phenotypic information to predict combination activity.

Genomic characterization of carbapenem-non-susceptible Pseudomonas aeruginosa in Singapore.

Pseudomonas aeruginosa is a clinically important pathogen implicated in many hospital-acquired infections. Its propensity to acquire broad-spectrum resistance has earned the organism its status as a severe public health threat requiring urgent control measures. While whole-genome sequencing-based genomic surveillance provides a means to track antimicrobial resistance, its use in molecular epidemiological surveys of P. aeruginosa remains limited, especially in the Southeast Asian region. We sequenced the whole genomes of 222 carbapenem-non-susceptible P. aeruginosa (CNPA) isolates collected in 2006-2020 at the largest public acute care hospital in Singapore. Antimicrobial susceptibilities were determined using broth microdilution. Clonal relatedness, multi-locus sequence types, and antimicrobial resistance determinants (acquired and chromosomal) were determined. In this study, CNPA exhibited broad-spectrum resistance (87.8% multi-drug resistance), retaining susceptibility only to polymyxin B (95.0%) and amikacin (55.0%). Carbapenemases were detected in 51.4% of the isolates, where IMP and NDM metallo-ß-lactamases were the most frequent. Carbapenem resistance was also likely associated with OprD alterations or efflux mechanisms (ArmZ/NalD mutations), which occurred in strains with or without carbapenemases. The population of CNPA in the hospital was diverse; the 222 isolates grouped into 68 sequence types (ST), which included various high-risk clones. We detected an emerging clone, the NDM-1-producing ST308, in addition to the global high-risk ST235 clone which was the predominant clone in our population. Our results thus provide a "snapshot" of the circulating lineages of CNPA locally and the prevailing genetic mechanisms contributing to carbapenem resistance. This database also serves as the baseline for future prospective surveillance studies.

A constant pool of Lgr5+ intestinal stem cells is required for intestinal homeostasis.

Lgr5+ crypt base columnar cells, the operational intestinal stem cells (ISCs), are thought to be dispensable for small intestinal (SI) homeostasis. Using a Lgr5-2A-DTR (diphtheria toxin receptor) model, which ablates Lgr5+ cells with near-complete efficiency and retains endogenous levels of Lgr5 expression, we show that persistent depletion of Lgr5+ ISCs in fact compromises SI epithelial integrity and reduces epithelial turnover in vivo. In vitro, Lgr5-2A-DTR SI organoids are unable to establish or survive when Lgr5+ ISCs are continuously eliminated by adding DT to the media. However, transient exposure to DT at the start of culture allows organoids to form, and the rate of outgrowth reduces with the increasing length of DT presence. Our results indicate that intestinal homeostasis requires a constant pool of Lgr5+ ISCs, which is supplied by rapidly reprogrammed non-Lgr5+ crypt populations when preexisting Lgr5+ ISCs are ablated.

Ceftolozane/Tazobactam Resistance and Mechanisms in Carbapenem-Nonsusceptible Pseudomonas aeruginosa.

This study established the in vitro activity of ceftolozane/tazobactam (C/T) and its genotypic resistance mechanisms by whole-genome sequencing (WGS) in 195 carbapenem-nonsusceptible Pseudomonas aeruginosa (CNSPA) clinical isolates recovered from Singapore between 2009 and 2020. C/T susceptibility rates were low, at 37.9%. Cross-resistance to ceftazidime/avibactam was observed, although susceptibility to the agent was slightly higher, at 41.0%. Whole-genome sequencing revealed that C/T resistance was largely mediated by the presence of horizontally acquired ß-lactamases, especially metallo-ß-lactamases. These were primarily disseminated in well-recognized high-risk clones belonging to sequence types (ST) 235, 308, and 179. C/T resistance was also observed in several non-carbapenemase-producing isolates, in which resistance was likely mediated by ß-lactamases and, to a smaller extent, mutations in AmpC-related genes. There was no obvious mechanism of resistance observed in five isolates. The high C/T resistance highlights the limited utility of the agent as an empirical agent in our setting. Knowledge of local molecular epidemiology is crucial in determining the potential of therapy with novel agents.IMPORTANCEPseudomonas aeruginosa infection is one of the most difficult health care-associated infections to treat due to the ability of the organism to acquire a multitude of resistance mechanisms and express the multidrug resistance phenotype. Ceftolozane/tazobactam (C/T), a novel ß-lactam/ß-lactamase inhibitor combination, addresses an unmet medical need in patients with these multidrug-resistant P. aeruginosa infections. Our findings demonstrate geographical variation in C/T susceptibility owing to the distinct local molecular epidemiology. This study adds on to the growing knowledge of C/T resistance, particularly mutational resistance, and will aid in the design of future ß-lactams and ß-lactamase inhibitors. WGS proved to be a useful tool to understand the P. aeruginosa resistome and its contribution to emerging resistance in novel antimicrobial agents.

AQP5 enriches for stem cells and cancer origins in the distal stomach.

LGR5 marks resident adult epithelial stem cells at the gland base in the mouse pyloric stomach1, but the identity of the equivalent human stem cell population remains unknown owing to a lack of surface markers that facilitate its prospective isolation and validation. In mouse models of intestinal cancer, LGR5+ intestinal stem cells are major sources of cancer following hyperactivation of the WNT pathway2. However, the contribution of pyloric LGR5+ stem cells to gastric cancer following dysregulation of the WNT pathway-a frequent event in gastric cancer in humans3-is unknown. Here we use comparative profiling of LGR5+ stem cell populations along the mouse gastrointestinal tract to identify, and then functionally validate, the membrane protein AQP5 as a marker that enriches for mouse and human adult pyloric stem cells. We show that stem cells within the AQP5+ compartment are a source of WNT-driven, invasive gastric cancer in vivo, using newly generated Aqp5-creERT2 mouse models. Additionally, tumour-resident AQP5+ cells can selectively initiate organoid growth in vitro, which indicates that this population contains potential cancer stem cells. In humans, AQP5 is frequently expressed in primary intestinal and diffuse subtypes of gastric cancer (and in metastases of these subtypes), and often displays altered cellular localization compared with healthy tissue. These newly identified markers and mouse models will be an invaluable resource for deciphering the early formation of gastric cancer, and for isolating and characterizing human-stomach stem cells as a prerequisite for harnessing the regenerative-medicine potential of these cells in the clinic.

Neonatal Wnt-dependent Lgr5 positive stem cells are essential for uterine gland development.

Wnt signaling is critical for directing epithelial gland development within the uterine lining to ensure successful gestation in adults. Wnt-dependent, Lgr5-expressing stem/progenitor cells are essential for the development of glandular epithelia in the intestine and stomach, but their existence in the developing reproductive tract has not been investigated. Here, we employ Lgr5-2A-EGFP/CreERT2/DTR mouse models to identify Lgr5-expressing cells in the developing uterus and to evaluate their stem cell identity and function. Lgr5 is broadly expressed in the uterine epithelium during embryogenesis, but becomes largely restricted to the tips of developing glands after birth. In-vivo lineage tracing/ablation/organoid culture assays identify these gland-resident Lgr5high cells as Wnt-dependent stem cells responsible for uterine gland development. Adjacent Lgr5neg epithelial cells within the neonatal glands function as essential niche components to support the function of Lgr5high stem cells ex-vivo. These findings constitute a major advance in our understanding of uterine development and lay the foundations for investigating potential contributions of Lgr5+ stem/progenitor cells to uterine disorders.

Recent Advances in Lgr5+ Stem Cell Research.

The discovery of leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5) as both a marker of adult stem cells and a critical modulator of their activity via its role as an effector of Wnt/R-spondin (Rspo) signaling has driven major advances in our understanding of stem cell biology during homeostasis, regeneration, and disease. Exciting new mouse and organoid culture models developed to study the endogenous behavior of Lgr5-expressing cells in health and disease settings have revealed the existence of facultative stem cell populations responsible for tissue regeneration, cancer stem cells (CSCs) driving metastasis in the gut, and Lgr5+ niche cells in the lung. Here we review these recent advances and discuss their impact on efforts to harness the therapeutic potential of adult stem cells and their cancer counterparts in the clinic.

Wnt Signaling in Adult Epithelial Stem Cells and Cancer.

Wnt/ß-catenin signaling is integral to the homeostasis and regeneration of many epithelial tissues due to its critical role in adult stem cell regulation. It is also implicated in many epithelial cancers, with mutations in core pathway components frequently present in patient tumors. In this chapter, we discuss the roles of Wnt/ß-catenin signaling and Wnt-regulated stem cells in homeostatic, regenerative and cancer contexts of the intestines, stomach, skin, and liver. We also examine the sources of Wnt ligands that form part of the stem cell niche. Despite the diversity in characteristics of various tissue stem cells, the role(s) of Wnt/ß-catenin signaling is generally coherent in maintaining stem cell fate and/or promoting proliferation. It is also likely to play similar roles in cancer stem cells, making the pathway a salient therapeutic target for cancer. While promising progress is being made in the field, deeper understanding of the functions and signaling mechanisms of the pathway in individual epithelial tissues will expedite efforts to modulate Wnt/ß-catenin signaling in cancer treatment and tissue regeneration.

In vivo lineage tracing reveals Axin2-expressing, long-lived cortical thymic epithelial progenitors in the postnatal thymus.

In the thymus, cortical and medullary thymic epithelial cells (TECs) are instrumental for generating a repertoire of functional T cells. Hence, there has been much interest in the ontogeny of TECs. While medullary TEC (mTEC) and bipotent progenitors have been identified, the existence of a cortical TEC (cTEC) progenitor remains ambiguous. In this study, we used lineage tracing based on a target gene of the Wnt pathway, Axin2. We found that Axin2 initially labels cells in both the cortical and medullary compartments. Using Axin2-CreERT2 mice to track the fate of labelled cells, we identified long-lived cortical TEC progenitors that give rise to expanding clones and contribute to homeostasis in postnatal thymus. In contrast, no clonal expansion was found in the medullary or in the K5K8-double positive compartments. The identification of cTEC progenitors and their regulation by Wnt signaling have important implications for our understanding of thymus physiology during homeostasis and TEC-related disorders.

Lgr5-expressing chief cells drive epithelial regeneration and cancer in the oxyntic stomach.

The daily renewal of the corpus epithelium is fuelled by adult stem cells residing within tubular glands, but the identity of these stem cells remains controversial. Lgr5 marks homeostatic stem cells and 'reserve' stem cells in multiple tissues. Here, we report Lgr5 expression in a subpopulation of chief cells in mouse and human corpus glands. Using a non-variegated Lgr5-2A-CreERT2 mouse model, we show by lineage tracing that Lgr5-expressing chief cells do not behave as corpus stem cells during homeostasis, but are recruited to function as stem cells to effect epithelial renewal following injury by activating Wnt signalling. Ablation of Lgr5+ cells severely impairs epithelial homeostasis in the corpus, indicating an essential role for these Lgr5+ cells in maintaining the homeostatic stem cell pool. We additionally define Lgr5+ chief cells as a major cell-of-origin of gastric cancer. These findings reveal clinically relevant insights into homeostasis, repair and cancer in the corpus.

A quantum approach to homomorphic encryption.

Encryption schemes often derive their power from the properties of the underlying algebra on the symbols used. Inspired by group theoretic tools, we use the centralizer of a subgroup of operations to present a private-key quantum homomorphic encryption scheme that enables a broad class of quantum computation on encrypted data. The quantum data is encoded on bosons of distinct species in distinct spatial modes, and the quantum computations are manipulations of these bosons in a manner independent of their species. A particular instance of our encoding hides up to a constant fraction of the information encrypted. This fraction can be made arbitrarily close to unity with overhead scaling only polynomially in the message length. This highlights the potential of our protocol to hide a non-trivial amount of information, and is suggestive of a large class of encodings that might yield better security.

Organoids as an in vitro model of human development and disease.

The in vitro organoid model is a major technological breakthrough that has already been established as an essential tool in many basic biology and clinical applications. This near-physiological 3D model facilitates an accurate study of a range of in vivo biological processes including tissue renewal, stem cell/niche functions and tissue responses to drugs, mutation or damage. In this Review, we discuss the current achievements, challenges and potential applications of this technique.

Axin2 marks quiescent hair follicle bulge stem cells that are maintained by autocrine Wnt/ß-catenin signaling.

How stem cells maintain their identity and potency as tissues change during growth is not well understood. In mammalian hair, it is unclear how hair follicle stem cells can enter an extended period of quiescence during the resting phase but retain stem cell potential and be subsequently activated for growth. Here, we use lineage tracing and gene expression mapping to show that the Wnt target gene Axin2 is constantly expressed throughout the hair cycle quiescent phase in outer bulge stem cells that produce their own Wnt signals. Ablating Wnt signaling in the bulge cells causes them to lose their stem cell potency to contribute to hair growth and undergo premature differentiation instead. Bulge cells express secreted Wnt inhibitors, including Dickkopf (Dkk) and secreted frizzled-related protein 1 (Sfrp1). However, the Dickkopf 3 (Dkk3) protein becomes localized to the Wnt-inactive inner bulge that contains differentiated cells. We find that Axin2 expression remains confined to the outer bulge, whereas Dkk3 continues to be localized to the inner bulge during the hair cycle growth phase. Our data suggest that autocrine Wnt signaling in the outer bulge maintains stem cell potency throughout hair cycle quiescence and growth, whereas paracrine Wnt inhibition of inner bulge cells reinforces differentiation.

Stemming Colorectal Cancer Growth and Metastasis: HOXA5 Forces Cancer Stem Cells to Differentiate.

Wnt signaling drives colorectal cancer stem cells, but effective therapeutics targeting these cells and their signaling pathways are lacking. In this issue of Cancer Cell, Ordóñez-Morán and colleagues describe a promising therapeutic intervention for colorectal cancers that selectively induces cancer stem cell differentiation through HOXA5 expression and Wnt signaling inhibition.