Corrections

BIOPHYSICS AND COMPUTATIONAL BIOLOGY

Correction for ‘‘A robust method for searching the smallest set
of smallest rings with a path-included distance matrix,’’ by Chang
Joon Lee, Young-Mook Kang, Kwang-Hwi Cho, and Kyoung Tai
No, which appeared in issue 41, October 13, 2009, of Proc Natl
Acad Sci USA (106:17355–17358; first published September 24,
2009; 10.1073/pnas.0813040106).
The authors note that, due to a printer’s error, the Supporting
Information materials did not appear online along with the main
article. The materials have since been made available online. The
online version of the main article has been corrected to include
a link to the Supporting Information.
www.pnas.org/cgi/doi/10.1073/pnas.0911801106

CELL BIOLOGY
Correction for ‘‘CIB1 functions as a Ca2⫹-sensitive modulator of
stress-induced signaling by targeting ASK1,’’ by Kyoung Wan
Yoon, Jun-Ho Cho, Jae Keun Lee, Young-Hee Kang, Ji Soo
Chae, Young Mok Kim, Jeehyun Kim, Eun Kyung Kim, Sung
Eun Kim, Ja-Hyun Baik, Ulhas P. Naik, Ssang-Goo Cho, and
Eui-Ju Choi, which appeared in issue 41, October 13, 2009, of
Proc Natl Acad Sci USA (106:17389–17394; first published
September 29, 2009; 10.1073/pnas.0812259106).
The authors note that during the publication process, the raw
data shown in Fig. 5C were found to be inaccurately labeled and
could not be used to confirm the results. The experiment was
rerun and new data from two repeating experiments were not
significantly different from those originally shown in Fig. 5C,

confirming the results as originally reported. The authors have
submitted a revised figure, replacing the data originally pub-
lished in Fig. 5C with those of the two new experiments to ensure
the raw data are available to readers. The corrected figure and
its legend appear below.
CORRECTIONS
Fig. 5. KCl-elicited Ca2⫹ influx prevents the inhibitory action of CIB1 on
6-OHDA-induced ASK1 activation and apoptosis. (A) SH-SY5Y cells were incu-
bated first with 6-OHDA (100 ␮M) for 50 min and then without or with KCl (40
mM) either alone or together with BAPTA-AM (2.5 ␮M) for 10 min, as indi-
cated. Cell lysates were subjected to immunoprecipitation with anti-ASK1
antibody or rabbit preimmune IgG (P.I.), and the resulting precipitates were
examined by immunoblotting with antibody to CIB1 (Left) or to TRAF2 (Right).
(B) SH-SY5Y cells expressing a control siRNA or CIB1 siRNA were treated with
6-OHDA, KCl, BAPTA-AM as in A. Cell lysates were assayed for ASK1 activity by
immune complex kinase assay. (C) SH-SY5Y cells expressing a control siRNA or
CIB1 siRNA were incubated consecutively with 6-OHDA (100 ␮M) for 50 min,
with KCl (40 mM) either alone or together with BAPTA-AM (2.5 ␮M) for 30
min, and in DMEM containing 2% FBS for 12 h, as indicated. Cells were
analyzed for apoptosis by flow cytometry. The percentages of apoptotic cells
in a representative experiment are indicated.

www.pnas.org/cgi/doi/10.1073/pnas.0911831106

www.pnas.org PNAS 兩 November 17, 2009 兩 vol. 106 兩 no. 46 兩 19629

A robust method for searching the smallest set of
smallest rings with a path-included distance matrix
Chang Joon Leea, Young-Mook Kanga, Kwang-Hwi Chob, and Kyoung Tai Noa,c,1
aDepartment of Biotechnology, Yonsei University, Seoul 120-749, Korea; bDepartment of Bioinformatics and CAMDRC, Soong Sil University,
Seoul 156-743, Korea; and cBioinformatics and Molecular Design Research Center, Seoul 120-749, Korea
Edited by Sung-Hou Kim, University of California, Berkeley, CA, and approved May 1, 2009 (received for review December 22, 2008)
The perception of rings in graphs is widely used in many fields of
science and engineering. Algorithms developed in the chemistry
community, called smallest set of smallest rings (SSSR), applicable
only for simple graphs or chemical structures. In contrast, algo-
rithms developed by the computer science community, called
minimum cycle basis (MCB) are identical to SSSR yet exhibit greater
robustness. MCB-based algorithms can correctly reveal all rings in
any complex graph. However, they are slow when applied to large
complex graphs due to the inherent limitations of the algorithms
used. Here, we suggest a heuristic method called RP-Path. This
method is a robust, simple, and fast search method with O(n3)
runtime algorithm that correctly identifies the SSSR of all of the
test case of complex graphs by using approach different from the
MCB-based method. Both the robustness and improvement in
speed are achieved by using a path-included distance matrix and
describing the characteristic features of rings in the matrix. This
method is accurate and faster than any other methods and may
find many application in various fields of science and engineering
that use complicated graphs with thousands of nodes.
graph theory 兩 MCB 兩 ring perception 兩 RP-Path 兩 SSSR
C omplicated systems, for example, biological networks, tele-
communication networks, and electrical circuits are de-
scribed with graphs for mathematical manipulation. Smallest set
of smallest ring (SSSR) is the characteristic feature of such
graphs. Therefore, it is crucial to have robust and fast SSSR
calculation method for accurate analysis and manipulations of a
graph.
All reported algorithms developed by the chemistry com-
munity to find the SSSR, are based on two main methods, a
walk-through connection table (1– 4), and graph manipula-
tions (5–8). Some theoretical aspects are summarized by Downs
et al. (9). Although various methods to find SSSRs have been
developed using algorithms based on both methods, none are
robust (10).
From a computer science perspective, identifying SSSRs,
known as minimum cycle basis (MCB), is also interesting. In
addition to its SSSR identification capability, the compute time
of a particular method represented by polynomial time is an
important consideration toward its performance. Horton pro-
posed a robust polynomial time algorithm to find the MCB of a
graph (11). The runtime was obtained as O(m3n) for a graph with
m edges and n vertices. In this approach, the algorithm created
a superset of MCB and then extracted it as the shortest m ⫺ n ⫹
1 linearly independent cycles from the superset using Gaussian
elimination. De Pina (12) proposed a method with a runtime of
O(m3 ⫹ mn2logn) by using a method similar to Padberg and Rao
(13) to solve the minimum weighted T-odd cut problem. Several
methods have been developed based on Horton and De Pina
methods and their computing performance are summarized in
Table 1 (14–17).
Here, we present a heuristic method for ring perception
method called RP-Path. Instead of using a distance matrix as in
Horton and De Pina’s methods, our method uses path-included
distance (PID) matrices, which allow us simply calculate path
www.pnas.org兾cgi兾doi兾10.1073兾pnas.0813040106
Table 1. Worst case performance of SSSR algorithm
Computing Time with Big-Oh notation
With m edges Complete
Algorithm and n vertices graph*
Horton (11) O(m3n) O(n7)
De Pina (12) O(m3 ⫹ mn2logn) O(n6 ⫹ n4logn)
Golynski and Horton (14) O(mwn)† O(n2w⫹1)
Berger et al. (15) O(m3 ⫹ mn2logn) O(n6 ⫹ n4logn)
Kavitha et al. (16) O(m2n ⫹ mn2logn) O(n5 ⫹ n4logn)
Mehlhorn et al. (17) O(m2n2) O(n6)
RP-Path (this work) O(n3) O(n3)
*Worst case, a complete graph, m corresponds to n(n1)/2.
†w ⬍ 2.376.
information and size of the ring simultaneously. With the aids of
PID matrices, a robust ring perception method was developed
with a runtime of O(n3). Consisting of two units, ring candidate
perception followed by ring making and SSSR selection from the
candidates, RP-Path is faster than any other algorithms devel-
oped thus far.
RP-Path is consist of two units, (i) ring candidates perception
and (ii) ring making and SSSR selection from the ring
candidates.
Path-Included Distance Matrix. Let G ⫽ (V, E) be a connected
graph with n vertices and m edges. V(G) ⫽ {v1, v2, v3, . . . , vn} is
a finite non-empty set of vertices and E(G) ⫽ {e1, e2, e3, . . . , em}
is a finite (possibly empty) set of edges eij represented by
unordered pairs of vertices in V. The distance matrix D ⫽ D(G)
of a graph G with n vertices is the square n⫻ n symmetric matrix
in which diagonal elements are zero, dii ⫽ 0. The element dij
corresponds to the minimum path length between vertices i and
j. The Floyd–Warshall method is efficient at finding all-pair
shortest paths on a graph (18, 19). For example, the distance
matrix of the graph in Fig. 1 is shown below.
To find a ring in a circuit with the shortest distance matrix
(SDM), Horton’s method uses the distance information between
one point(v) and two points(x and y) connected with one edge,
C(v, x,y) ⫽ p(v, x) ⫹ p(v, y) ⫹ p(x, y), as described in Fig. 2. Using
the SDM, this method finds the paths of p(v, x), p(v, y), and p(x, COMPUTATIONAL BIOLOGY
y). In order for the three points v, x, and y to be members of a
BIOPHYSICS AND
ring, the edges of the three paths, p(v, x), p(v, y), and p(x, y), are
not shared among them (Fig. 2 A). In the case of Fig. 2B, the
three points are not members of a ring because p(v, x) and p(v, y)
overlap. Because the SDM contains information on the shortest
Author contributions: C.J.L., Y.-M.K., K.-H.C., and K.T.N. designed research, performed
research, contributed new reagents/analytic tools, analyzed data, and wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
1To whom correspondence should be addressed. E-mail: ktno@yonsei.ac.kr.
This article contains supporting information online at www.pnas.org/cgi/content/full/
0813040106/DCSupplemental.
PNAS 兩 October 13, 2009 兩 vol. 106 兩 no. 41 兩 17355–17358

Fig. 1. A graph with two SSSRs and its distance matrix.
distances between two vertices only, another time-consuming
procedure is needed to identify the exact path. All possible rings
can be revealed by considering all possible combinations of one
point and two points connected by one edge, C(v, x, y) ⫽ p(v, x) ⫹
p(v, y) ⫹ p(x, y); however, this is also a time-consuming procedure.
To optimize the SSSR identification procedure, variations of Hor-
ton’s method have tried to improve performance by increasing the
speed of calculating the shortest path between all vertices or by
eliminating unnecessary calculations for finding rings with the
shortest path. However, due to shortcoming inherit in using a
distance matrix, Horton’s method and its variations have limitations
in reducing computation time.
To overcome the limitations in path search resulting from
using distance matrix, we introduced the PID matrix. The PID
matrix calculation was based on the Floyd–Warshall method,
which was originally developed to calculate the distance matrix.
During the shortest path calculation, the path and the shortest
path’s number were stored in the PID matrix, which is crucial for
increasing the speed of the ring perception. In addition to
distance matrix, RP-path introduce additional two PID matrices,
P and P⬘, that store shortest-path information compared with the
other methods in Table 1. RP-path requires additional memory
for P and P⬘ than other method. Whereas, the other methods in
Table 1 require more memory than RP-path during ring per-
ception procedure because other methods have to save all of the
intermediate rings informations(Horton Set). The memory re-
quirement varies depending on the types of graphs, a typical
three graph types are shown in Table 2. Each elements of PID
matrix are integers, which are assigned to an edge for an integer,
and have different sizes depending on the length of the path
information. For implementation, some programming lan-
guages, e.g., C, might need a indexing to indicate the starting
points of each element.
For RP-Path, two matrices, Pe and P⬘e were newly defined. Pe
stores all of the possible shortest paths with a length of dij
between vertices i and j. P⬘e stores all paths that have one more
vertex than the shortest paths with a length of dij ⫹ 1. Pe and P⬘e
for the graph in Fig. 1 are presented in Fig. 3.
With these two matrices, one can identify easily all possible
rings and the size of these rings. Knowing the size of ring is very
important for speeding up in terms of ring perception. Let
Fig. 2. The schematic diagram of ring perception in Horton’s method.
Examples of a ring made with three points (A) and an incomplete ring (B).
17356 兩 www.pnas.org兾cgi兾doi兾10.1073兾pnas.0813040106
Table 2. Comparison of Memory requirements of RP-Path and
Horton’s method
*Because both methods need distance matrix, D, memory requirement for D
is not included.
†K is complete graph with n vertices and n is the number of vertices.
n
‡C is cycle graph that consists of a single cycle.
n
兩Pe [i, j]兩 be the number of possible path of Pe [i, j]. If 兩Pe [i, j]兩
is larger than 2 or 兩Pe [i, j]兩 is 1 and 兩P⬘e[i, j]兩 is larger than 1, then
the vertices i and j are members of a ring (Fig. 4).
In this manner, if the paths pij,1 and pij,2 in Fig. 4 are the
shortest path between vi and vj and the edges are not shared, then
the vertices vi and vj are bounded by two paths pij,1 and pij,2, which
form an even-membered ring.
兩pij,1兩 ⫽ 兩pij,2兩, pij,1 艚 pij,2 ⫽ 0/
then p ij,1 and p 1j,2 form an even-membered ring [1]
where 兩pij,1兩 and 兩pij,2兩 are the lengths of pij,1 and pij,2, respectively.
If pik is the shortest path (dik) between vi and vk in the Pe matrix
and the dij ⫹ 1 path p⬘ik in the P⬘e matrix exists with edges not
shared by the paths pik and p⬘ik, then the vertices vi and vk are
bounded by the paths pik and p⬘ik to form an odd-membered ring.
兩p⬘ik兩 ⫽ 兩pik兩 ⫹ 1, pik 艚 p⬘ik ⫽ 0/
then p ik and p⬘ik form an odd-membered ring [2]
Finding the SSSR. Because a set of all possible rings in a graph {C}
can be described by two PID matrices Pe and P⬘e, then the next
step was to select SSSR members {CSSSR} within {C}. The XOR
operation (20) was introduced to select the SSSR from {C}.
Once a ring is characterized by the PID matrices, the ring is
compared with previously identified rings in {CSSSR} by XOR.
If a newly identified ring is not identical to any members of
{CSSSR} or does not contain any members in {CSSSR}, it becomes
a new member of {CSSSR}.
Because large-membered rings may contain smaller rings and
are not members of {CSSSR}, ring identification starts from the
smallest ring (e.g., a three-membered ring) and repeated with
increasing numbers of ring members until the total number of
SSSRs reaches the theoretical number of smallest rings, nSSSR
(nullity, cyclomatic number), as defined by the Euler rule (9).
nSSSR ⫽ m ⫺ n ⫹ 1 [3]
With Horton’s methods, ring size is unknown until all paths are
fully identified. In contrast, RP-Path recognize the ring size and
paths immediately. With this information, RP-Path can start
with the smallest rings to identify the SSSR. RP-Path consider
Lee et al.
 Fig. 3. The PID matrices for the graphs in Fig. 1.

fewer candidate rings than Horton’s methods. A detailed com-
parison of computing time for each stage in Horton’s method
and RP-Path is summarized in Table 3.
Results
The robustness of RP-Path in finding the SSSR was compared
with some widely used SSSR finding methods in chemical
information, namely the Figueras (21) and Welch (5) methods,
which are implemented in the chemistry development kit (CDK)
(22) and PreADMET (BMDRC), respectively.
A set of graphs tested by Berger et al. was used to test the
robustness of RP-Path in finding SSSR (10). Fig. 5A has a unique
minimum cycle basis consisting entirely of 36 triangles. Our
RP-Path identified all three-membered rings correctly, whereas
the Figueras and Welch methods failed to uncover all of
them(Table 4). Moreover, these methods did not produce the
correct outcome even for simpler test graphs that were analo-
gous to the molecular graph, whereas the RP-Path correct
identified the SSSR of all graphs (B, C, and D in Table 4).
Computing performance described by the worst case perfor-
mance of RP-Path was compared with Horton’s method (Table
3). RP-Path calculates the PID(Pe and P⬘e) and the distance
matrices, whereas Horton method calculates only the distance
matrix, Thus, RP-Path has a slightly longer computing time
during stage 1. However, the whole procedure for ring percep-
tion became much simpler and faster once PID was introduced.
In stage 2, because Horton’s method considers three paths using
the SDM, all rings could be identified by considering all possible
combinations of the three points. In contrast, RP-Path identifies
the rings and their size easily with little computation. Because
RP-Path discovers rings using a simple algorithm and considers
fewer candidates in finding the SSSR, The computing speed of
the stages 3 and 4 are much faster than that of Horton’s method.
The variations of Horton’s methods have tried to focus on
increasing the speed of this calculation. However, due to limi-
tations inherent in using an SDM, Horton’s method and its
variations cannot be improved much more.
For the case of a graph with a single cycle, m is equal to n and
the performance of RP-path algorithm is comparable with the
De Pina, Berger, and Kavitha algorithms. For the case of a
complete graph, every pair of distinct vertices are connected by
edges, m is n(n ⫺ 1)/2 and then m is proportional to n2. In
complete graph, RP-Path is faster than the other methods in
Table 1. General cases are between the two extreme cases.
Conclusion
We present a robust and computationally fast method for ring
perception and SSSR identification from complex graphs. In-
stead of using an SDM, RP-Path uses a PID matrix that contains
information on the paths and size of the rings. With this
information, we developed a robust ring perception method with
dramatically reduced computing time. This method may have
considerable influence on various fields of science and engi-
neering, including electrical circuit testing (23, 24), periodic
timetable planning (25), dealing with rigidity of framework
structure (26), chemical ring perception (9), and in network
analysis of complicated biological pathways with thousands of
nodes.
Methods
A ring perception method is presented here followed by the SSSR identifica-
tion method that incorporates all of the features described by the RP-Path
method.
Table 3. Comparison of worst case performance for each stage
Horton RP-Path (this work)

Stage Method BigOh Method BigOh

1 Distance Matrix O(n3) Distance matrix, O(n3)* COMPUTATIONAL BIOLOGY

Calculation PID matrices(P,

BIOPHYSICS AND

P⬘) calculation

2 Ring Search O(mn2)† Ring candidate O(n2)

search
3 Sort({C}) O(a log a)‡ Sort (Cset) O(a⬘ log a⬘)§
4 Finding O(m3n) Finding SSSR O(a⬘k)
MCB(SSSR)

*n is the number of vertices.

†m is the number of edges.
‡a is the total number of circle({C}).
§a⬘ is the total number of ring candidate({C }).
set
Fig. 4. A path diagram between vertices. ¶k is the number of the minimum path between i and j.

Lee et al. PNAS 兩 October 13, 2009 兩 vol. 106 兩 no. 41 兩 17357
 Table 4. Comparison of ring perception results for the graphs
in Fig. 5
Number of n-membered ring
n-membered
Graph ring/Nurity Figureas (21) Welch (5) This work

3*/36 25† 32 36
4/0 8 1 0
A 5/0 1 1 0
7/0 2 1 0
8/0 0 1 0
3/0 0 0 0
B 4/6 5 6 6
5/2 1 2 2
6/0 2 0 0
3/12 10 12 12
C 4/0 1 0 0
5/2 2 1 2
6/0 1 1 0
3/5 5 5 5
D 4/1 1 1 1
6/1 1 0 1
7/0 0 1 0

Fig. 5. Graphs introduced by Berger et al. for testing the robustness of the
SSSR finding algorithm. *The number of x-membered rings.
†25 means 25 of 3-membered rings.

Y Step 1. Take information from a graph with M vertices and N edges.

Y Step 7. Construct ring using the PID matrix from the smallest-membered
Y Step 2. Remove all open acyclic nodes with one edge(connectivity equal to
rings.
1, corresponding to terminal nodes) and repeat the procedure, stoping at
Y Step 8. Use the XOR operation to find the SSSR from this ring.
nodes with a connectivity larger than 1. Now, M and N become m and n,
Y Step 9. If a ring is a new member of the SSSR, then save it.
respectively.
Y Step 10. Repeat steps 7 to 9, until nringidx reaches nSSSR, where nringidx is the
Y Step 3. Calculate the theoretical number of SSSR : nSSSR ⫽ m ⫺ n ⫹ 1, If nSSSR ⫽
number of founded SSSR.
0, stop process.
Y Step 4. Calculate the PID matrices Pe and P⬘e.
ACKNOWLEDGMENTS. This work was partly supported by the IT R&D program
Y Step 5. Create the cycle set([Cnum, Pe[i,j], P⬘e[i,j]]) using the PID matrices. Cases
of MKE/IITA, which is funded by MKE/IITA Grant 2008-F-029-01, Development
in which the shortest path number equals zero, or [兩Pe[i,j]兩 ⫽ 1 and 兩P⬘e[i,j] ⫽ of e-Organ system based on Cyber Computing; and the 21st Century Frontier
0] can be omitted. R&D Program Grant CBM31-B2000-01-00-00 of the Center for Biological Mod-
Y Step 6. Order the cycle set by Cnum number. ulators funded by the Ministry of Education, Science and Technology, Korea.

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17358 兩 www.pnas.org兾cgi兾doi兾10.1073兾pnas.0813040106 Lee et al.