Strain Tracking with Uncertainty Quantification.

The ability to detect and quantify microbiota over time has a plethora of clinical, basic science, and public health applications. One of the primary means of tracking microbiota is through sequencing technologies. When the microorganism of interest is well characterized or known a priori, targeted sequencing is often used. In many applications, however, untargeted bulk (shotgun) sequencing is more appropriate; for instance, the tracking of infection transmission events and nucleotide variants across multiple genomic loci, or studying the role of multiple genes in a particular phenotype. Given these applications, and the observation that pathogens (e.g. Clostridioides difficile, Escherichia coli, Salmonella enterica) and other taxa of interest can reside at low relative abundance in the gastrointestinal tract, there is a critical need for algorithms that accurately track low-abundance taxa with strain level resolution. Here we present a sequence quality- and time-aware model, ChronoStrain, that introduces uncertainty quantification to gauge low-abundance species and significantly outperforms the current state-of-the-art on both real and synthetic data. ChronoStrain leverages sequences' quality scores and the samples' temporal information to produce a probability distribution over abundance trajectories for each strain tracked in the model. We demonstrate Chronostrain's improved performance in capturing post-antibiotic E. coli strain blooms among women with recurrent urinary tract infections (UTIs) from the UTI Microbiome (UMB) Project. Other strain tracking models on the same data either show inconsistent temporal colonization or can only track consistently using very coarse groupings. In contrast, our probabilistic outputs can reveal the relationship between low-confidence strains present in the sample that cannot be reliably assigned a single reference label (either due to poor coverage or novelty) while simultaneously calling high-confidence strains that can be unambiguously assigned a label. We also include and analyze newly sequenced cultured samples from the UMB Project.

Gut metabolites predict Clostridioides difficile recurrence.

BACKGROUND: Clostridioides difficile infection (CDI) is the most common hospital acquired infection in the USA, with recurrence rates > 15%. Although primary CDI has been extensively linked to gut microbial dysbiosis, less is known about the factors that promote or mitigate recurrence. Moreover, previous studies have not shown that microbial abundances in the gut measured by 16S rRNA amplicon sequencing alone can accurately predict CDI recurrence. RESULTS: We conducted a prospective, longitudinal study of 53 non-immunocompromised participants with primary CDI. Stool sample collection began pre-CDI antibiotic treatment at the time of diagnosis, and continued up to 8 weeks post-antibiotic treatment, with weekly or twice weekly collections. Samples were analyzed using (1) 16S rRNA amplicon sequencing, (2) liquid chromatography/mass-spectrometry metabolomics measuring 1387 annotated metabolites, and (3) short-chain fatty acid profiling. The amplicon sequencing data showed significantly delayed recovery of microbial diversity in recurrent participants, and depletion of key anaerobic taxa at multiple time-points, including Clostridium cluster XIVa and IV taxa. The metabolomic data also showed delayed recovery in recurrent participants, and moreover mapped to pathways suggesting distinct functional abnormalities in the microbiome or host, such as decreased microbial deconjugation activity, lowered levels of endocannabinoids, and elevated markers of host cell damage. Further, using predictive statistical/machine learning models, we demonstrated that the metabolomic data, but not the other data sources, can accurately predict future recurrence at 1 week (AUC 0.77 [0.71, 0.86; 95% interval]) and 2 weeks (AUC 0.77 [0.69, 0.85; 95% interval]) post-treatment for primary CDI. CONCLUSIONS: The prospective, longitudinal, and multi-omic nature of our CDI recurrence study allowed us to uncover previously unrecognized dynamics in the microbiome and host presaging recurrence, and, in particular, to elucidate changes in the understudied gut metabolome. Moreover, we demonstrated that a small set of metabolites can accurately predict future recurrence. Our findings have implications for development of diagnostic tests and treatments that could ultimately short-circuit the cycle of CDI recurrence, by providing candidate metabolic biomarkers for diagnostics development, as well as offering insights into the complex microbial and metabolic alterations that are protective or permissive for recurrence. Video Abstract.

Prevalence of Dental Anomalies in Patients With Unilateral Cleft Lip and Alveolus Treated With Gingivoperiosteoplasty.

OBJECTIVE: To compare the prevalence of dental malformations and agenesis in patients who received or did not receive gingivoperiosteoplasty (GPP). DESIGN: Retrospective cohort study. PATIENTS: Review of patients born January 1, 2000, to December 31, 2007, with unilateral cleft lip and alveolus, with or without clefting of the secondary palate, who received GPP and/or secondary alveolar bone grafting (ABG). Patients were included if they had clinical images and dental radiographs available at ages 5 to 9 and 10 to 12 years. Ninety-four patients met the inclusion criteria; 46 treated with GPP, and 48 who did not receive GPP. OUTCOME MEASURES: Records were assessed for supernumerary, missing, and malformed teeth by a blinded examiner, and prevalence compared between groups using χ2 tests. RESULTS: Cleft side lateral incisors were absent in 54% of GPP patients, compared to 50% in the no-GPP group. Two patients in the GPP group and 1 in the no-GPP group had supernumerary lateral incisors. Most lateral incisors were undersized or peg shaped in both the no-GPP (83.3%) and GPP (71.4%) groups. In the GPP group, 5 (10.9%) patients exhibited central incisor agenesis, and 3 had significant hypoplasia. In the no-GPP group, 4 (8.3%) patients exhibited central incisor agenesis, and 5 (10.5%) significant hypoplasia. These differences were not statistically significant. CONCLUSIONS: Gingivoperiosteoplasty was not associated with increased prevalence of dental malformation or agenesis. When performed appropriately, GPP is a safe treatment technique that does not increase the risk of dental anomalies.

One-Year Stability of LeFort I Advancement in Patients With Complete Cleft Lip and Palate Using a Standardized Clinical and Surgical Protocol.

AIM: To assess treatment outcome and 1-year stability of LeFort I advancement in patients with complete cleft lip and palate. METHODS: Thirty-five patients (age 20.65 ±â€Š2.20 years) with unilateral (n = 25) or bilateral (n = 10) complete cleft lip and palate who underwent LeFort I advancement were included.Lateral cephalograms before surgery (T1), immediately postsurgery (T2), and at 1-year follow-up (T3) were superimposed, and the position of anterior nasal spine (ANS), A-point, and U1 Tip assessed using an x, y coordinate system. Differences between landmark positions at the 3-time points were analyzed using paired sample t-tests, with a significance defined as α ≤ 0.05. RESULTS: The mean surgical advancement in the horizontal direction (T2-T1) was 6.50 ±â€Š2.62 mm at ANS (P < 0.001) and 7.05 ±â€Š2.51 mm at A-point (P < 0.001). At a 1-year follow-up (T3-T2), the mean horizontal relapse at ANS was -1.41 ±â€Š1.89 mm (P < 0.001) and -0.79 ±â€Š1.48 mm at A-point (P 0.003). Mean horizontal relapse was 21.7% and 11% of surgical advancement when assessed at ANS and A-point, respectively. The central incisor tip position remained stable during the postsurgical period (0.12 ±â€Š2.11 mm, P 0.732). At A-point, the mean vertical surgical change (T2-T1) was -0.96 ±â€Š2.57 mm (P < 0.001). No significant post-treatment (T3-T2) vertical changes were detected at ANS or A-point. Phenotypic stability was excellent, with all patients maintaining positive overjet at 1-year follow-up. CONCLUSIONS: LeFort I advancement in complete cleft lip and palate is stable, with less than a 2 mm relapse after 1-year. Surgical overcorrection by 10% to 20% is recommended to compensate for the expected skeletal relapse.

Sociodemographic Predictors of Treatment Success and Difficulty in Nasoalveolar Molding.

OBJECTIVE: To assess social and demographic influences on caregiver success and difficulty with nasoalveolar molding (NAM). DESIGN: Retrospective review identified patients who began NAM between April 22, 2013, and April 18, 2017, at the New York University Langone Medical Center. Records were reviewed, and the following sociodemographic data retrieved: parental marital status, parental ages, number of siblings, distance traveled to clinic, insurance coverage, concurrent medical conditions, and need for an interpreter. PATIENTS: Patients were included if complete charting was available; 106 patients met the inclusion criteria; 79 patients with unilateral and 27 with bilateral clefts. OUTCOME MEASURES: Chart entries indicating incorrect appliance usage, emergency visits, phone calls, and noncompliance were recorded. Alveolar cleft gap closure was measured on pre- and posttreatment models in unilateral cases. Multiple regression analyses were performed to assess the influence of social variables on these outcomes. RESULTS: Alveolar cleft gap closure was 7.2 ± 3.0 mm, or 78.5% ± 19.1%. Cleft closure increased with paternal age by 0.33 mm (P = .007) or 2.0% (P = .017) per year, decreased with maternal age by 0.29 mm (P = .041) per year, and increased in married and partnered parents by 39% (P = .018). Incorrect appliance usage averaged 0.62 fewer instances for married and partnered parents (P = .018) and 0.43 fewer for those with private insurance (P = .019). CONCLUSIONS: Alveolar cleft gap closure was more successful for older fathers, younger mothers, and married couples. Married couples were also less likely to experience treatment difficulties such as incorrect appliance usage or inadequate duration of wear, as were those with private insurance coverage.

Ultra-Sensitive Serial Profiling of SARS-CoV-2 Antigens and Antibodies in Plasma to Understand Disease Progression in COVID-19 Patients with Severe Disease.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 21 million people worldwide since August 16, 2020. Compared to PCR and serology tests, SARS-CoV-2 antigen assays are underdeveloped, despite their potential to identify active infection and monitor disease progression. METHODS: We used Single Molecule Array (Simoa) assays to quantitatively detect SARS-CoV-2 spike, S1 subunit, and nucleocapsid antigens in the plasma of patients with coronavirus disease (COVID-19). We studied plasma from 64 patients who were COVID-19 positive, 17 who were COVID-19 negative, and 34 prepandemic patients. Combined with Simoa anti-SARS-CoV-2 serological assays, we quantified changes in 31 SARS-CoV-2 biomarkers in 272 longitudinal plasma samples obtained for 39 patients with COVID-19. Data were analyzed by hierarchical clustering and were compared to longitudinal RT-PCR test results and clinical outcomes. RESULTS: SARS-CoV-2 S1 and N antigens were detectable in 41 out of 64 COVID-19 positive patients. In these patients, full antigen clearance in plasma was observed a mean ± 95% CI of 5 ± 1 days after seroconversion and nasopharyngeal RT-PCR tests reported positive results for 15 ± 5 days after viral-antigen clearance. Correlation between patients with high concentrations of S1 antigen and ICU admission (77%) and time to intubation (within 1 day) was statistically significant. CONCLUSIONS: The reported SARS-CoV-2 Simoa antigen assay is the first to detect viral antigens in the plasma of patients who were COVID-19 positive to date. These data show that SARS-CoV-2 viral antigens in the blood are associated with disease progression, such as respiratory failure, in COVID-19 cases with severe disease.

NAM Therapy-Evidence-Based Results.

Many orthodontists working on patients with cleft lip and palate (CLP) have shown great enthusiasm for presurgical infant orthopedics (PSIO) to improve surgical outcomes with minimal intervention. Even though every clinician aims to use the best treatment modality for their patients, PSIO effects can be confounded by surgical type and timing of the primary repair, as is discussed in many studies. In such cases, one should be cautious when evaluating the particular outcomes for patients with CLP since it is difficult to differentiate the sole effect of an individual surgical or orthodontic intervention. As with any treatment methodology, nasoalveolar molding (NAM) has both benefits and limitations. Commonly cited concerns with NAM, and PSIO in general, include increased cost, increased burden of care, and a negative impact on maxillary growth. However, NAM cannot be deemed as having apparent long-term negative or positive effects on skeletal or soft tissue facial growth, based on previous studies. A review of the literature suggests that NAM does not alter skeletal facial growth when compared with the samples that did not receive PSIO. Nevertheless, the published studies on NAM show evidence of benefits to the patient, caregivers, the surgeon, and society. These benefits include documented reduction in severity of the cleft deformity prior to surgery and as a consequence improved surgical outcomes, reduced burden of care on the care givers, reduction in the need for revision surgery, and consequent reduced overall cost of care to the patient and society.

Zygomatic Rotation-Advancement: A New Concept for the Correction of Exorbitism in Patients With Syndromic Craniosynostosis.

BACKGROUND: The exophthalmos and class III malocclusion seen in Crouzon syndrome can be treated by Le Fort III advancement/distraction. However, reconstructive options for zygomatic retrusion are limited. The authors describe the repair of isolated exorbitism in a patient with Crouzon syndrome, via bilateral zygomatic rotation-advancement. METHODS: A 34-year-old woman with Crouzon syndrome complained of exorbitism and malar hypoplasia. Four years prior, she declined Le Fort III advancement and underwent orthodontic/orthognathic correction of malocclusion. Radiographs were used to develop a computerized surgical plan. Bilateral periorbital osteotomy with advancement/rotation of the zygomatic process was performed using custom osteotomy guides and plates. Images obtained immediately postoperative and 3- and 19-month postoperative were compared to assess surgical stability, accuracy, and soft tissue changes. RESULTS: Decreased globe exposure and increased malar prominence have improved facial balance. Superimposed pre- and postoperative radiographs demonstrate bilateral advancement of the zygomatic body and inferior orbital rim. Superimposition of immediate postoperative and 19-month radiographs showed no relapse. Soft tissue histogram showed increased prominence of the malar eminence, lateral orbital rim, and cheek. CONCLUSIONS: Zygomatic rotation-advancement proved a safe, effective, stable, and predictable treatment for isolated malar hypoplasia in a patient with Crouzon syndrome. Virtual planning can enhance novel complex craniofacial procedures.

Maxillomandibular and occlusal relationships in preadolescent patients with syndromic craniosynostosis treated by LeFort III distraction osteogenesis: 10-year surgical and phenotypic stability.

INTRODUCTION: LeFort III distraction osteogenesis may be indicated in the treatment of syndromic craniosynostosis with severe midface retrusion. This study investigates long-term changes in patients undergoing distraction as children, and compares outcomes to an unaffected, untreated control. METHODS: Fifteen patients (9 males, 6 females) with syndromic craniosynostosis treated by LeFort III distraction at an average age of 4.9 ± 1.5 years were identified. Lateral cephalograms at predistraction, immediate, 1-, 5-, and 10-year postdistraction were superimposed using the best-fit of cranial base details. An untreated, unaffected matched control was obtained from the American Association of Orthodontists Foundation Legacy Collection. Differences in landmark location and cephalometric relationships were assessed between time points and between treatment and control groups. RESULTS: LeFort III distraction produced an average advancement of 14.86 ± 5.14 mm at A-point and 10.54 ± 3.78 mm at orbitale. This advancement produced overcorrection of anteroposterior occlusal relationships and phenotypic correction of midface position. Surgical stability over a 10-year follow-up was excellent. Posttreatment growth was characterized by absent anteroposterior maxillary growth, preservation of dentoalveolar development and maxillary remodeling, and delayed mandibular growth. Subsequent growth resulted in a long-term phenotypic relapse of pretreatment Class III maxillomandibular relationship and negative overjet. CONCLUSIONS: LeFort III distraction osteogenesis produces stable advancement of the midface. Overcorrection is required for long-term phenotypic stability because of deficient postdistraction sagittal midface growth. Late mandibular growth contributes to underestimation of the amount of distraction required to produce long-term phenotypic correction.

Engineered Interspecies Amino Acid Cross-Feeding Increases Population Evenness in a Synthetic Bacterial Consortium.

In nature, microbes interact antagonistically, neutrally, or beneficially. To shed light on the effects of positive interactions in microbial consortia, we introduced metabolic dependencies and metabolite overproduction into four bacterial species. While antagonistic interactions govern the wild-type consortium behavior, the genetic modifications alleviated antagonistic interactions and resulted in beneficial interactions. Engineered cross-feeding increased population evenness, a component of ecological diversity, in different environments, including in a more complex gnotobiotic mouse gut environment. Our findings suggest that metabolite cross-feeding could be used as a tool for intentionally shaping microbial consortia in complex environments.IMPORTANCE Microbial communities are ubiquitous in nature. Bacterial consortia live in and on our body and in our environment, and more recently, biotechnology is applying microbial consortia for bioproduction. As part of our body, bacterial consortia influence us in health and disease. Microbial consortium function is determined by its composition, which in turn is driven by the interactions between species. Further understanding of microbial interactions will help us in deciphering how consortia function in complex environments and may enable us to modify microbial consortia for health and environmental benefits.

Dynamic Modulation of the Gut Microbiota and Metabolome by Bacteriophages in a Mouse Model.

The human gut microbiome is comprised of densely colonizing microorganisms including bacteriophages, which are in dynamic interaction with each other and the mammalian host. To address how bacteriophages impact bacterial communities in the gut, we investigated the dynamic effects of phages on a model microbiome. Gnotobiotic mice were colonized with defined human gut commensal bacteria and subjected to predation by cognate lytic phages. We found that phage predation not only directly impacts susceptible bacteria but also leads to cascading effects on other bacterial species via interbacterial interactions. Metabolomic profiling revealed that shifts in the microbiome caused by phage predation have a direct consequence on the gut metabolome. Our work provides insight into the ecological importance of phages as modulators of bacterial colonization, and it additionally suggests the potential impact of gut phages on the mammalian host with implications for their therapeutic use to precisely modulate the microbiome.

Three-Dimensional Soft Tissue Nasal Changes After Nasoalveolar Molding and Primary Cheilorhinoplasty in Infants With Unilateral Cleft Lip and Palate.

OBJECTIVE: To quantify 3-dimensional (3D) nasal changes in infants with unilateral cleft lip with or without cleft palate (UCL±P) treated by nasoalveolar molding (NAM) and cheilorhinoplasty and compare to noncleft controls. DESIGN: Retrospective case series of infants treated with NAM and primary cheilorhinoplasty between September, 2012 and July, 2016. Infants were included if they had digital stereophotogrammetric records at initial presentation (T1), completion of NAM (T2), and following primary cheilorhinoplasty (T3). Images were oriented in 3dMD Vultus software, and 16 nasolabial points identified. PATIENTS: Twenty consecutively treated infants with UCL±P. INTERVENTIONS: Nasoalveolar molding and primary cheilorhinoplasty. MAIN OUTCOME MEASURES: Anthropometric measures of nasal symmetry and morphology were compared in the treatment group between time points using paired Student t tests. Postsurgical nasal morphology was compared to noncleft controls. RESULTS: Nasal tip protrusion increased, and at T3 was 2.64 mm greater than noncleft controls. Nasal base width decreased on the cleft side by 4.01 mm after NAM and by 6.73 mm after cheilorhinoplasty. Columellar length of the noncleft to cleft side decreased from 2:1 to 1:1 following NAM. Significant improvements in subnasale, columella, and nasal tip deviations from midsagittal plane were observed. Treatment improved symmetry of the alar morphology angle and the nasal base-columella angle between cleft and noncleft sides. CONCLUSIONS: Three-dimensional analysis of UCL±P patients demonstrated significant improvements in nasal projection, columella length, nasal symmetry, and nasal width. Compared to noncleft controls, nasal form was generally corrected, with overcorrection of nasal tip projection, columella angle, and outer nasal widths.

Proptosis Correction in Pre-Adolescent Patients With Syndromic Craniosynostosis by Le Fort III Distraction Osteogenesis.

Le Fort III distraction osteogenesis may be indicated in the treatment of syndromic craniosynostosis with severe midface retrusion and proptosis. This study assesses the stability of proptosis correction over 10-years.A retrospective review identified 15 patients with syndromic craniosynostosis treated by Le Fort III distraction prior to age 10 (9 males, 6 females; age 4.9 ±â€Š1.5 years). Untreated, non-craniosynostotic age- and gender-matched controls were obtained from historical growth records. Lateral cephalometric tracings at pre-surgery (T1), immediate (T2), 1 year (T3), 5 years (T4), and 10 years (T5) (n = 11) post-distraction were superimposed using the best-fit of cranial base. Proptosis severity was defined as the horizontal distance between the Ant. Globe cephalometric point and orbital rim landmarks Orbitale and Lat. Orbit.The orbital rim advanced 10.54 ±â€Š3.78 mm (P < 0.001) at Orbitale and 9.73 ±â€Š4.54 mm (P > 0.001) at Lat. Orbit from T1 to T2; Ant. Globe advanced 3.13 ±â€Š3.02 mm (p 0.001). Proptosis decreased 7.41 ±â€Š5.29 mm (P < .001) from Orbitale and 6.60 ±â€Š6.50 mm (p 0.002) from Lat. Orbit. Comparison to controls demonstrated phenotypic correction. In craniosynostotic patients from T2 to T5, the bony orbital rim demonstrated non-significant remodeling posteriorly and inferiorly. Anterior Globe moved 3.79 ±â€Š1.47 mm anteriorly (P < .001), which did not differ significantly from controls. Proptosis increased by 4.18 ±â€Š2.94 mm in craniosynostotic patients from T2 to T5.Le Fort III distraction was stable, with no significant anteroposterior relapse of the maxilla or bony orbit. Phenotypic relapse of proptosis to pre-treatment levels occurred through deficient growth of the midface, surface resorption at the orbital rim, and preservation of normal forward movement of Ant. Globe.

CONVERGENCE PROPERTIES OF ADAPTIVE SYSTEMS AND THE DEFINITION OF EXPONENTIAL STABILITY.

The convergence properties of adaptive systems in terms of excitation conditions on the regressor vector are well known. With persistent excitation of the regressor vector in model reference adaptive control the state error and the adaptation error are globally exponentially stable or, equivalently, exponentially stable in the large. When the excitation condition, however, is imposed on the reference input or the reference model state, it is often incorrectly concluded that the persistent excitation in those signals also implies exponential stability in the large. The definition of persistent excitation is revisited so as to address some possible confusion in the adaptive control literature. It is then shown that persistent excitation of the reference model only implies local persistent excitation (weak persistent excitation). Weak persistent excitation of the regressor is still sufficient for uniform asymptotic stability in the large, but not exponential stability in the large. We show that there exists an infinite region in the state-space of adaptive systems where the state rate is bounded. This infinite region with finite rate of convergence is shown to exist not only in classic open-loop reference model adaptive systems but also in a new class of closed-loop reference model adaptive systems.

Preoperative Alveolar Segment Position as a Predictor of Successful Gingivoperiosteoplasty in Patients with Unilateral Cleft Lip and Palate.

BACKGROUND: Gingivoperiosteoplasty can avoid secondary alveolar bone grafting in up to 60 percent of patients with a cleft. However, preoperative predictors of success have not been characterized. This study reports on the preoperative alveolar segment position most favorable for successful gingivoperiosteoplasty. METHODS: The authors performed a single-institution, retrospective review of patients with a unilateral cleft who underwent nasoalveolar molding. Alveolar segment morphology was directly measured from maxillary dental models created before and after nasoalveolar molding. Statistical analysis was performed to identify parameters associated with the decision to perform gingivoperiosteoplasty and its success, defined as the absence of an eventual need for alveolar bone grafting. RESULTS: Fifty patients with a unilateral cleft who received nasoalveolar molding therapy were included in this study (40 underwent gingivoperiosteoplasty and 10 did not). Eighteen alveolar morphology and position characteristics were tested, including cleft gap width, horizontal and vertical positions of the alveolar segments, alveolar stepoff, and degree of alveolar segment apposition. Post-nasoalveolar molding vertical rotation of the greater segment and the percentage of segment alignment in the correct anatomical zone were statistically significant predictors of the decision to perform gingivoperiosteoplasty (86 percent predictive power). Cleft gap, greater/lesser segment overlap, alveolar segment alignment, greater segment horizontal rotation, and alveolar segment width following nasoalveolar molding were significant predictors of gingivoperiosteoplasty success (86.5 percent predictive power). CONCLUSIONS: Greater segment vertical rotation and proper alveolar segment anatomical alignment are positive predictors of the decision to perform gingivoperiosteoplasty. Post-nasoalveolar molding evidence of proper alignment and direct contact between the alveolar segments were significant predictors of successful gingivoperiosteoplasty. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Inferring human microbial dynamics from temporal metagenomics data: Pitfalls and lessons.

The human gut microbiota is a very complex and dynamic ecosystem that plays a crucial role in health and well-being. Inferring microbial community structure and dynamics directly from time-resolved metagenomics data is key to understanding the community ecology and predicting its temporal behavior. Many methods have been proposed to perform the inference. Yet, as we point out in this review, there are several pitfalls along the way. Indeed, the uninformative temporal measurements and the compositional nature of the relative abundance data raise serious challenges in inference. Moreover, the inference results can be largely distorted when only focusing on highly abundant species by ignoring or grouping low-abundance species. Finally, the implicit assumptions in various regularization methods may not reflect reality. Those issues have to be seriously considered in ecological modeling of human gut microbiota.

Universality of human microbial dynamics.

Human-associated microbial communities have a crucial role in determining our health and well-being, and this has led to the continuing development of microbiome-based therapies such as faecal microbiota transplantation. These microbial communities are very complex, dynamic and highly personalized ecosystems, exhibiting a high degree of inter-individual variability in both species assemblages and abundance profiles. It is not known whether the underlying ecological dynamics of these communities, which can be parameterized by growth rates, and intra- and inter-species interactions in population dynamics models, are largely host-independent (that is, universal) or host-specific. If the inter-individual variability reflects host-specific dynamics due to differences in host lifestyle, physiology or genetics, then generic microbiome manipulations may have unintended consequences, rendering them ineffective or even detrimental. Alternatively, microbial ecosystems of different subjects may exhibit universal dynamics, with the inter-individual variability mainly originating from differences in the sets of colonizing species. Here we develop a new computational method to characterize human microbial dynamics. By applying this method to cross-sectional data from two large-scale metagenomic studies--the Human Microbiome Project and the Student Microbiome Project--we show that gut and mouth microbiomes display pronounced universal dynamics, whereas communities associated with certain skin sites are probably shaped by differences in the host environment. Notably, the universality of gut microbial dynamics is not observed in subjects with recurrent Clostridium difficile infection but is observed in the same set of subjects after faecal microbiota transplantation. These results fundamentally improve our understanding of the processes that shape human microbial ecosystems, and pave the way to designing general microbiome-based therapies.

Controllability analysis of the directed human protein interaction network identifies disease genes and drug targets.

The protein-protein interaction (PPI) network is crucial for cellular information processing and decision-making. With suitable inputs, PPI networks drive the cells to diverse functional outcomes such as cell proliferation or cell death. Here, we characterize the structural controllability of a large directed human PPI network comprising 6,339 proteins and 34,813 interactions. This network allows us to classify proteins as "indispensable," "neutral," or "dispensable," which correlates to increasing, no effect, or decreasing the number of driver nodes in the network upon removal of that protein. We find that 21% of the proteins in the PPI network are indispensable. Interestingly, these indispensable proteins are the primary targets of disease-causing mutations, human viruses, and drugs, suggesting that altering a network's control property is critical for the transition between healthy and disease states. Furthermore, analyzing copy number alterations data from 1,547 cancer patients reveals that 56 genes that are frequently amplified or deleted in nine different cancers are indispensable. Among the 56 genes, 46 of them have not been previously associated with cancer. This suggests that controllability analysis is very useful in identifying novel disease genes and potential drug targets.

On the Origins and Control of Community Types in the Human Microbiome.

Microbiome-based stratification of healthy individuals into compositional categories, referred to as "enterotypes" or "community types", holds promise for drastically improving personalized medicine. Despite this potential, the existence of community types and the degree of their distinctness have been highly debated. Here we adopted a dynamic systems approach and found that heterogeneity in the interspecific interactions or the presence of strongly interacting species is sufficient to explain community types, independent of the topology of the underlying ecological network. By controlling the presence or absence of these strongly interacting species we can steer the microbial ecosystem to any desired community type. This open-loop control strategy still holds even when the community types are not distinct but appear as dense regions within a continuous gradient. This finding can be used to develop viable therapeutic strategies for shifting the microbial composition to a healthy configuration.